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Christopher Bang Newgard

W. David and Sarah W. Stedman Distinguished Professor of Nutrition in the School of Medicine
Pharmacology & Cancer Biology
Duke Box 104775, Durham, NC 27710
300 North Duke Street, Durham, NC 27701

Selected Publications


Metabolite signature of diabetes remission in individuals with obesity undergoing weight loss interventions.

Journal Article Obesity (Silver Spring) · February 2024 OBJECTIVE: This observational study investigated metabolomic changes in individuals with type 2 diabetes (T2D) after weight loss. We hypothesized that metabolite changes associated with T2D-relevant phenotypes are signatures of improved health. METHODS: Fa ... Full text Link to item Cite

Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation.

Journal Article Cell Rep · June 27, 2023 Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that ID ... Full text Link to item Cite

KLF15 controls brown adipose tissue transcriptional flexibility and metabolism in response to various energetic demands.

Journal Article iScience · November 18, 2022 Brown adipose tissue (BAT) is a specialized metabolic organ responsible for non-shivering thermogenesis. Recently, its activity has been shown to be critical in systemic metabolic health through its utilization and consumption of macronutrients. In the fac ... Full text Link to item Cite

Maternal Exercise and Paternal Exercise Induce Distinct Metabolite Signatures in Offspring Tissues.

Journal Article Diabetes · October 1, 2022 That maternal and paternal exercise improve the metabolic health of adult offspring is well established. Tissue and serum metabolites play a fundamental role in the health of an organism, but how parental exercise affects offspring tissue and serum metabol ... Full text Link to item Cite

Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue.

Journal Article Mol Metab · October 2022 OBJECTIVES: Tirzepatide, a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to selective GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes (T2D). These results have fueled mechanistic studies ... Full text Link to item Cite

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice.

Journal Article J Biol Chem · October 2022 Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis ... Full text Link to item Cite

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF.

Journal Article Circulation · September 13, 2022 BACKGROUND: Sodium-glucose cotransporter-2 inhibitors are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), but underlying mechanisms of benefit are not well defined. We sought to investigate the relationships betw ... Full text Link to item Cite

Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity.

Journal Article JCI Insight · August 8, 2022 Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). Here, we aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-keto acids (BCKAs), and hepa ... Full text Link to item Cite

Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes.

Journal Article J Clin Endocrinol Metab · January 18, 2022 CONTEXT: Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating ... Full text Link to item Cite

Ildr1 gene deletion protects against diet-induced obesity and hyperglycemia.

Journal Article PLoS One · 2022 OBJECTIVE: Immunoglobulin-like Domain-Containing Receptor 1 (ILDR1) is expressed on nutrient sensing cholecystokinin-positive enteroendocrine cells of the gastrointestinal tract and it has the unique ability to induce fat-mediated CCK secretion. However, t ... Full text Link to item Cite

NADH inhibition of SIRT1 links energy state to transcription during time-restricted feeding.

Journal Article Nature metabolism · December 2021 In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+, a cosubstrate of the class III histone deacetylase sirtuin 1 (SIRT1) that associates with clock transcription factors. Although NAD Full text Cite

Maternal Metabolites Associated With Gestational Diabetes Mellitus and a Postpartum Disorder of Glucose Metabolism.

Journal Article J Clin Endocrinol Metab · October 21, 2021 CONTEXT: Gestational diabetes is associated with a long-term risk of developing a disorder of glucose metabolism. However, neither the metabolic changes characteristic of gestational diabetes in a large, multi-ancestry cohort nor the ability of metabolic c ... Full text Link to item Cite

Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.

Journal Article Molecular metabolism · October 2021 BackgroundA strong association of obesity and insulin resistance with increased circulating levels of branched-chain and aromatic amino acids and decreased glycine levels has been recognized in human subjects for decades.Scope of reviewMo ... Full text Cite

Circulating long chain acylcarnitines and outcomes in diabetic heart failure: an HF-ACTION clinical trial substudy.

Journal Article Cardiovasc Diabetol · August 3, 2021 BACKGROUND: Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown ... Full text Link to item Cite

BCAA Supplementation in Mice with Diet-induced Obesity Alters the Metabolome Without Impairing Glucose Homeostasis.

Journal Article Endocrinology · July 1, 2021 Circulating branched chain amino acid (BCAA) levels are elevated in obese humans and genetically obese rodents. However, the relationship of BCAAs to insulin resistance in diet-induced obese mice, a commonly used model to study glucose homeostasis, is stil ... Full text Link to item Cite

Gut microbiome contributions to altered metabolism in a pig model of undernutrition.

Journal Article Proceedings of the National Academy of Sciences of the United States of America · May 2021 The concept that gut microbiome-expressed functions regulate ponderal growth has important implications for infant and child health, as well as animal health. Using an intergenerational pig model of diet restriction (DR) that produces reduced weight gain, ... Full text Cite

Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion.

Journal Article Cell metabolism · April 2021 Metabolic fuels regulate insulin secretion by generating second messengers that drive insulin granule exocytosis, but the biochemical pathways involved are incompletely understood. Here we demonstrate that stimulation of rat insulinoma cells or primary rat ... Full text Cite

Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart.

Journal Article Nat Commun · March 15, 2021 Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-13C-labeled α-ketoisovalerate ([U-13C]KIV) in the heart is reaminati ... Full text Link to item Cite

The Pediatric Obesity Microbiome and Metabolism Study (POMMS): Methods, Baseline Data, and Early Insights.

Journal Article Obesity (Silver Spring) · March 2021 OBJECTIVE: The purpose of this study was to establish a biorepository of clinical, metabolomic, and microbiome samples from adolescents with obesity as they undergo lifestyle modification. METHODS: A total of 223 adolescents aged 10 to 18 years with BMI ≥9 ... Full text Open Access Link to item Cite

Metabolites and diabetes remission after weight loss.

Journal Article Nutr Diabetes · February 24, 2021 There is marked heterogeneity in the response to weight loss interventions with regards to weight loss amount and metabolic improvement. We sought to identify biomarkers predictive of type 2 diabetes remission and amount of weight loss in individuals with ... Full text Link to item Cite

Metabolite signature of diabetes remission in individuals with obesity undergoing weight loss interventions.

Journal Article Obesity (Silver Spring) · February 2024 OBJECTIVE: This observational study investigated metabolomic changes in individuals with type 2 diabetes (T2D) after weight loss. We hypothesized that metabolite changes associated with T2D-relevant phenotypes are signatures of improved health. METHODS: Fa ... Full text Link to item Cite

Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation.

Journal Article Cell Rep · June 27, 2023 Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that ID ... Full text Link to item Cite

KLF15 controls brown adipose tissue transcriptional flexibility and metabolism in response to various energetic demands.

Journal Article iScience · November 18, 2022 Brown adipose tissue (BAT) is a specialized metabolic organ responsible for non-shivering thermogenesis. Recently, its activity has been shown to be critical in systemic metabolic health through its utilization and consumption of macronutrients. In the fac ... Full text Link to item Cite

Maternal Exercise and Paternal Exercise Induce Distinct Metabolite Signatures in Offspring Tissues.

Journal Article Diabetes · October 1, 2022 That maternal and paternal exercise improve the metabolic health of adult offspring is well established. Tissue and serum metabolites play a fundamental role in the health of an organism, but how parental exercise affects offspring tissue and serum metabol ... Full text Link to item Cite

Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue.

Journal Article Mol Metab · October 2022 OBJECTIVES: Tirzepatide, a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to selective GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes (T2D). These results have fueled mechanistic studies ... Full text Link to item Cite

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice.

Journal Article J Biol Chem · October 2022 Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis ... Full text Link to item Cite

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF.

Journal Article Circulation · September 13, 2022 BACKGROUND: Sodium-glucose cotransporter-2 inhibitors are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), but underlying mechanisms of benefit are not well defined. We sought to investigate the relationships betw ... Full text Link to item Cite

Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity.

Journal Article JCI Insight · August 8, 2022 Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). Here, we aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-keto acids (BCKAs), and hepa ... Full text Link to item Cite

Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes.

Journal Article J Clin Endocrinol Metab · January 18, 2022 CONTEXT: Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating ... Full text Link to item Cite

Ildr1 gene deletion protects against diet-induced obesity and hyperglycemia.

Journal Article PLoS One · 2022 OBJECTIVE: Immunoglobulin-like Domain-Containing Receptor 1 (ILDR1) is expressed on nutrient sensing cholecystokinin-positive enteroendocrine cells of the gastrointestinal tract and it has the unique ability to induce fat-mediated CCK secretion. However, t ... Full text Link to item Cite

NADH inhibition of SIRT1 links energy state to transcription during time-restricted feeding.

Journal Article Nature metabolism · December 2021 In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+, a cosubstrate of the class III histone deacetylase sirtuin 1 (SIRT1) that associates with clock transcription factors. Although NAD Full text Cite

Maternal Metabolites Associated With Gestational Diabetes Mellitus and a Postpartum Disorder of Glucose Metabolism.

Journal Article J Clin Endocrinol Metab · October 21, 2021 CONTEXT: Gestational diabetes is associated with a long-term risk of developing a disorder of glucose metabolism. However, neither the metabolic changes characteristic of gestational diabetes in a large, multi-ancestry cohort nor the ability of metabolic c ... Full text Link to item Cite

Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.

Journal Article Molecular metabolism · October 2021 BackgroundA strong association of obesity and insulin resistance with increased circulating levels of branched-chain and aromatic amino acids and decreased glycine levels has been recognized in human subjects for decades.Scope of reviewMo ... Full text Cite

Circulating long chain acylcarnitines and outcomes in diabetic heart failure: an HF-ACTION clinical trial substudy.

Journal Article Cardiovasc Diabetol · August 3, 2021 BACKGROUND: Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown ... Full text Link to item Cite

BCAA Supplementation in Mice with Diet-induced Obesity Alters the Metabolome Without Impairing Glucose Homeostasis.

Journal Article Endocrinology · July 1, 2021 Circulating branched chain amino acid (BCAA) levels are elevated in obese humans and genetically obese rodents. However, the relationship of BCAAs to insulin resistance in diet-induced obese mice, a commonly used model to study glucose homeostasis, is stil ... Full text Link to item Cite

Gut microbiome contributions to altered metabolism in a pig model of undernutrition.

Journal Article Proceedings of the National Academy of Sciences of the United States of America · May 2021 The concept that gut microbiome-expressed functions regulate ponderal growth has important implications for infant and child health, as well as animal health. Using an intergenerational pig model of diet restriction (DR) that produces reduced weight gain, ... Full text Cite

Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion.

Journal Article Cell metabolism · April 2021 Metabolic fuels regulate insulin secretion by generating second messengers that drive insulin granule exocytosis, but the biochemical pathways involved are incompletely understood. Here we demonstrate that stimulation of rat insulinoma cells or primary rat ... Full text Cite

Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart.

Journal Article Nat Commun · March 15, 2021 Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-13C-labeled α-ketoisovalerate ([U-13C]KIV) in the heart is reaminati ... Full text Link to item Cite

The Pediatric Obesity Microbiome and Metabolism Study (POMMS): Methods, Baseline Data, and Early Insights.

Journal Article Obesity (Silver Spring) · March 2021 OBJECTIVE: The purpose of this study was to establish a biorepository of clinical, metabolomic, and microbiome samples from adolescents with obesity as they undergo lifestyle modification. METHODS: A total of 223 adolescents aged 10 to 18 years with BMI ≥9 ... Full text Open Access Link to item Cite

Metabolites and diabetes remission after weight loss.

Journal Article Nutr Diabetes · February 24, 2021 There is marked heterogeneity in the response to weight loss interventions with regards to weight loss amount and metabolic improvement. We sought to identify biomarkers predictive of type 2 diabetes remission and amount of weight loss in individuals with ... Full text Link to item Cite

Efficacy of metformin and fermentable fiber combination therapy in adolescents with severe obesity and insulin resistance: study protocol for a double-blind randomized controlled trial.

Journal Article Trials · February 17, 2021 BACKGROUND: Accumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Pre-clinical animal ... Full text Link to item Cite

Muscle Krüppel-like factor 15 regulates lipid flux and systemic metabolic homeostasis.

Journal Article J Clin Invest · February 15, 2021 Skeletal muscle is a major determinant of systemic metabolic homeostasis that plays a critical role in glucose metabolism and insulin sensitivity. By contrast, despite being a major user of fatty acids, and evidence that muscular disorders can lead to abno ... Full text Link to item Cite

Mechanisms controlling pancreatic islet cell function in insulin secretion.

Journal Article Nat Rev Mol Cell Biol · February 2021 Metabolic homeostasis in mammals is tightly regulated by the complementary actions of insulin and glucagon. The secretion of these hormones from pancreatic β-cells and α-cells, respectively, is controlled by metabolic, endocrine, and paracrine regulatory m ... Full text Link to item Cite

Metabolomic profiling identifies complex lipid species and amino acid analogues associated with response to weight loss interventions.

Journal Article PLoS One · 2021 Obesity is an epidemic internationally. While weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic biomarkers that are associated with ... Full text Link to item Cite

A tribute to Roger H. Unger (1924-2020).

Journal Article J Clin Invest · December 1, 2020 Full text Link to item Cite

Muscle-Liver Trafficking of BCAA-Derived Nitrogen Underlies Obesity-Related Glycine Depletion.

Journal Article Cell Rep · November 10, 2020 Glycine levels are inversely associated with branched-chain amino acids (BCAAs) and cardiometabolic disease phenotypes, but biochemical mechanisms that explain these relationships remain uncharted. Metabolites and genes related to BCAA metabolism and nitro ... Full text Link to item Cite

β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice.

Journal Article Am J Physiol Endocrinol Metab · October 1, 2020 Sirtuins are a family of proteins that regulate biological processes such as cellular stress and aging by removing posttranslational modifications (PTMs). We recently identified several novel PTMs that can be removed by sirtuin 4 (SIRT4), which is found in ... Full text Link to item Cite

Metabolomic and genetic associations with insulin resistance in pregnancy.

Journal Article Diabetologia · September 2020 AIMS/HYPOTHESIS: Our study aimed to integrate maternal metabolic and genetic data related to insulin sensitivity during pregnancy to provide novel insights into mechanisms underlying pregnancy-induced insulin resistance. METHODS: Fasting and 1 h serum samp ... Full text Link to item Cite

Dietary branched-chain amino acid restriction alters fuel selection and reduces triglyceride stores in hearts of Zucker fatty rats.

Journal Article Am J Physiol Endocrinol Metab · February 1, 2020 Elevations in circulating levels of branched-chain amino acids (BCAAs) are associated with a variety of cardiometabolic diseases and conditions. Restriction of dietary BCAAs in rodent models of obesity lowers circulating BCAA levels and improves whole-anim ... Full text Link to item Cite

Identification of a small molecule that stimulates human β-cell proliferation and insulin secretion, and protects against cytotoxic stress in rat insulinoma cells.

Journal Article PLoS One · 2020 A key event in the development of both major forms of diabetes is the loss of functional pancreatic islet β-cell mass. Strategies aimed at enhancing β-cell regeneration have long been pursued, but methods for reliably inducing human β-cell proliferation wi ... Full text Link to item Cite

Cord Blood Metabolomics: Association With Newborn Anthropometrics and C-Peptide Across Ancestries.

Journal Article J Clin Endocrinol Metab · October 1, 2019 CONTEXT: Newborn adiposity is associated with childhood obesity. Cord blood metabolomics is one approach that can be used to understand early-life contributors to adiposity and insulin resistance. OBJECTIVE: To determine the association of cord blood metab ... Full text Link to item Cite

Dietary Sugars Alter Hepatic Fatty Acid Oxidation via Transcriptional and Post-translational Modifications of Mitochondrial Proteins.

Journal Article Cell Metab · October 1, 2019 Dietary sugars, fructose and glucose, promote hepatic de novo lipogenesis and modify the effects of a high-fat diet (HFD) on the development of insulin resistance. Here, we show that fructose and glucose supplementation of an HFD exert divergent effects on ... Full text Link to item Cite

Near-roadway air pollution exposure and altered fatty acid oxidation among adolescents and young adults - The interplay with obesity.

Journal Article Environ Int · September 2019 BACKGROUND: Air pollution exposure has been shown to increase the risk of obesity and metabolic dysfunction in animal models and human studies. However, the metabolic pathways altered by air pollution exposure are unclear, especially in adolescents and you ... Full text Link to item Cite

Effects of microbiota-directed foods in gnotobiotic animals and undernourished children.

Journal Article Science · July 12, 2019 To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Ba ... Full text Link to item Cite

Disrupted Maturation of the Microbiota and Metabolome among Extremely Preterm Infants with Postnatal Growth Failure.

Journal Article Sci Rep · June 3, 2019 Growth failure during infancy is a major global problem that has adverse effects on long-term health and neurodevelopment. Preterm infants are disproportionately affected by growth failure and its effects. Herein we found that extremely preterm infants wit ... Full text Link to item Cite

Regulation of UCP1 and Mitochondrial Metabolism in Brown Adipose Tissue by Reversible Succinylation.

Journal Article Mol Cell · May 16, 2019 Brown adipose tissue (BAT) is rich in mitochondria and plays important roles in energy expenditure, thermogenesis, and glucose homeostasis. We find that levels of mitochondrial protein succinylation and malonylation are high in BAT and subject to physiolog ... Full text Link to item Cite

Peripheral blood metabolite profiles associated with new onset atrial fibrillation.

Journal Article Am Heart J · May 2019 BACKGROUND: Peripheral blood metabolite profiles have yielded mechanistic insights into various cardiovascular disease states. We hypothesized that peripheral blood metabolite profiles would be associated with new onset atrial fibrillation (AF). METHODS AN ... Full text Link to item Cite

Maternal metabolites during pregnancy are associated with newborn outcomes and hyperinsulinaemia across ancestries.

Journal Article Diabetologia · March 2019 AIMS/HYPOTHESIS: We aimed to determine the association of maternal metabolites with newborn adiposity and hyperinsulinaemia in a multi-ethnic cohort of mother-newborn dyads. METHODS: Targeted and non-targeted metabolomics assays were performed on fasting a ... Full text Link to item Cite

Respiratory Capacity and Reserve Predict Cell Sensitivity to Mitochondria Inhibitors: Mechanism-Based Markers to Identify Metformin-Responsive Cancers.

Journal Article Mol Cancer Ther · March 2019 Metformin has been extensively studied for its impact on cancer cell metabolism and anticancer potential. Despite evidence of significant reduction in cancer occurrence in diabetic patients taking metformin, phase II cancer trials of the agent have been di ... Full text Link to item Cite

Creation of versatile cloning platforms for transgene expression and dCas9-based epigenome editing.

Journal Article Nucleic Acids Res · February 28, 2019 Genetic manipulation via transgene overexpression, RNAi, or Cas9-based methods is central to biomedical research. Unfortunately, use of these tools is often limited by vector options. We have created a modular platform (pMVP) that allows a gene of interest ... Full text Link to item Cite

Branched-chain amino acids in disease.

Journal Article Science · February 8, 2019 Full text Link to item Cite

Improving human β-cell maturation in vitro.

Journal Article Nat Cell Biol · February 2019 Full text Link to item Cite

Type-2-Diabetes Alters CSF but Not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys.

Journal Article Front Neurosci · 2019 Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer's disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the major ... Full text Link to item Cite

Adverse Effects of Fenofibrate in Mice Deficient in the Protein Quality Control Regulator, CHIP.

Journal Article J Cardiovasc Dev Dis · August 15, 2018 We previously reported how the loss of CHIP expression (Carboxyl terminus of Hsc70-Interacting Protein) during pressure overload resulted in robust cardiac dysfunction, which was accompanied by a failure to maintain ATP levels in the face of increased ener ... Full text Link to item Cite

Improvement in insulin resistance after gastric bypass surgery is correlated with a decline in plasma 2-hydroxybutyric acid.

Journal Article Surg Obes Relat Dis · August 2018 BACKGROUND: Gastric bypass surgery for weight reduction often corrects dysglycemia in diabetic patients, but a full understanding of the underlying biochemical pathways continues to be investigated. OBJECTIVES: To explore the effects of weight loss by surg ... Full text Link to item Cite

Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or β Cell Metabolism in the Absence of Overnutrition.

Journal Article Cell Rep · July 3, 2018 SIRT3 is a nicotinamide adenine dinucleotide (NAD+)-dependent mitochondrial protein deacetylase purported to influence metabolism through post-translational modification of metabolic enzymes. Fuel-stimulated insulin secretion, which involves mitochondrial ... Full text Link to item Cite

Dietary Patterns among Asian Indians Living in the United States Have Distinct Metabolomic Profiles That Are Associated with Cardiometabolic Risk.

Journal Article J Nutr · July 1, 2018 BACKGROUND: Recent studies, primarily in non-Hispanic whites, suggest that dietary patterns have distinct metabolomic signatures that may influence disease risk. However, evidence in South Asians, a group with unique dietary patterns and a high prevalence ... Full text Open Access Link to item Cite

The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase.

Journal Article Cell Metab · June 5, 2018 Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that r ... Full text Link to item Cite

Cardiovascular Metabolomics.

Journal Article Circ Res · April 27, 2018 Disturbances in cardiac metabolism underlie most cardiovascular diseases. Metabolomics, one of the newer omics technologies, has emerged as a powerful tool for defining changes in both global and cardiac-specific metabolism that occur across a spectrum of ... Full text Link to item Cite

Effect of Progressive Weight Loss on Lactate Metabolism: A Randomized Controlled Trial.

Journal Article Obesity (Silver Spring) · April 2018 OBJECTIVE: Lactate is an intermediate of glucose metabolism that has been implicated in the pathogenesis of insulin resistance. This study evaluated the relationship between glucose kinetics and plasma lactate concentration ([LAC]) before and after manipul ... Full text Link to item Cite

Physiological mechanisms of sustained fumagillin-induced weight loss.

Journal Article JCI Insight · March 8, 2018 Current obesity interventions suffer from lack of durable effects and undesirable complications. Fumagillin, an inhibitor of methionine aminopeptidase-2, causes weight loss by reducing food intake, but with effects on weight that are superior to pair-feedi ... Full text Link to item Cite

Kruppel-like factor 15 is required for the cardiac adaptive response to fasting.

Journal Article PLoS One · 2018 Cardiac metabolism is highly adaptive in response to changes in substrate availability, as occur during fasting. This metabolic flexibility is essential to the maintenance of contractile function and is under the control of a group of select transcriptiona ... Full text Link to item Cite

Temporal dynamics of liver mitochondrial protein acetylation and succinylation and metabolites due to high fat diet and/or excess glucose or fructose.

Journal Article PLoS One · 2018 Dietary macronutrient composition alters metabolism through several mechanisms, including post-translational modification (PTM) of proteins. To connect diet and molecular changes, here we performed short- and long-term feeding of mice with standard chow di ... Full text Link to item Cite

Metabolomic signatures and metabolic complications in childhood obesity

Chapter · January 1, 2018 Type 2 diabetes is caused by complex interactions between genetic and environmental factors. Comprehensive metabolite profiling or "metabolomics" defines the chemical phenotype of biological systems and explores their integrated responses to genetic variat ... Full text Cite

Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis.

Journal Article Br J Pharmacol · December 2017 BACKGROUND AND PURPOSE: The human kinome consists of roughly 500 kinases, including 150 that have been proposed as therapeutic targets. Protein kinases regulate an array of signalling pathways that control metabolism, cell cycle progression, cell death, di ... Full text Link to item Cite

Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.

Journal Article The Journal of clinical investigation · November 2017 Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with ... Full text Cite

Perinatal western-type diet and associated gestational weight gain alter postpartum maternal mood.

Journal Article Brain Behav · October 2017 INTRODUCTION: The role of perinatal diet in postpartum maternal mood disorders, including depression and anxiety, remains unclear. We investigated whether perinatal consumption of a Western-type diet (high in fat and branched-chain amino acids [BCAA]) and ... Full text Link to item Cite

The Prohormone VGF Regulates β Cell Function via Insulin Secretory Granule Biogenesis.

Journal Article Cell Rep · September 5, 2017 The prohormone VGF is expressed in neuroendocrine and endocrine tissues and regulates nutrient and energy status both centrally and peripherally. We and others have shown that VGF-derived peptides have direct action on the islet β cell as secretagogues and ... Full text Link to item Cite

Metabolomics applied to islet nutrient sensing mechanisms.

Journal Article Diabetes Obes Metab · September 2017 After multiple decades of investigation, the precise mechanisms involved in fuel-stimulated insulin secretion are still being revealed. One avenue for gaining deeper knowledge is to apply emergent tools of "metabolomics," involving mass spectrometry and nu ... Full text Link to item Cite

Recommendations for Improving Identification and Quantification in Non-Targeted, GC-MS-Based Metabolomic Profiling of Human Plasma.

Journal Article Metabolites · August 25, 2017 The field of metabolomics as applied to human disease and health is rapidly expanding. In recent efforts of metabolomics research, greater emphasis has been placed on quality control and method validation. In this study, we report an experience with qualit ... Full text Link to item Cite

Sildenafil Treatment in Heart Failure With Preserved Ejection Fraction: Targeted Metabolomic Profiling in the RELAX Trial.

Journal Article JAMA cardiology · August 2017 ImportancePhosphodiesterase-5 inhibition with sildenafil compared with a placebo had no effect on the exercise capacity or clinical status of patients with heart failure with preserved ejection fraction (HFpEF) in the PhosphodiesteRasE-5 Inhibitio ... Full text Cite

Non-Targeted Metabolomics Analysis of Golden Retriever Muscular Dystrophy-Affected Muscles Reveals Alterations in Arginine and Proline Metabolism, and Elevations in Glutamic and Oleic Acid In Vivo.

Journal Article Metabolites · July 29, 2017 BACKGROUND: Like Duchenne muscular dystrophy (DMD), the Golden Retriever Muscular Dystrophy (GRMD) dog model of DMD is characterized by muscle necrosis, progressive paralysis, and pseudohypertrophy in specific skeletal muscles. This severe GRMD phenotype i ... Full text Link to item Cite

Kv2.1 Clustering Contributes to Insulin Exocytosis and Rescues Human β-Cell Dysfunction.

Journal Article Diabetes · July 2017 Insulin exocytosis is regulated by ion channels that control excitability and Ca2+ influx. Channels also play an increasingly appreciated role in microdomain structure. In this study, we examine the mechanism by which the voltage-dependent K+ (Kv) channel ... Full text Link to item Cite

Targeted Metabolomics Demonstrates Distinct and Overlapping Maternal Metabolites Associated With BMI, Glucose, and Insulin Sensitivity During Pregnancy Across Four Ancestry Groups.

Journal Article Diabetes Care · July 2017 OBJECTIVE: We used targeted metabolomics in pregnant mothers to compare maternal metabolite associations with maternal BMI, glycemia, and insulin sensitivity. RESEARCH DESIGN AND METHODS: Targeted metabolomic assays of clinical metabolites, amino acids, an ... Full text Link to item Cite

Maternal BMI and Glycemia Impact the Fetal Metabolome.

Journal Article Diabetes Care · July 2017 OBJECTIVE: We used targeted metabolomics to determine associations of maternal BMI and glucose levels with cord blood metabolites and associations of cord blood metabolites with newborn birth weight and adiposity in mother-offspring dyads. RESEARCH DESIGN ... Full text Link to item Cite

Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation.

Journal Article Cell Metab · June 6, 2017 Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to α cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for α cell p ... Full text Link to item Cite

Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model.

Journal Article Prostate · April 2017 BACKGROUND: Epidemiologic data suggest cholesterol-lowering drugs may prevent the progression of prostate cancer, but not the incidence of the disease. However, the association of combination therapy in cholesterol reduction on prostate or any cancer is un ... Full text Link to item Cite

Associations of maternal BMI and insulin resistance with the maternal metabolome and newborn outcomes.

Journal Article Diabetologia · March 2017 AIMS/HYPOTHESIS: Maternal obesity increases the risk for large-for-gestational-age birth and excess newborn adiposity, which are associated with adverse long-term metabolic outcomes in offspring, probably due to effects mediated through the intrauterine en ... Full text Link to item Cite

Plasma acylcarnitines are associated with pulmonary hypertension.

Journal Article Pulm Circ · March 2017 Quantifying metabolic derangements in pulmonary hypertension (PH) by plasma metabolomics could identify biomarkers useful for diagnosis and treatment. The objective of this paper is to test the hypotheses that circulating metabolites are differentially exp ... Full text Link to item Cite

Mixture model normalization for non-targeted gas chromatography/mass spectrometry metabolomics data.

Journal Article BMC Bioinformatics · February 2, 2017 BACKGROUND: Metabolomics offers a unique integrative perspective for health research, reflecting genetic and environmental contributions to disease-related phenotypes. Identifying robust associations in population-based or large-scale clinical studies dema ... Full text Link to item Cite

Prior Dietary Practices and Connections to a Human Gut Microbial Metacommunity Alter Responses to Diet Interventions.

Journal Article Cell Host Microbe · January 11, 2017 Ensuring that gut microbiota respond consistently to prescribed dietary interventions, irrespective of prior dietary practices (DPs), is critical for effective nutritional therapy. To address this, we identified DP-associated gut bacterial taxa in individu ... Full text Link to item Cite

Metabolomics and Metabolic Diseases: Where Do We Stand?

Journal Article Cell Metab · January 10, 2017 Metabolomics, or the comprehensive profiling of small molecule metabolites in cells, tissues, or whole organisms, has undergone a rapid technological evolution in the past two decades. These advances have led to the application of metabolomics to defining ... Full text Link to item Cite

Delayed apoptosis allows islet β-cells to implement an autophagic mechanism to promote cell survival.

Journal Article PLoS One · 2017 Increased β-cell death coupled with the inability to replicate existing β-cells drives the decline in β-cell mass observed in the progression of both major forms of diabetes. Understanding endogenous mechanisms of islet cell survival could have considerabl ... Full text Link to item Cite

HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism.

Journal Article J Immunol · December 15, 2016 The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cro ... Full text Link to item Cite

A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation.

Journal Article Mol Cell Biol · December 1, 2016 The homeodomain transcription factor Pdx-1 has important roles in pancreas and islet development as well as in β-cell function and survival. We previously reported that Pdx-1 overexpression stimulates islet cell proliferation, but the mechanism remains unc ... Full text Link to item Cite

Enhanced GLUT4-Dependent Glucose Transport Relieves Nutrient Stress in Obese Mice Through Changes in Lipid and Amino Acid Metabolism.

Journal Article Diabetes · December 2016 Impaired GLUT4-dependent glucose uptake is a contributing factor in the development of whole-body insulin resistance in obese patients and obese animal models. Previously, we demonstrated that transgenic mice engineered to express the human GLUT4 gene unde ... Full text Link to item Cite

Plasma amino acid levels are elevated in young, healthy low birth weight men exposed to short-term high-fat overfeeding.

Journal Article Physiol Rep · December 2016 Low birth weight (LBW) individuals exhibit a disproportionately increased, incomplete fatty acid oxidation and a decreased glucose oxidation, compared with normal birth weight (NBW) individuals, and furthermore have an increased risk of developing insulin ... Full text Link to item Cite

Effects of a gut pathobiont in a gnotobiotic mouse model of childhood undernutrition.

Journal Article Sci Transl Med · November 23, 2016 To model how interactions among enteropathogens and gut microbial community members contribute to undernutrition, we colonized gnotobiotic mice fed representative Bangladeshi diets with sequenced bacterial strains cultured from the fecal microbiota of two ... Full text Link to item Cite

Association of Plasma Small-Molecule Intermediate Metabolites With Age and Body Mass Index Across Six Diverse Study Populations.

Journal Article J Gerontol A Biol Sci Med Sci · November 2016 BACKGROUND: Older age and obesity are associated with metabolic dysregulation; the mechanism by which these factors impact metabolism across the lifespan is important, but relatively unknown. We evaluated a panel of amino acids (AAs) and acylcarnitines (AC ... Full text Link to item Cite

Plasma acylcarnitine profiling indicates increased fatty acid oxidation relative to tricarboxylic acid cycle capacity in young, healthy low birth weight men.

Journal Article Physiol Rep · October 2016 We hypothesized that an increased, incomplete fatty acid beta-oxidation in mitochondria could be part of the metabolic events leading to insulin resistance and thereby an increased type 2 diabetes risk in low birth weight (LBW) compared with normal birth w ... Full text Link to item Cite

Multi-omic profiles of hepatic metabolism in TPN-fed preterm pigs administered new generation lipid emulsions.

Journal Article J Lipid Res · September 2016 We aimed to characterize the lipidomic, metabolomic, and transcriptomic profiles in preterm piglets administered enteral (ENT) formula or three parenteral lipid emulsions [parenteral nutrition (PN)], Intralipid (IL), Omegaven (OV), or SMOFlipid (SL), for 1 ... Full text Link to item Cite

Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling.

Journal Article Am J Pathol · August 2016 The Bcl2-associated anthanogene (BAG) 3 protein is a member of the BAG family of cochaperones, which supports multiple critical cellular processes, including critical structural roles supporting desmin and interactions with heat shock proteins and ubiquiti ... Full text Link to item Cite

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.

Journal Article J Am Heart Assoc · July 29, 2016 BACKGROUND: Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine ... Full text Open Access Link to item Cite

Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity.

Journal Article Cell Rep · July 12, 2016 Dysregulated mitochondrial metabolism during hepatic insulin resistance may contribute to pathophysiologies ranging from elevated glucose production to hepatocellular oxidative stress and inflammation. Given that obesity impairs insulin action but paradoxi ... Full text Link to item Cite

Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export.

Journal Article Mol Metab · July 2016 OBJECTIVE: A branched-chain amino acid (BCAA)-related metabolic signature is strongly associated with insulin resistance and predictive of incident diabetes and intervention outcomes. To better understand the role that this metabolite cluster plays in obes ... Full text Link to item Cite

Metabolic Networks and Metabolites Underlie Associations Between Maternal Glucose During Pregnancy and Newborn Size at Birth.

Journal Article Diabetes · July 2016 Maternal metabolites and metabolic networks underlying associations between maternal glucose during pregnancy and newborn birth weight and adiposity demand fuller characterization. We performed targeted and nontargeted gas chromatography/mass spectrometry ... Full text Link to item Cite

Proteomic Profiling Reveals Adaptive Responses to Surgical Myocardial Ischemia-Reperfusion in Hibernating Arctic Ground Squirrels Compared to Rats.

Journal Article Anesthesiology · June 2016 BACKGROUND: Hibernation is an adaptation to extreme environments known to provide organ protection against ischemia-reperfusion (I/R) injury. An unbiased systems approach was utilized to investigate hibernation-induced changes that are characteristic of th ... Full text Link to item Cite

Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.

Journal Article Circulation · May 24, 2016 BACKGROUND: Although metabolic reprogramming is critical in the pathogenesis of heart failure, studies to date have focused principally on fatty acid and glucose metabolism. Contribution of amino acid metabolic regulation in the disease remains understudie ... Full text Link to item Cite

Research Resource: Roles for Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) in Systems Metabolism.

Journal Article Mol Endocrinol · May 2016 A number of epidemiological studies have implicated calcium (Ca(2+)) signaling as a major factor in obesity that contributes to aberrant systems metabolism. Somewhat paradoxically, obesity correlates with decreased circulating Ca(2+) levels, leading to inc ... Full text Link to item Cite

Human amylin proteotoxicity impairs protein biosynthesis, and alters major cellular signaling pathways in the heart, brain and liver of humanized diabetic rat model in vivo.

Journal Article Metabolomics · May 2016 INTRODUCTION: Chronic hypersecretion of the 37 amino acid amylin is common in type 2 diabetics (T2D). Recent studies implicate human amylin aggregates cause proteotoxicity (cell death induced by misfolded proteins) in both the brain and the heart. OBJECTIV ... Full text Link to item Cite

Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins.

Journal Article Cell Rep · April 12, 2016 Metabolism is a highly integrated process that is coordinately regulated between tissues and within individual cells. FoxO proteins are major targets of insulin action and contribute to the regulation of gluconeogenesis, glycolysis, and lipogenesis in the ... Full text Link to item Cite

Sialylated Milk Oligosaccharides Promote Microbiota-Dependent Growth in Models of Infant Undernutrition.

Journal Article Cell · February 25, 2016 Identifying interventions that more effectively promote healthy growth of children with undernutrition is a pressing global health goal. Analysis of human milk oligosaccharides (HMOs) from 6-month-postpartum mothers in two Malawian birth cohorts revealed t ... Full text Link to item Cite

The Gut Microbiota Modulates Energy Metabolism in the Hibernating Brown Bear Ursus arctos.

Journal Article Cell Rep · February 23, 2016 Hibernation is an adaptation that helps many animals to conserve energy during food shortage in winter. Brown bears double their fat depots during summer and use these stored lipids during hibernation. Although bears seasonally become obese, they remain me ... Full text Link to item Cite

Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children.

Journal Article Science · February 19, 2016 Undernourished children exhibit impaired development of their gut microbiota. Transplanting microbiota from 6- and 18-month-old healthy or undernourished Malawian donors into young germ-free mice that were fed a Malawian diet revealed that immature microbi ... Full text Link to item Cite

Metabolomics applied to the pancreatic islet.

Journal Article Arch Biochem Biophys · January 1, 2016 Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of metabolites simultaneously provides a broad perspective on metabolic changes as the is ... Full text Link to item Cite

Liver receptor homolog-1 is a critical determinant of methyl-pool metabolism.

Journal Article Hepatology · January 2016 UNLABELLED: Balance of labile methyl groups (choline, methionine, betaine, and folate) is important for normal liver function. Quantitatively, a significant use of labile methyl groups is in the production of phosphatidylcholines (PCs), which are ligands f ... Full text Link to item Cite

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

Journal Article PLoS Genet · November 2015 Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the bi ... Full text Open Access Link to item Cite

Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism.

Journal Article Cell Rep · October 6, 2015 Pancreatic islet failure, involving loss of glucose-stimulated insulin secretion (GSIS) from islet β cells, heralds the onset of type 2 diabetes (T2D). To search for mediators of GSIS, we performed metabolomics profiling of the insulinoma cell line 832/13 ... Full text Link to item Cite

Non-targeted metabolomics of Brg1/Brm double-mutant cardiomyocytes reveals a novel role for SWI/SNF complexes in metabolic homeostasis.

Journal Article Metabolomics · October 1, 2015 Mammalian SWI/SNF chromatin-remodeling complexes utilize either BRG1 or Brm as alternative catalytic subunits to alter the position of nucleosomes and regulate gene expression. Genetic studies have demonstrated that SWI/SNF complexes are required during ca ... Full text Link to item Cite

Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans.

Journal Article Diabetologia · October 2015 AIMS/HYPOTHESES: Obesity is associated with decreased insulin sensitivity (IS) and elevated plasma branched-chain amino acids (BCAAs). The purpose of this study was to investigate the relationship between BCAA metabolism and IS in overweight (OW) individua ... Full text Link to item Cite

Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells.

Journal Article J Clin Invest · October 1, 2015 Insulin secretion from β cells of the pancreatic islets of Langerhans controls metabolic homeostasis and is impaired in individuals with type 2 diabetes (T2D). Increases in blood glucose trigger insulin release by closing ATP-sensitive K+ channels, depolar ... Full text Link to item Cite

The ubiquitin ligase MuRF1 regulates PPARα activity in the heart by enhancing nuclear export via monoubiquitination.

Journal Article Mol Cell Endocrinol · September 15, 2015 The transcriptional regulation of peroxisome proliferator-activated receptor (PPAR) α by post-translational modification, such as ubiquitin, has not been described. We report here for the first time an ubiquitin ligase (muscle ring finger-1/MuRF1) that inh ... Full text Link to item Cite

Induction of miR-132 and miR-212 Expression by Glucagon-Like Peptide 1 (GLP-1) in Rodent and Human Pancreatic β-Cells.

Journal Article Mol Endocrinol · September 2015 Better understanding how glucagon-like peptide 1 (GLP-1) promotes pancreatic β-cell function and/or mass may uncover new treatment for type 2 diabetes. In this study, we investigated the potential involvement of microRNAs (miRNAs) in the effect of GLP-1 on ... Full text Link to item Cite

Left-Biased Spermatogenic Failure in 129/SvJ Dnd1Ter/+ Mice Correlates with Differences in Vascular Architecture, Oxygen Availability, and Metabolites.

Journal Article Biol Reprod · September 2015 Homozygosity for the Ter mutation in the RNA-binding protein Dead end 1 (Dnd1(Ter/Ter)) sensitizes germ cells to degeneration in all mouse strains. In 129/SvJ mice, approximately 10% of Dnd1(Ter/+) heterozygotes develop spermatogenic failure, and 95% of un ... Full text Link to item Cite

MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet.

Journal Article Cardiovasc Diabetol · August 5, 2015 BACKGROUND: In diabetes mellitus the morbidity and mortality of cardiovascular disease is increased and represents an important independent mechanism by which heart disease is exacerbated. The pathogenesis of diabetic cardiomyopathy involves the enhanced a ... Full text Link to item Cite

Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet.

Journal Article BMC Endocr Disord · July 28, 2015 BACKGROUND: The pathogenesis of diabetic cardiomyopathy (DCM) involves the enhanced activation of peroxisome proliferator activating receptor (PPAR) transcription factors, including the most prominent isoform in the heart, PPARα. In cancer cells and adipoc ... Full text Link to item Cite

Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism.

Journal Article Oncogene · June 2015 Isoprenylcysteine carboxylmethyltransferase (Icmt) catalyzes the last of the three-step posttranslational protein prenylation process for the so-called CaaX proteins, which includes many signaling proteins, such as most small GTPases. Despite extensive stu ... Full text Link to item Cite

HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism.

Journal Article Radiat Res · June 2015 Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy. While hypoxia increases tumor cell survival after radiation exposure because there is less oxygen to oxidize damaged DNA, it remains unclear ... Full text Link to item Cite

CAPER is vital for energy and redox homeostasis by integrating glucose-induced mitochondrial functions via ERR-α-Gabpa and stress-induced adaptive responses via NF-κB-cMYC.

Journal Article PLoS Genet · April 2015 Ever since we developed mitochondria to generate ATP, eukaryotes required intimate mito-nuclear communication. In addition, since reactive oxygen species are a cost of mitochondrial oxidative phosphorylation, this demands safeguards as protection from thes ... Full text Link to item Cite

Non-targeted metabolomics analysis of cardiac Muscle Ring Finger-1 (MuRF1), MuRF2, and MuRF3 in vivo reveals novel and redundant metabolic changes.

Journal Article Metabolomics · April 2015 The muscle-specific ubiquitin ligases MuRF1, MuRF2, MuRF3 have been reported to have overlapping substrate specificities, interacting with each other as well as proteins involved in metabolism and cardiac function. In the heart, all three MuRF family prote ... Full text Link to item Cite

Integrated metabolomics and genomics: systems approaches to biomarkers and mechanisms of cardiovascular disease.

Journal Article Circ Cardiovasc Genet · April 2015 The genetic architecture underlying the heritability of cardiovascular disease is incompletely understood. Metabolomics is an emerging technology platform that has shown early success in identifying biomarkers and mechanisms of common chronic diseases. Int ... Full text Link to item Cite

Metabolomics in the developmental origins of obesity and its cardiometabolic consequences.

Journal Article J Dev Orig Health Dis · April 2015 In this review, we discuss the potential role of metabolomics to enhance understanding of obesity-related developmental origins of health and disease (DOHaD). We first provide an overview of common techniques and analytical approaches to help interested in ... Full text Link to item Cite

Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study.

Journal Article J Clin Endocrinol Metab · March 2015 CONTEXT: Metabolomic profiling of amino acids and acylcarnitines has revealed consistent patterns associated with metabolic disease. OBJECTIVE: This study used metabolomic profiling to identify analytes associated with insulin sensitivity (SI) and conversi ... Full text Link to item Cite

Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1.

Journal Article Nat Commun · February 4, 2015 Maternal glucose levels during pregnancy impact the developing fetus, affecting metabolic health both early and later on in life. Both genetic and environmental factors influence maternal metabolism, but little is known about the genetic mechanisms that al ... Full text Link to item Cite

Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction.

Journal Article Mol Metab · February 2015 OBJECTIVE: Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of glucagon receptor (Gcgr) signaling are being explored for the treatment of diabetes or obe ... Full text Link to item Cite

Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction

Journal Article Molecular Metabolism · February 1, 2015 Objective: Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of glucagon receptor (Gcgr) signaling are being explored for the treatment of diabetes or obe ... Full text Cite

Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.

Journal Article Diabetes · January 2015 The impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle-sp ... Full text Link to item Cite

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.

Journal Article J Clin Invest · January 2015 Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T ... Full text Open Access Link to item Cite

Comparison of proteomic and metabolomic profiles of mutants of the mitochondrial respiratory chain in Caenorhabditis elegans.

Journal Article Mitochondrion · January 2015 Single-gene mutations that disrupt mitochondrial respiratory chain function in Caenorhabditis elegans change patterns of protein expression and metabolites. Our goal was to develop useful molecular fingerprints employing adaptable techniques to recognize m ... Full text Link to item Cite

Diabetes: The good in fat.

Journal Article Nature · December 4, 2014 A new class of fatty acid — found in food and synthesized by mammalian tissues — enhances glucose uptake from the blood and reduces inflammation, suggesting that these fats might be used to treat diabetes. ... Full text Link to item Cite

MED13-dependent signaling from the heart confers leanness by enhancing metabolism in adipose tissue and liver.

Journal Article EMBO Mol Med · December 2014 The heart requires a continuous supply of energy but has little capacity for energy storage and thus relies on exogenous metabolic sources. We previously showed that cardiac MED13 modulates systemic energy homeostasis in mice. Here, we sought to define the ... Full text Link to item Cite

Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

Journal Article Cell Metab · November 4, 2014 Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expres ... Full text Link to item Cite

Hepatic SRC-1 activity orchestrates transcriptional circuitries of amino acid pathways with potential relevance for human metabolic pathogenesis.

Journal Article Mol Endocrinol · October 2014 Disturbances in amino acid metabolism are increasingly recognized as being associated with, and serving as prognostic markers for chronic human diseases, such as cancer or type 2 diabetes. In the current study, a quantitative metabolomics profiling strateg ... Full text Link to item Cite

Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice.

Journal Article J Lipid Res · July 2014 Nonalcoholic fatty liver disease is a major public health concern in the obese and type 2 diabetic populations. The high-fat lard diet induces obesity and fatty liver in C57BL/6J mice and suppresses expression of the PPAR-target gene, FA elongase 5 (Elovl5 ... Full text Link to item Cite

Severe acute malnutrition in childhood: hormonal and metabolic status at presentation, response to treatment, and predictors of mortality.

Journal Article J Clin Endocrinol Metab · June 2014 OBJECTIVE: Malnutrition is a major cause of childhood morbidity and mortality. To identify and target those at highest risk, there is a critical need to characterize biomarkers that predict complications prior to and during treatment. METHODS: We used targ ... Full text Link to item Cite

Recent progress in metabolic signaling pathways regulating aging and life span.

Journal Article J Gerontol A Biol Sci Med Sci · June 2014 The NIH Summit, Advances in Geroscience: Impact on Health Span and Chronic Disease, discusses several aspects of cellular degeneration that underlie susceptibility to chronic aging-associated diseases, morbidity, and mortality. In particular, the session o ... Full text Link to item Cite

Mechanical unloading promotes myocardial energy recovery in human heart failure.

Journal Article Circ Cardiovasc Genet · June 2014 BACKGROUND: Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. METHODS AND RESULTS: We compared metabolomic, gene transcript, and protein data from 6 paired samples of faili ... Full text Link to item Cite

Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors.

Journal Article Proc Natl Acad Sci U S A · April 8, 2014 Loss of functional β-cell mass is a hallmark of type 1 and type 2 diabetes, and methods for restoring these cells are needed. We have previously reported that overexpression of the homeodomain transcription factor NK6 homeobox 1 (Nkx6.1) in rat pancreatic ... Full text Link to item Cite

Obesity and lipid stress inhibit carnitine acetyltransferase activity.

Journal Article J Lipid Res · April 2014 Carnitine acetyltransferase (CrAT) is a mitochondrial matrix enzyme that catalyzes the interconversion of acetyl-CoA and acetylcarnitine. Emerging evidence suggests that this enzyme functions as a positive regulator of total body glucose tolerance and musc ... Full text Link to item Cite

Postprandial metabolite profiles reveal differential nutrient handling after bariatric surgery compared with matched caloric restriction.

Journal Article Ann Surg · April 2014 BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery results in exaggerated postprandial insulin and incretin responses and increased susceptibility to hypoglycemia. OBJECTIVE: We examined whether these features are due to caloric restriction (CR) or altere ... Full text Link to item Cite

Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice.

Journal Article Hepatology · April 2014 UNLABELLED: Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for nonalcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the majo ... Full text Link to item Cite

BMI, RQ, diabetes, and sex affect the relationships between amino acids and clamp measures of insulin action in humans.

Journal Article Diabetes · February 2014 Previous studies have used indirect measures of insulin sensitivity to link circulating amino acids with insulin resistance and identify potential biomarkers of diabetes risk. Using direct measures (i.e., hyperinsulinemic-euglycemic clamps), we examined th ... Full text Link to item Cite

Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization.

Journal Article Atherosclerosis · January 2014 OBJECTIVE: To validate independent associations between branched-chain amino acids (BCAA) and other metabolites with coronary artery disease (CAD). METHODS: We conducted mass-spectrometry-based profiling of 63 metabolites in fasting plasma from 1983 sequen ... Full text Link to item Cite

Effects of HIV infection on the metabolic and hormonal status of children with severe acute malnutrition.

Journal Article PLoS One · 2014 BACKGROUND: HIV infection occurs in 30% of children with severe acute malnutrition in sub-Saharan Africa. Effects of HIV on the pathophysiology and recovery from malnutrition are poorly understood. METHODS: We conducted a prospective cohort study of 75 sev ... Full text Link to item Cite

Metabolomics reveals broad-scale metabolic perturbations in hyperglycemic mothers during pregnancy.

Journal Article Diabetes Care · 2014 OBJECTIVE To characterize metabolites across the range of maternal glucose by comparing metabolomic profiles of mothers with high and low fasting plasma glucose (FPG). RESEARCH DESIGN AND METHODS We compared fasting serum from an oral glucose tolerance tes ... Full text Link to item Cite

SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks.

Journal Article Cell Metab · December 3, 2013 Reversible posttranslational modifications are emerging as critical regulators of mitochondrial proteins and metabolism. Here, we use a label-free quantitative proteomic approach to characterize the lysine succinylome in liver mitochondria and its regulati ... Full text Link to item Cite

Race and sex differences in small-molecule metabolites and metabolic hormones in overweight and obese adults.

Journal Article OMICS · December 2013 In overweight/obese individuals, cardiometabolic risk factors differ by race and sex categories. Small-molecule metabolites and metabolic hormone levels might also differ across these categories and contribute to risk factor heterogeneity. To explore this ... Full text Link to item Cite

Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice.

Journal Article Science · November 1, 2013 Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop produces cycles of nicotinamide adenine dinucleotide (NAD(+)) b ... Full text Link to item Cite

Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation.

Journal Article Diabetes · October 2013 Sirt3 is an NAD(+)-dependent deacetylase that regulates mitochondrial function by targeting metabolic enzymes and proteins. In fasting mice, Sirt3 expression is decreased in skeletal muscle resulting in increased mitochondrial protein acetylation. Deletion ... Full text Link to item Cite

Pdx-1 activates islet α- and β-cell proliferation via a mechanism regulated by transient receptor potential cation channels 3 and 6 and extracellular signal-regulated kinases 1 and 2.

Journal Article Mol Cell Biol · October 2013 The homeodomain transcription factor Pdx-1 has important roles in pancreatic development and β-cell function and survival. In the present study, we demonstrate that adenovirus-mediated overexpression of Pdx-1 in rat or human islets also stimulates cell rep ... Full text Link to item Cite

Gut microbiota from twins discordant for obesity modulate metabolism in mice.

Journal Article Science · September 6, 2013 The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels o ... Full text Link to item Cite

Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion.

Journal Article J Biol Chem · August 9, 2013 Recent studies have shown that the pyruvate-isocitrate cycling pathway, involving the mitochondrial citrate/isocitrate carrier and the cytosolic NADP-dependent isocitrate dehydrogenase (ICDc), is involved in control of glucose-stimulated insulin secretion ... Full text Link to item Cite

Effect of Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding on branched-chain amino acid metabolism.

Journal Article Diabetes · August 2013 It has been hypothesized that a greater decline in circulating branched-chain amino acids (BCAAs) after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery than after calorie restriction alone has independent effects on glucose homeostasis, poss ... Full text Link to item Cite

Diminished acyl-CoA synthetase isoform 4 activity in INS 832/13 cells reduces cellular epoxyeicosatrienoic acid levels and results in impaired glucose-stimulated insulin secretion.

Journal Article J Biol Chem · July 26, 2013 Glucose-stimulated insulin secretion (GSIS) in pancreatic beta-cells is potentiated by fatty acids (FA). The initial step in the metabolism of intracellular FA is the conversion to acyl-CoA by long chain acyl-CoA synthetases (Acsls). Because the predominan ... Full text Link to item Cite

Branched chain amino acids are novel biomarkers for discrimination of metabolic wellness.

Journal Article Metabolism · July 2013 OBJECTIVE: To identify novel biomarkers through metabolomic profiles that distinguish metabolically well (MW) from metabolically unwell (MUW) individuals, independent of body mass index (BMI). MATERIALS/METHODS: This study was conducted as part of the Meas ... Full text Link to item Cite

Metabolomic profiling reveals a role for caspase-2 in lipoapoptosis.

Journal Article J Biol Chem · May 17, 2013 The accumulation of long-chain fatty acids (LCFAs) in non-adipose tissues results in lipid-induced cytotoxicity (or lipoapoptosis). Lipoapoptosis has been proposed to play an important role in the pathogenesis of several metabolic diseases, including non-a ... Full text Link to item Cite

Application of combined omics platforms to accelerate biomedical discovery in diabesity.

Journal Article Ann N Y Acad Sci · May 2013 Diabesity has become a popular term to describe the specific form of diabetes that develops late in life and is associated with obesity. While there is a correlation between diabetes and obesity, the association is not universally predictive. Defining the ... Full text Link to item Cite

Pathogenesis of A⁻β⁺ ketosis-prone diabetes.

Journal Article Diabetes · March 2013 A⁻β⁺ ketosis-prone diabetes (KPD) is an emerging syndrome of obesity, unprovoked ketoacidosis, reversible β-cell dysfunction, and near-normoglycemic remission. We combined metabolomics with targeted kinetic measurements to investigate its pathophysiology. ... Full text Link to item Cite

Coming of age: molecular drivers of aging and therapeutic opportunities.

Journal Article J Clin Invest · March 2013 Aging is like the weather: everyone talks about it, but no one seems to do anything about it. We believe this may soon change, as an improved understanding of the molecular and genetic pathways underlying aging suggests it is possible to therapeutically ta ... Full text Link to item Cite

Branched-chain amino acids alter neurobehavioral function in rats.

Journal Article Am J Physiol Endocrinol Metab · February 15, 2013 Recently, we have described a strong association of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) with obesity and insulin resistance. In the current study, we have investigated the potential impact of BCAA on behavioral functions. We de ... Full text Link to item Cite

Research resource: tissue- and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family.

Journal Article Mol Endocrinol · February 2013 The rapidly growing family of transcriptional coregulators includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have emerged as important regulators of metabolic homeostasis, inc ... Full text Link to item Cite

The role of voltage-gated potassium channels Kv2.1 and Kv2.2 in the regulation of insulin and somatostatin release from pancreatic islets.

Journal Article J Pharmacol Exp Ther · February 2013 The voltage-gated potassium channels Kv2.1 and Kv2.2 are highly expressed in pancreatic islets, yet their contribution to islet hormone secretion is not fully understood. Here we investigate the role of Kv2 channels in pancreatic islets using a combination ... Full text Link to item Cite

Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.

Journal Article Science · January 11, 2013 Concentrations of acetyl-coenzyme A and nicotinamide adenine dinucleotide (NAD(+)) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body d-β-hydroxybutyrate (βOHB) is an endog ... Full text Link to item Cite

Effect of Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding on branched-chain amino acid metabolism

Journal Article Diabetes · 2013 It has been hypothesized that a greater decline in circulating branched-chain amino acids (BCAAs) after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery than after calorie restriction alone has independent effects on glucose homeostasis, poss ... Full text Cite

Metabolomic analysis reveals extended metabolic consequences of marginal vitamin B-6 deficiency in healthy human subjects.

Journal Article PLoS One · 2013 Marginal deficiency of vitamin B-6 is common among segments of the population worldwide. Because pyridoxal 5'-phosphate (PLP) serves as a coenzyme in the metabolism of amino acids, carbohydrates, organic acids, and neurotransmitters, as well as in aspects ... Full text Link to item Cite

Application of combined omics platforms to accelerate biomedical discovery in diabesity

Journal Article Annals of the New York Academy of Sciences · 2013 Diabesity has become a popular term to describe the specific form of diabetes that develops late in life and is associated with obesity. While there is a correlation between diabetes and obesity, the association is not universally predictive. Defining the ... Full text Cite

Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance.

Journal Article Cell Metab · December 5, 2012 Obesity and type 2 diabetes are associated with mitochondrial dysfunction in adipose tissue, but the role for adipose tissue mitochondria in the development of these disorders is currently unknown. To understand the impact of adipose tissue mitochondria on ... Full text Link to item Cite

Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization.

Journal Article J Lipid Res · December 2012 Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. Identifying novel regulators of mitochondrial bioenergetics will broaden our understanding of regulatory checkpoints that coordinate complex metabolic pathways. We previo ... Full text Link to item Cite

Marginal vitamin B-6 deficiency decreases plasma (n-3) and (n-6) PUFA concentrations in healthy men and women.

Journal Article J Nutr · October 2012 Previous animal studies showed that severe vitamin B-6 deficiency altered fatty acid profiles of tissue lipids, often with an increase of linoleic acid and a decrease of arachidonic acid. However, little is known about the extent to which vitamin B-6 defic ... Full text Link to item Cite

Analysis of serum metabolic profiles in women with endometrial cancer and controls in a population-based case-control study.

Journal Article J Clin Endocrinol Metab · September 2012 CONTEXT: Endometrial cancer is associated with metabolic disturbances related to its underlying risk factors, including obesity and diabetes. Identifying metabolite biomarkers associated with endometrial cancer may have value for early detection, risk asse ... Full text Link to item Cite

Rapid and weight-independent improvement of glucose tolerance induced by a peptide designed to elicit apoptosis in adipose tissue endothelium.

Journal Article Diabetes · September 2012 A peptide designed to induce apoptosis of endothelium in white adipose tissue (WAT) decreases adiposity. The goal of this work is to determine whether targeting of WAT endothelium results in impaired glucose regulation as a result of impaired WAT function. ... Full text Link to item Cite

Daily Variation of Serum Acylcarnitines and Amino Acids.

Journal Article Metabolomics · August 2012 To characterize daily variation of amino acids (AAs) and acylcarnitines (ACs) in response to feeding and activity, we measured serum metabolites at various times and after various activities during the day. Subjects were admitted overnight for serial serum ... Full text Link to item Cite

A VGF-derived peptide attenuates development of type 2 diabetes via enhancement of islet β-cell survival and function.

Journal Article Cell Metab · July 3, 2012 Deterioration of functional islet β-cell mass is the final step in progression to Type 2 diabetes. We previously reported that overexpression of Nkx6.1 in rat islets has the dual effects of enhancing glucose-stimulated insulin secretion (GSIS) and increasi ... Full text Link to item Cite

Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy.

Journal Article J Clin Invest · July 2012 For more than a century, thyroid hormones (THs) have been known to exert powerful catabolic effects, leading to weight loss. Although much has been learned about the molecular mechanisms used by TH receptors (TRs) to regulate gene expression, little is kno ... Full text Link to item Cite

Deletion of GαZ protein protects against diet-induced glucose intolerance via expansion of β-cell mass.

Journal Article J Biol Chem · June 8, 2012 Insufficient plasma insulin levels caused by deficits in both pancreatic β-cell function and mass contribute to the pathogenesis of type 2 diabetes. This loss of insulin-producing capacity is termed β-cell decompensation. Our work is focused on defining th ... Full text Link to item Cite

The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance.

Journal Article Cell Metab · May 2, 2012 Excessive deposition of fat in the liver (hepatic steatosis) is frequently accompanied by hepatic insulin resistance. Whether this correlation is due to a causal relationship between the conditions has been the subject of considerable debate, and the liter ... Full text Link to item Cite

Ablation of steroid receptor coactivator-3 resembles the human CACT metabolic myopathy.

Journal Article Cell Metab · May 2, 2012 Oxidation of lipid substrates is essential for survival in fasting and other catabolic conditions, sparing glucose for the brain and other glucose-dependent tissues. Here we show Steroid Receptor Coactivator-3 (SRC-3) plays a central role in long chain fat ... Full text Link to item Cite

Interplay between lipids and branched-chain amino acids in development of insulin resistance.

Journal Article Cell Metab · May 2, 2012 Fatty acids (FA) and FA-derived metabolites have long been implicated in the development of insulin resistance and type 2 diabetes. Surprisingly, application of metabolomics technologies has revealed that branched-chain amino acids (BCAA) and related metab ... Full text Link to item Cite

Baseline metabolomic profiles predict cardiovascular events in patients at risk for coronary artery disease.

Journal Article Am Heart J · May 2012 BACKGROUND: Cardiovascular risk models remain incomplete. Small-molecule metabolites may reflect underlying disease and, as such, serve as novel biomarkers of cardiovascular risk. METHODS: We studied 2,023 consecutive patients undergoing cardiac catheteriz ... Full text Link to item Cite

Metabolic profiles predict adverse events after coronary artery bypass grafting.

Journal Article J Thorac Cardiovasc Surg · April 2012 OBJECTIVE: Clinical models incompletely predict the outcomes after coronary artery bypass grafting. Novel molecular technologies can identify biomarkers to improve risk stratification. We examined whether metabolic profiles can predict adverse events in pa ... Full text Link to item Cite

Deletion of CaMKK2 from the liver lowers blood glucose and improves whole-body glucose tolerance in the mouse.

Journal Article Mol Endocrinol · February 2012 Ca(2+)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a member of the Ca(2+)/CaM-dependent protein kinase family that is expressed abundantly in brain. Previous work has revealed that CaMKK2 knockout (CaMKK2 KO) mice eat less due to a central ner ... Full text Link to item Cite

Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss.

Journal Article Diabetologia · February 2012 AIMS/HYPOTHESIS: Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR with weight loss. METHODS: Targeted mass spectrometry-base ... Full text Link to item Cite

Caloric restriction alters the metabolic response to a mixed-meal: results from a randomized, controlled trial.

Journal Article PLoS One · 2012 OBJECTIVES: To determine if caloric restriction (CR) would cause changes in plasma metabolic intermediates in response to a mixed meal, suggestive of changes in the capacity to adapt fuel oxidation to fuel availability or metabolic flexibility, and to dete ... Full text Open Access Link to item Cite

Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis.

Journal Article PLoS One · 2012 The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, s ... Full text Link to item Cite

Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation.

Journal Article PLoS One · 2012 Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to "Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previou ... Full text Link to item Cite

SRC-2 coactivator deficiency decreases functional reserve in response to pressure overload of mouse heart.

Journal Article PLoS One · 2012 A major component of the cardiac stress response is the simultaneous activation of several gene regulatory networks. Interestingly, the transcriptional regulator steroid receptor coactivator-2, SRC-2 is often decreased during cardiac failure in humans. We ... Full text Link to item Cite

Effect of heparin administration on metabolomic profiles in samples obtained during cardiac catheterization.

Journal Article Circ Cardiovasc Genet · December 2011 BACKGROUND: Metabolic profiling holds promise for early detection of coronary artery disease and assessing risk for ischemic events. Heparin is frequently administered (1) to treat acute coronary syndromes; and (2) during routine cardiac catheterization pr ... Full text Link to item Cite

The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins.

Journal Article Sci Transl Med · October 26, 2011 Understanding how the human gut microbiota and host are affected by probiotic bacterial strains requires carefully controlled studies in humans and in mouse models of the gut ecosystem where potentially confounding variables that are difficult to control i ... Full text Link to item Cite

SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome.

Journal Article Mol Cell · October 21, 2011 Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic ... Full text Link to item Cite

Cafeteria diet is a robust model of human metabolic syndrome with liver and adipose inflammation: comparison to high-fat diet.

Journal Article Obesity (Silver Spring) · June 2011 Obesity has reached epidemic proportions worldwide and reports estimate that American children consume up to 25% of calories from snacks. Several animal models of obesity exist, but studies are lacking that compare high-fat diets (HFD) traditionally used i ... Full text Link to item Cite

Branching out for detection of type 2 diabetes.

Journal Article Cell Metab · May 4, 2011 Type 2 diabetes is an epidemic disease worldwide, but it is difficult to predict its appearance in the general population. A recent study demonstrates that circulating concentrations of a small group of essential amino acids predict risk for diabetes, cont ... Full text Link to item Cite

Plasma acylcarnitines are associated with physical performance in elderly men.

Journal Article J Gerontol A Biol Sci Med Sci · May 2011 BACKGROUND: Metabolic profiling might provide insight into the biologic underpinnings of disability in older adults. METHODS: A targeted mass spectrometry-based platform was used to identify and quantify 45 plasma acylcarnitines in 77 older men with a mean ... Full text Link to item Cite

Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss.

Journal Article Sci Transl Med · April 27, 2011 Glycemic control is improved more after gastric bypass surgery (GBP) than after equivalent diet-induced weight loss in patients with morbid obesity and type 2 diabetes mellitus. We applied metabolomic profiling to understand the mechanisms of this better m ... Full text Link to item Cite

Regulation of mitochondrial morphology by APC/CCdh1-mediated control of Drp1 stability.

Journal Article Mol Biol Cell · April 15, 2011 Homeostatic maintenance of cellular mitochondria requires a dynamic balance between fission and fusion, and controlled changes in morphology are important for processes such as apoptosis and cellular division. Interphase mitochondria have been described as ... Full text Link to item Cite

Ubiquitin fold modifier 1 (UFM1) and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis.

Journal Article PLoS One · April 6, 2011 UFM1 is a member of the ubiquitin like protein family. While the enzymatic cascade of UFM1 conjugation has been elucidated in recent years, the biological function remains largely unknown. In this report we demonstrate that the recently identified C20orf11 ... Full text Link to item Cite

Effect of caloric restriction with and without exercise on metabolic intermediates in nonobese men and women.

Journal Article J Clin Endocrinol Metab · February 2011 OBJECTIVES: The objective of the study was to evaluate whether serum concentrations of metabolic intermediates are related to adiposity and insulin sensitivity (Si) in overweight healthy subjects and compare changes in metabolic intermediates with similar ... Full text Link to item Cite

The metabolic phenotype of Prader-Willi syndrome (PWS) in childhood: heightened insulin sensitivity relative to body mass index.

Journal Article J Clin Endocrinol Metab · January 2011 CONTEXT: Insulin sensitivity is higher in patients with Prader-Willi syndrome (PWS) than in body mass index-matched obese controls (OCs). Factors contributing to the heightened insulin sensitivity of PWS remain obscure. We compared the fasting levels of va ... Full text Link to item Cite

Exercise-induced changes in metabolic intermediates, hormones, and inflammatory markers associated with improvements in insulin sensitivity.

Journal Article Diabetes Care · January 2011 OBJECTIVE: To understand relationships between exercise training-mediated improvements in insulin sensitivity (S(I)) and changes in circulating concentrations of metabolic intermediates, hormones, and inflammatory mediators. RESEARCH DESIGN AND METHODS: Ta ... Full text Open Access Link to item Cite

The coactivator SRC-1 is an essential coordinator of hepatic glucose production.

Journal Article Cell Metab · December 1, 2010 Gluconeogenesis makes a major contribution to hepatic glucose production, a process critical for survival in mammals. In this study, we identify the p160 family member, SRC-1, as a key coordinator of the hepatic gluconeogenic program in vivo. SRC-1-null mi ... Full text Link to item Cite

Comprehensive Metabolic Analysis for Understanding of Disease

Journal Article · December 1, 2010 Comprehensive measurement of intermediary metabolites and changes in metabolic activity lead to the improved detection and understanding of diseases. Metabolomics is increasingly getting integrated with genomic and transcriptomic profiling methods. This ch ... Full text Cite

Dissecting the in vivo metabolic potential of two human gut acetogens.

Journal Article J Biol Chem · July 16, 2010 Fermenting microbial communities generate hydrogen; its removal through the production of acetate, methane, or hydrogen sulfide modulates the efficiency of energy extraction from available nutrients in many ecosystems. We noted that pathway components for ... Full text Link to item Cite

Lower brain-derived neurotrophic factor in patients with prader-willi syndrome compared to obese and lean control subjects.

Journal Article J Clin Endocrinol Metab · July 2010 CONTEXT: Brain-derived neurotrophic factor (BDNF) haploinsufficiency is associated with hyperphagia and obesity in both animals and humans. BDNF appears to function downstream of the leptin-melanocortin signaling pathway to control energy balance. The pote ... Full text Link to item Cite

Energetics and metabolism in the failing heart: important but poorly understood.

Journal Article Curr Opin Clin Nutr Metab Care · July 2010 PURPOSE OF REVIEW: Profound abnormalities in myocardial energy metabolism occur in heart failure and correlate with clinical symptoms and survival. Available comprehensive human metabolic data come from small studies, enrolling patients across heart failur ... Full text Link to item Cite

The mitochondrial 2-oxoglutarate carrier is part of a metabolic pathway that mediates glucose- and glutamine-stimulated insulin secretion.

Journal Article J Biol Chem · May 28, 2010 Glucose-stimulated insulin secretion from pancreatic islet beta-cells is dependent in part on pyruvate cycling through the pyruvate/isocitrate pathway, which generates cytosolic alpha-ketoglutarate, also known as 2-oxoglutarate (2OG). Here, we have investi ... Full text Link to item Cite

Rap1 promotes multiple pancreatic islet cell functions and signals through mammalian target of rapamycin complex 1 to enhance proliferation.

Journal Article J Biol Chem · May 21, 2010 Recent studies have implicated Epac2, a guanine-nucleotide exchange factor for the Rap subfamily of monomeric G proteins, as an important regulator of insulin secretion from pancreatic beta-cells. Although the Epac proteins were originally identified as cA ... Full text Link to item Cite

Regulation of skeletal muscle oxidative capacity and insulin signaling by the mitochondrial rhomboid protease PARL.

Journal Article Cell Metab · May 5, 2010 Type 2 diabetes mellitus (T2DM) and aging are characterized by insulin resistance and impaired mitochondrial energetics. In lower organisms, remodeling by the protease pcp1 (PARL ortholog) maintains the function and lifecycle of mitochondria. We examined w ... Full text Link to item Cite

Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events.

Journal Article Circ Cardiovasc Genet · April 2010 BACKGROUND: Molecular tools may provide insight into cardiovascular risk. We assessed whether metabolites discriminate coronary artery disease (CAD) and predict risk of cardiovascular events. METHODS AND RESULTS: We performed mass-spectrometry-based profil ... Full text Open Access Link to item Cite

Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men.

Journal Article Diabetologia · April 2010 AIMS/HYPOTHESIS: Insulin resistance (IR) is associated with obesity, but can also develop in individuals with normal body weight. We employed comprehensive profiling methods to identify metabolic events associated with IR, while controlling for obesity. ME ... Full text Link to item Cite

Getting biological about the genetics of diabetes.

Journal Article Nat Med · April 2010 New technology has provided methods for collecting large amounts of data reflecting gene expression, metabolite and protein abundance, and post-translational modification of proteins. Integration of these various data sets enable the genetic mapping of man ... Full text Link to item Cite

Leptin therapy in insulin-deficient type I diabetes.

Journal Article Proc Natl Acad Sci U S A · March 16, 2010 In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy a ... Full text Link to item Cite

Cholinergic augmentation of insulin release requires ankyrin-B.

Journal Article Sci Signal · March 16, 2010 Parasympathetic stimulation of pancreatic islets augments glucose-stimulated insulin secretion by inducing inositol trisphosphate receptor (IP(3)R)-mediated calcium ion (Ca2+) release. Ankyrin-B binds to the IP(3)R and is enriched in pancreatic beta cells. ... Full text Link to item Cite

Gp93, the Drosophila GRP94 ortholog, is required for gut epithelial homeostasis and nutrient assimilation-coupled growth control.

Journal Article Dev Biol · March 15, 2010 GRP94, the endoplasmic reticulum Hsp90, is a metazoan-restricted chaperone essential for early development in mammals, yet dispensable for mammalian cell viability. This dichotomy suggests that GRP94 is required for the functional expression of secretory a ... Full text Link to item Cite

SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.

Journal Article Nature · March 4, 2010 Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation ... Full text Link to item Cite

Adenovirus-mediated leptin expression normalises hypertension associated with diet-induced obesity.

Journal Article J Neuroendocrinol · March 2010 In our previous study, moderate increases in plasma leptin levels achieved via administration of recombinant adenovirus containing the rat leptin cDNA were shown to correct the abnormal metabolic profile in rats with diet-induced obesity, suggesting that t ... Full text Link to item Cite

Contamination with E1A-positive wild-type adenovirus accounts for species-specific stimulation of islet cell proliferation by CCK: a cautionary note.

Journal Article Mol Endocrinol · February 2010 We have previously reported that adenovirus-mediated expression of preprocholecystokin (CCK) stimulates human and mouse islet cell proliferation. In follow-up studies, we became concerned that the CCK adenovirus might have been contaminated with a wild-typ ... Full text Link to item Cite

Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77.

Journal Article Diabetes · December 2009 OBJECTIVE: Nur77 is an orphan nuclear receptor with pleotropic functions. Previous studies have identified Nur77 as a transcriptional regulator of glucose utilization genes in skeletal muscle and gluconeogenesis in liver. However, the net functional impact ... Full text Link to item Cite

Cooperative transcriptional regulation of the essential pancreatic islet gene NeuroD1 (beta2) by Nkx2.2 and neurogenin 3.

Journal Article J Biol Chem · November 6, 2009 Nkx2.2 and NeuroD1 are two critical regulators of pancreatic beta cell development. Nkx2.2 is a homeodomain transcription factor that is essential for islet cell type specification and mature beta cell function. NeuroD1 is a basic helix-loop-helix transcri ... Full text Link to item Cite

Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease.

Journal Article Proc Natl Acad Sci U S A · November 3, 2009 Constitutive androstane receptor CAR (NR1I3) has been identified as a central mediator of coordinate responses to xenobiotic and endobiotic stress. Here we use leptin-deficient mice (ob/ob) and ob/ob, CAR(-/-) double mutant mice to identify a metabolic rol ... Full text Link to item Cite

Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women.

Journal Article Diabetes Care · September 2009 OBJECTIVE: To determine whether circulating metabolic intermediates are related to insulin resistance and beta-cell dysfunction in individuals at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS: In 73 sedentary, overweight to obese, dyslipidemic indi ... Full text Link to item Cite

Fasting-induced hepatic production of DHEA is regulated by PGC-1alpha, ERRalpha, and HNF4alpha.

Journal Article Mol Endocrinol · August 2009 The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is involved in the coordinate induction of changes in gene expression in the liver that enable a homeostatic response to alterations in metabolic stat ... Full text Link to item Cite

Increased insulin sensitivity in mice lacking collectrin, a downstream target of HNF-1alpha.

Journal Article Mol Endocrinol · June 2009 Collectrin is a downstream target of the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha), which is mutated in maturity-onset diabetes of the young subtype 3 (MODY3). Evidence from transgenic mouse models with collectrin overexpression in ... Full text Link to item Cite

Biochemistry. A glucose-to-gene link.

Journal Article Science · May 22, 2009 Full text Link to item Cite

Metabolomic profiling reveals distinct patterns of myocardial substrate use in humans with coronary artery disease or left ventricular dysfunction during surgical ischemia/reperfusion.

Journal Article Circulation · April 2009 BACKGROUND: Human myocardial metabolism has been incompletely characterized in the setting of surgical cardioplegic arrest and ischemia/reperfusion. Furthermore, the effect of preexisting ventricular state on ischemia-induced metabolic derangements has not ... Cite

A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance.

Journal Article Cell Metab · April 2009 Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis ... Full text Link to item Cite

Glucose metabolism as a target of histone deacetylase inhibitors.

Journal Article Mol Endocrinol · March 2009 The therapeutic efficacy of histone deacetylase inhibitors (HDACI) is generally attributed to their ability to alter gene expression secondary to their effects on the acetylation status of transcription factors and histones. However, because HDACIs exhibit ... Full text Link to item Cite

Moderate dietary vitamin B-6 restriction raises plasma glycine and cystathionine concentrations while minimally affecting the rates of glycine turnover and glycine cleavage in healthy men and women.

Journal Article J Nutr · March 2009 Glycine is a precursor of purines, protein, glutathione, and 1-carbon units as 5,10-methylenetetrahydrofolate. Glycine decarboxylation through the glycine cleavage system (GCS) and glycine-serine transformation by serine hydroxymethyltransferase (SHMT) req ... Full text Link to item Cite

The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain.

Journal Article OMICS · February 2009 The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body com ... Full text Link to item Cite

The liver--a potential new player in islet regeneration?

Journal Article Cell Metab · January 7, 2009 Pancreatic islet beta cell mass expands in response to certain physiological conditions such as pregnancy and obesity, but the signaling pathways involved are not well understood. Possible insights come from a newly described regulatory circuit through whi ... Full text Link to item Cite

High heritability of metabolomic profiles in families burdened with premature cardiovascular disease.

Journal Article Mol Syst Biol · 2009 Integration of genetic and metabolic profiling holds promise for providing insight into human disease. Coronary artery disease (CAD) is strongly heritable, but the heritability of metabolomic profiles has not been evaluated in humans. We performed quantita ... Full text Link to item Cite

Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.

Journal Article PLoS Genet · January 2009 Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). We have previously identified genetic linkage to familial CAD in the genomic region of NPY. We performed follow-up genetic, biostatistical, and functional analysis of NPY in ... Full text Open Access Link to item Cite

Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalizes plasma glucose in zucker diabetic fatty rats.

Journal Article Diabetes · January 2009 OBJECTIVE: We examined in 20-week-old Zucker diabetic fatty (ZDF) rats whether restoration of hepatic glucokinase (GK) expression would alter hepatic glucose flux and improve hyperglycemia. RESEARCH DESIGN AND METHODS: ZDF rats were treated at various dose ... Full text Link to item Cite

Ghrelin concentrations in Prader-Willi syndrome (PWS) infants and children: changes during development.

Journal Article Clin Endocrinol (Oxf) · December 2008 BACKGROUND: Prader-Willi syndrome (PWS) is associated with failure to thrive in infancy and progressive hyperphagia and obesity in childhood. This progressive weight gain is associated with hyperghrelinaemia and increased insulin sensitivity. The role of g ... Full text Link to item Cite

Metabolic cycling in control of glucose-stimulated insulin secretion.

Journal Article Am J Physiol Endocrinol Metab · December 2008 Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of beta-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in beta- ... Full text Link to item Cite

Overexpression of pre-pro-cholecystokinin stimulates beta-cell proliferation in mouse and human islets with retention of islet function.

Journal Article Mol Endocrinol · December 2008 Type 1 and type 2 diabetes result from a deficit in insulin production and beta-cell mass. Methods to expand beta-cell mass are under intensive investigation for the treatment of type 1 and type 2 diabetes. We tested the hypothesis that cholecystokinin (CC ... Full text Link to item Cite

Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease.

Journal Article Science · November 28, 2008 Hepatic glucose production is critical for basal brain function and survival when dietary glucose is unavailable. Glucose-6-phosphatase (G6Pase) is an essential, rate-limiting enzyme that serves as a terminal gatekeeper for hepatic glucose release into the ... Full text Link to item Cite

Silencing of cytosolic or mitochondrial isoforms of malic enzyme has no effect on glucose-stimulated insulin secretion from rodent islets.

Journal Article J Biol Chem · October 24, 2008 We have previously demonstrated a role for pyruvate cycling in glucose-stimulated insulin secretion (GSIS). Some of the possible pyruvate cycling pathways are completed by conversion of malate to pyruvate by malic enzyme. Using INS-1-derived 832/13 cells, ... Full text Link to item Cite

Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism.

Journal Article J Biol Chem · May 23, 2008 Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) dup ... Full text Link to item Cite

Stimulation of human and rat islet beta-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1.

Journal Article Mol Cell Biol · May 2008 The homeodomain transcription factor Nkx6.1 plays an important role in pancreatic islet beta-cell development, but its effects on adult beta-cell function, survival, and proliferation are not well understood. In the present study, we demonstrated that trea ... Full text Link to item Cite

Trefoil factor 3 stimulates human and rodent pancreatic islet beta-cell replication with retention of function.

Journal Article Mol Endocrinol · May 2008 Both major forms of diabetes involve a decline in beta-cell mass, mediated by autoimmune destruction of insulin-producing cells in type 1 diabetes and by increased rates of apoptosis secondary to metabolic stress in type 2 diabetes. Methods for controlled ... Full text Link to item Cite

Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling.

Journal Article PLoS Genet · March 14, 2008 Although numerous quantitative trait loci (QTL) influencing disease-related phenotypes have been detected through gene mapping and positional cloning, identification of the individual gene(s) and molecular pathways leading to those phenotypes is often elus ... Full text Link to item Cite

Mechanisms of disease:Molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes.

Journal Article Nat Rev Mol Cell Biol · March 2008 Nearly unlimited supplies of energy-dense foods and technologies that encourage sedentary behaviour have introduced a new threat to the survival of our species: obesity and its co-morbidities. Foremost among the co-morbidities is type 2 diabetes, which is ... Full text Link to item Cite

Galphaz negatively regulates insulin secretion and glucose clearance.

Journal Article J Biol Chem · February 22, 2008 Relatively little is known about the in vivo functions of the alpha subunit of the heterotrimeric G protein Gz (Galphaz). Clues to one potential function recently emerged with the finding that activation of Galphaz inhibits glucose-stimulated insulin secre ... Full text Link to item Cite

Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance.

Journal Article Cell Metab · January 2008 Previous studies have suggested that insulin resistance develops secondary to diminished fat oxidation and resultant accumulation of cytosolic lipid molecules that impair insulin signaling. Contrary to this model, the present study used targeted metabolomi ... Full text Link to item Cite

Hepatic regulation of fuel metabolism

Journal Article · December 1, 2007 It has been recognized for more than a century that the liver plays an important role in maintaining metabolic fuel homeostasis. The purpose of this chapter is to summarize mechanisms by which circulating glucose and lipid concentrations are controlled by ... Full text Cite

Altered distribution of adiponectin isoforms in children with Prader-Willi syndrome (PWS): association with insulin sensitivity and circulating satiety peptide hormones.

Journal Article Clin Endocrinol (Oxf) · December 2007 OBJECTIVE: Prader-Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized that this increased insulin sensitivity is mediated by increased l ... Full text Link to item Cite

Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic (type II) muscle.

Journal Article Am J Physiol Endocrinol Metab · December 2007 Insulin resistance and type 2 diabetes are frequently accompanied by lipid accumulation in skeletal muscle. However, it is unknown whether primary lipid deposition in skeletal muscle is sufficient to cause insulin resistance or whether the type of muscle f ... Full text Link to item Cite

Normal flux through ATP-citrate lyase or fatty acid synthase is not required for glucose-stimulated insulin secretion.

Journal Article J Biol Chem · October 26, 2007 It has been proposed that de novo synthesis of long-chain acyl-CoA (LC-CoA) is a signal for glucose-stimulated insulin secretion (GSIS). Key enzymes involved in synthesis of fatty acids from glucose include ATP-citrate lyase (CL) and fatty acid synthase (F ... Full text Link to item Cite

Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver.

Journal Article Cell Metab · July 2007 Hepatic steatosis, the accumulation of lipids in the liver, is widely believed to result in insulin resistance. To test the causal relationship between hepatic steatosis and insulin resistance, we generated mice that overexpress acyl-CoA:diacylglycerol acy ... Full text Link to item Cite

Expression and glycogenic effect of glycogen-targeting protein phosphatase 1 regulatory subunit GL in cultured human muscle.

Journal Article Biochem J · July 1, 2007 Glycogen-targeting PP1 (protein phosphatase 1) subunit G(L) (coded for by the PPP1R3B gene) is expressed in human, but not rodent, skeletal muscle. Its effects on muscle glycogen metabolism are unknown. We show that G(L) mRNA levels in primary cultured hum ... Full text Link to item Cite

Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance.

Journal Article J Biol Chem · May 18, 2007 Fatty liver is commonly associated with insulin resistance and type 2 diabetes, but it is unclear whether triacylglycerol accumulation or an excess flux of lipid intermediates in the pathway of triacyglycerol synthesis are sufficient to cause insulin resis ... Full text Link to item Cite

The role of AMPK and mTOR in nutrient sensing in pancreatic beta-cells.

Journal Article J Biol Chem · April 6, 2007 The AMP-activated protein kinase (AMPK) is a central regulator of the energy status of the cell, based on its unique ability to respond directly to fluctuations in the ratio of AMP:ATP. Because glucose and amino acids stimulate insulin release from pancrea ... Full text Link to item Cite

Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis.

Journal Article Chem Biol · March 2007 Coenzyme A (CoA) is the major acyl group carrier in intermediary metabolism. Hopantenate (HoPan), a competitive inhibitor of the pantothenate kinases, was used to chemically antagonize CoA biosynthesis. HoPan dramatically reduced liver CoA and mice develop ... Full text Link to item Cite

Functional genomics of the beta-cell: short-chain 3-hydroxyacyl-coenzyme A dehydrogenase regulates insulin secretion independent of K+ currents.

Journal Article Mol Endocrinol · March 2007 Recent advances in functional genomics afford the opportunity to interrogate the expression profiles of thousands of genes simultaneously and examine the function of these genes in a high-throughput manner. In this study, we describe a rational and efficie ... Full text Link to item Cite

The promoter for the gene encoding the catalytic subunit of rat glucose-6-phosphatase contains two distinct glucose-responsive regions.

Journal Article Am J Physiol Endocrinol Metab · March 2007 Glucose homeostasis requires the proper expression and regulation of the catalytic subunit of glucose-6-phosphatase (G-6-Pase), which hydrolyzes glucose 6-phosphate to glucose in glucose-producing tissues. Glucose induces the expression of G-6-Pase at the ... Full text Link to item Cite

Overexpression of rat long chain acyl-coa synthetase 1 alters fatty acid metabolism in rat primary hepatocytes.

Journal Article J Biol Chem · December 1, 2006 Long chain acyl-CoA synthetases (ACSL) activate fatty acids (FA) and provide substrates for both anabolic and catabolic pathways. We have hypothesized that each of the five ACSL isoforms partitions FA toward specific downstream pathways. Acsl1 mRNA is incr ... Full text Link to item Cite

The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion.

Journal Article J Biol Chem · November 24, 2006 Glucose-stimulated insulin secretion (GSIS) is mediated in part by glucose metabolism-driven increases in ATP/ADP ratio, but by-products of mitochondrial glucose metabolism also play an important role. Here we investigate the role of the mitochondrial citr ... Full text Link to item Cite

A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion.

Journal Article J Biol Chem · October 13, 2006 Glucose-stimulated insulin secretion (GSIS) from pancreatic islet beta-cells is central to control of mammalian fuel homeostasis. Glucose metabolism mediates GSIS in part via ATP-regulated K+ (KATP) channels, but multiple lines of evidence suggest particip ... Full text Link to item Cite

Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion.

Journal Article J Biol Chem · August 4, 2006 We have previously reported that glucose-stimulated insulin secretion (GSIS) is tightly correlated with pyruvate carboxylase (PC)-catalyzed anaplerotic flux into the tricarboxylic acid cycle and stimulation of pyruvate cycling activity. To further evaluate ... Full text Link to item Cite

FoxA2, Nkx2.2, and PDX-1 regulate islet beta-cell-specific mafA expression through conserved sequences located between base pairs -8118 and -7750 upstream from the transcription start site.

Journal Article Mol Cell Biol · August 2006 The MafA transcription factor is both critical to islet beta-cell function and has a unique pancreatic cell-type-specific expression pattern. To localize the potential transcriptional regulatory region(s) involved in directing expression to the beta cell, ... Full text Link to item Cite

TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism.

Journal Article Science · June 23, 2006 During fasting, increased concentrations of circulating catecholamines promote the mobilization of lipid stores from adipose tissue in part by phosphorylating and inactivating acetyl-coenzyme A carboxylase (ACC), the rate-limiting enzyme in fatty acid synt ... Full text Link to item Cite

Efficient gene delivery to pancreatic islets with ultrasonic microbubble destruction technology.

Journal Article Proc Natl Acad Sci U S A · May 30, 2006 This study describes a method of gene delivery to pancreatic islets of adult, living animals by ultrasound targeted microbubble destruction (UTMD). The technique involves incorporation of plasmids into the phospholipid shell of gas-filled microbubbles, whi ... Full text Link to item Cite

Pro- and antiapoptotic proteins regulate apoptosis but do not protect against cytokine-mediated cytotoxicity in rat islets and beta-cell lines.

Journal Article Diabetes · May 2006 Type 1 diabetes results from islet beta-cell death and dysfunction induced by an autoimmune mechanism. Proinflammatory cytokines such as interleukin-1beta and gamma-interferon are mediators of this beta-cell cytotoxicity, but the mechanism by which damage ... Full text Link to item Cite

Obesity-related derangements in metabolic regulation.

Journal Article Annu Rev Biochem · 2006 An epidemic surge in the incidence of obesity has occurred worldwide over the past two decades. This alarming trend has been triggered by lifestyle habits that encourage overconsumption of energy-rich foods while also discouraging regular physical activity ... Full text Link to item Cite

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) weight loss project: Rationale and design.

Journal Article Contemp Clin Trials · December 2005 This paper outlines the rationale and design of the Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) weight loss project, in which detailed biologic profiling of three hundred and fifty obese individuals (body mass index (BMI): 30-50 kg/m ... Full text Link to item Cite

Islets for all?

Journal Article Nat Biotechnol · October 2005 Full text Link to item Cite

Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency.

Journal Article J Biol Chem · September 30, 2005 Peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC1alpha) is a promiscuous co-activator that plays a key role in regulating mitochondrial biogenesis and fuel homeostasis. Emergent evidence links decreased skeletal muscle PGC1alpha ac ... Full text Link to item Cite

Metabolism: A is for adipokine.

Journal Article Nature · July 21, 2005 Full text Link to item Cite

Peptide-mediated targeting of the islets of Langerhans.

Journal Article Diabetes · July 2005 Strategies for restoring beta-cell function in diabetic patients would be greatly aided by the ability to target genes, proteins, or small molecules specifically to these cells. Furthermore, the ability to direct imaging agents specifically to beta-cells w ... Full text Link to item Cite

Isolation of a mycoplasma-specific binding peptide from an unbiased phage-displayed peptide library.

Journal Article Mol Biosyst · July 2005 An important goal in medicine is the development of methods for cell-specific targeting of therapeutic molecules to pathogens or pathogen-infected cells. However, little progress has been made in cell-specific targeting of bacterially infected cells. Using ... Full text Link to item Cite

The Nkx6.1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet beta cells.

Journal Article Proc Natl Acad Sci U S A · May 17, 2005 We have previously described rat insulinoma INS-1-derived cell lines with robust or poor glucose-stimulated insulin secretion (GSIS). In the current study, we have further resolved these lines into three classes: class 1, glucose-unresponsive/glucagon-expr ... Full text Link to item Cite

Mechanism of insulin gene regulation by the pancreatic transcription factor Pdx-1: application of pre-mRNA analysis and chromatin immunoprecipitation to assess formation of functional transcriptional complexes.

Journal Article J Biol Chem · April 29, 2005 The homeodomain factor Pdx-1 regulates an array of genes in the developing and mature pancreas, but whether regulation of each specific gene occurs by a direct mechanism (binding to promoter elements and activating basal transcriptional machinery) or an in ... Full text Link to item Cite

Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP.

Journal Article Cell · January 28, 2005 The PGC-1 family of coactivators stimulates the activity of certain transcription factors and nuclear receptors. Transcription factors in the sterol responsive element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. W ... Full text Link to item Cite

Cell lines derived from pancreatic islets.

Journal Article Mol Cell Endocrinol · December 30, 2004 The islets of Langerhans play a major role in control of metabolic fuel homeostasis. The rapid increase in incidence of diabetes worldwide has spurred renewed interest in islet cell biology. However, gaining a detailed understanding of islet function at a ... Full text Link to item Cite

An adenovirus vector for efficient RNA interference-mediated suppression of target genes in insulinoma cells and pancreatic islets of langerhans.

Journal Article Diabetes · September 2004 Silencing gene expression by RNA interference (RNAi) can provide insight into gene function but requires efficient delivery of small interfering RNAs (siRNAs) into cells. Introduction of exogenous nucleic acids can be especially difficult in cultured pancr ... Full text Link to item Cite

Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue.

Journal Article J Biol Chem · June 25, 2004 Hyperlipidemia appears to play an integral role in loss of glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. This impairment can be simulated in vitro by chronic culture of 832/13 insulinoma cells with high concentrations of free fatty acids, ... Full text Link to item Cite

Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance.

Journal Article Nat Med · March 2004 Lipid infusion or ingestion of a high-fat diet results in insulin resistance, but the mechanism underlying this phenomenon remains unclear. Here we show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated fol ... Full text Link to item Cite

Understanding of basic mechanisms of beta-cell function and survival: prelude to new diabetes therapies.

Journal Article Cell Biochem Biophys · 2004 Type 1 and type 2 diabetes are both diseases of insulin insufficiency, although they develop by distinct pathways. The recent surge in the incidence of type 2 diabetes and the chronic ailments confronted by patients with either form of the disease highligh ... Full text Link to item Cite

Pancreatic islets and insulinoma cells express a novel isoform of group VIA phospholipase A2 (iPLA2 beta) that participates in glucose-stimulated insulin secretion and is not produced by alternate splicing of the iPLA2 beta transcript.

Journal Article Biochemistry · December 2, 2003 Many cells express a group VIA 84 kDa phospholipase A(2) (iPLA(2)beta) that is sensitive to inhibition by a bromoenol lactone (BEL) suicide substrate. Inhibition of iPLA(2)beta in pancreatic islets and insulinoma cells suppresses, and overexpression of iPL ... Full text Link to item Cite

Inflammatory mechanisms in diabetes: lessons from the beta-cell.

Journal Article Int J Obes Relat Metab Disord · December 2003 Inflammation plays an important role in the destruction of pancreatic islet beta-cells that leads to type I diabetes. This involves infiltration of T-cells and macrophages into the islets and local production of inflammatory cytokines such as interleukin ( ... Full text Link to item Cite

Regulation and function of the muscle glycogen-targeting subunit of protein phosphatase 1 (GM) in human muscle cells depends on the COOH-terminal region and glycogen content.

Journal Article Diabetes · September 2003 G(M), the muscle-specific glycogen-targeting subunit of protein phosphatase 1 (PP1) targeted to the sarcoplasmic reticulum, was proposed to regulate recovery of glycogen in exercised muscle, whereas mutation truncation of its COOH-terminal domain is known ... Full text Link to item Cite

PGC-1beta in the regulation of hepatic glucose and energy metabolism.

Journal Article J Biol Chem · August 15, 2003 Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that regulates multiple aspects of cellular energy metabolism, including mitochondrial biogenesis, hepatic gluconeogenesis, and beta-oxidation ... Full text Link to item Cite

Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells.

Journal Article J Biol Chem · July 18, 2003 Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several components of energy metabolism, particularly certain aspects of adaptive thermogenesis i ... Full text Link to item Cite

Suppression of beta cell energy metabolism and insulin release by PGC-1alpha.

Journal Article Dev Cell · July 2003 Featured Publication beta cell dysfunction is an important component of type 2 diabetes, but the molecular basis for this defect is poorly understood. The transcriptional coactivator PGC-1alpha mRNA and protein levels are significantly elevated in islets from multiple animal m ... Full text Link to item Cite

Hepatic expression of a targeting subunit of protein phosphatase-1 in streptozotocin-diabetic rats reverses hyperglycemia and hyperphagia despite depressed glucokinase expression.

Journal Article J Biol Chem · June 27, 2003 Featured Publication Glycogen-targeting subunits of protein phosphatase-1 (PP-1) are scaffolding proteins that facilitate the regulation of key enzymes of glycogen metabolism by PP-1. In the current study, we have tested the effects of hepatic expression of GMDeltaC, a truncat ... Full text Link to item Cite

Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy.

Journal Article Diabetes · June 2003 Featured Publication We have been investigating the potential utility of engineered cell lines as surrogates for primary islet cells in treatment of type 1 diabetes. To this end, two strategies that have emerged for procuring cell lines with resistance to immune-mediated damag ... Full text Link to item Cite

Stimulus/secretion coupling factors in glucose-stimulated insulin secretion: insights gained from a multidisciplinary approach.

Journal Article Diabetes · December 2002 There is a growing appreciation for the complexity of the pathways involved in glucose-stimulated insulin secretion (GSIS) from pancreatic islet beta-cells. In our laboratory, this has stimulated the development of an interdisciplinary approach to the prob ... Full text Link to item Cite

While tinkering with the beta-cell...metabolic regulatory mechanisms and new therapeutic strategies: American Diabetes Association Lilly Lecture, 2001.

Journal Article Diabetes · November 2002 Featured Publication A common feature of the two major forms of human diabetes is the partial or complete loss of insulin secretion from beta-cells in the pancreatic islets of Langerhans. In this article, we review the development of a set of tools for studying beta-cell biolo ... Full text Link to item Cite

A futile metabolic cycle activated in adipocytes by antidiabetic agents.

Journal Article Nat Med · October 2002 Featured Publication Thiazolidinediones (TZDs) are effective therapies for type 2 diabetes, which has reached epidemic proportions in industrialized societies. TZD treatment reduces circulating free fatty acids (FFAs), which oppose insulin actions in skeletal muscle and other ... Full text Link to item Cite

Mitochondrial metabolism sets the maximal limit of fuel-stimulated insulin secretion in a model pancreatic beta cell: a survey of four fuel secretagogues.

Journal Article J Biol Chem · April 5, 2002 The precise metabolic steps that couple glucose catabolism to insulin secretion in the pancreatic beta cell are incompletely understood. ATP generated from glycolytic metabolism in the cytosol, from mitochondrial metabolism, and/or from the hydrogen shuttl ... Full text Link to item Cite

13C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS).

Journal Article Proc Natl Acad Sci U S A · March 5, 2002 Featured Publication Cellular metabolism of glucose is required for stimulation of insulin secretion from pancreatic beta cells, but the precise metabolic coupling factors involved in this process are not known. In an effort to better understand mechanisms of fuel-mediated ins ... Full text Link to item Cite

Effects of modulation of glycerol kinase expression on lipid and carbohydrate metabolism in human muscle cells.

Journal Article J Biol Chem · January 25, 2002 Glycerol is taken up by human muscle in vivo and incorporated into lipids, but little is known about regulation of glycerol metabolism in this tissue. In this study, we have analyzed the role of glycerol kinase (GlK) in the regulation of glycerol metabolis ... Full text Link to item Cite

Glycogen-targeting subunits and glucokinase differentially affect pathways of glycogen metabolism and their regulation in hepatocytes.

Journal Article J Biol Chem · January 11, 2002 Overexpression of the glucose-phosphorylating enzyme glucokinase (GK) or members of the family of glycogen-targeting subunits of protein phosphatase-1 increases hepatic glucose disposal and glycogen synthesis. This study was undertaken to evaluate the func ... Full text Link to item Cite

Reversal of diet-induced glucose intolerance by hepatic expression of a variant glycogen-targeting subunit of protein phosphatase-1.

Journal Article J Biol Chem · January 11, 2002 Glycogen-targeting subunits of protein phosphatase-1 facilitate interaction of the phosphatase with enzymes of glycogen metabolism. Expression of one family member, PTG, in the liver of normal rats improves glucose tolerance without affecting other plasma ... Full text Link to item Cite

Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes.

Journal Article Am J Physiol Endocrinol Metab · January 2002 Hepatic glucose production is increased as a metabolic consequence of insulin resistance in type 2 diabetes. Because fructose 2,6-bisphosphate is an important regulator of hepatic glucose production, we used adenovirus-mediated enzyme overexpression to inc ... Full text Link to item Cite

Glucokinase gene transfer to skeletal muscle of diabetic Zucker fatty rats improves insulin-sensitive glucose uptake.

Journal Article Metabolism · January 2002 Skeletal muscle has a prime role in glucose homeostasis. We have previously demonstrated that adenovirus-mediated glucokinase (GK) gene transfer to skeletal muscle of Wistar rats enhances muscle glucose uptake and whole body glucose disposal under conditio ... Full text Link to item Cite

Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1.

Journal Article Nature · September 13, 2001 Featured Publication Blood glucose levels are maintained by the balance between glucose uptake by peripheral tissues and glucose secretion by the liver. Gluconeogenesis is strongly stimulated during fasting and is aberrantly activated in diabetes mellitus. Here we show that th ... Full text Link to item Cite

Protein synthesis. The perks of balancing glucose.

Journal Article Science · August 3, 2001 What do the regulation of translation initiation and glucose metabolism have to do with each other? Quite a lot, it seems, according to Sonenberg and Newgard in their Perspective. They discuss new findings that identify the kinase responsible for inactivat ... Full text Link to item Cite

Overexpression of the P46 (T1) translocase component of the glucose-6-phosphatase complex in hepatocytes impairs glycogen accumulation via hydrolysis of glucose 1-phosphate.

Journal Article J Biol Chem · April 6, 2001 The final step of gluconeogenesis and glycogenolysis is catalyzed by the glucose-6-phosphatase (Glc-6-Pase) enzyme complex, located in the endoplasmic reticulum. The complex consists of a 36-kDa catalytic subunit (P36), a 46-kDa glucose 6-phosphate translo ... Full text Link to item Cite

Overexpression of a modified human malonyl-CoA decarboxylase blocks the glucose-induced increase in malonyl-CoA level but has no impact on insulin secretion in INS-1-derived (832/13) beta-cells.

Journal Article J Biol Chem · March 2, 2001 Featured Publication The long-chain acyl-CoA (LC-CoA) model of glucose-stimulated insulin secretion (GSIS) holds that secretion is linked to a glucose-induced increase in malonyl-CoA level and accumulation of LC-CoA in the cytosol. We have previously tested the validity of thi ... Full text Link to item Cite

Expression of the transcription factor STAT-1 alpha in insulinoma cells protects against cytotoxic effects of multiple cytokines.

Journal Article J Biol Chem · January 5, 2001 Featured Publication Destruction of pancreatic islet beta-cells in type 1 diabetes appears to result from direct contact with infiltrating T-cells and macrophages and exposure to inflammatory cytokines such as interferon (IFN)-gamma, interleukin (IL)-1 beta, and tumor necrosis ... Full text Link to item Cite

Overexpression of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase in mouse liver lowers blood glucose by suppressing hepatic glucose production.

Journal Article J Clin Invest · January 2001 Hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is an important regulatory enzyme of glucose metabolism. By controlling the level of fructose-2,6-bisphosphate, an allosteric activator of the glycolytic enzyme 6-phosphofructo-1-kinase and an in ... Full text Link to item Cite

Glucose activates mitogen-activated protein kinase (extracellular signal-regulated kinase) through proline-rich tyrosine kinase-2 and the Glut1 glucose transporter.

Journal Article J Biol Chem · December 29, 2000 Glucose serves as both a nutrient and regulator of physiological and pathological processes. Presently, we found that glucose and certain sugars rapidly activated extracellular signal-regulated kinase (ERK) by a mechanism that was: (a) independent of gluco ... Full text Link to item Cite

Overexpression of protein targeting to glycogen in cultured human muscle cells stimulates glycogen synthesis independent of glycogen and glucose 6-phosphate levels.

Journal Article J Biol Chem · December 22, 2000 There is growing evidence that glycogen targeting subunits of protein phosphatase-1 play a critical role in regulation of glycogen metabolism. In the current study, we have investigated the effects of adenovirus-mediated overexpression of a specific glycog ... Full text Link to item Cite

Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1.

Journal Article Diabetes · December 2000 Glucose is stored in mammalian tissues in the form of glycogen. Glycogen levels are markedly reduced in liver or muscle cells of patients with insulin-resistant or insulin-deficient forms of diabetes, suggesting that impaired glycogen synthesis may contrib ... Full text Link to item Cite

Glucose down-regulates the expression of the peroxisome proliferator-activated receptor-alpha gene in the pancreatic beta -cell.

Journal Article J Biol Chem · November 17, 2000 To better understand the action of glucose on fatty acid metabolism in the beta-cell and the link between chronically elevated glucose or fatty acids and beta-cell decompensation in adipogenic diabetes, we investigated whether glucose regulates peroxisomal ... Full text Link to item Cite

Distinctive regulatory and metabolic properties of glycogen-targeting subunits of protein phosphatase-1 (PTG, GL, GM/RGl) expressed in hepatocytes.

Journal Article J Biol Chem · August 25, 2000 Glycogen-targeting subunits of protein phosphatase-1 facilitate interaction of the phosphatase with enzymes of glycogen metabolism. We have shown that overexpression of one member of the family, protein targeting to glycogen (PTG), causes large increases i ... Full text Link to item Cite

Selection of insulinoma cell lines with resistance to interleukin-1beta- and gamma-interferon-induced cytotoxicity.

Journal Article Diabetes · April 2000 Engineered insulinoma cell lines may represent an alternative to isolated islets for transplantation therapy of type 1 diabetes. Success of this approach may require development of cell lines that can withstand cytokine-mediated damage. To this end, we hav ... Full text Link to item Cite

Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion.

Journal Article Diabetes · March 2000 The biochemical mechanisms involved in regulation of insulin secretion are not completely understood. The rat INS-1 cell line has been used to gain insight in this area because it secretes insulin in response to glucose concentrations in the physiological ... Full text Link to item Cite

Correction of diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance by moderate hyperleptinemia.

Journal Article Am J Physiol Endocrinol Metab · March 2000 Human obesity and high fat feeding in rats are associated with the development of insulin resistance and perturbed carbohydrate and lipid metabolism. It has been proposed that these metabolic abnormalities may be reversible by interventions that increase p ... Full text Link to item Cite

New lessons in the regulation of glucose metabolism taught by the glucose 6-phosphatase system.

Journal Article Eur J Biochem · March 2000 The operation of glucose 6-phosphatase (EC 3.1.3.9) (Glc6Pase) stems from the interaction of at least two highly hydrophobic proteins embedded in the ER membrane, a heavily glycosylated catalytic subunit of m 36 kDa (P36) and a 46-kDa putative glucose 6-ph ... Full text Link to item Cite

Activation of direct and indirect pathways of glycogen synthesis by hepatic overexpression of protein targeting to glycogen.

Journal Article J Clin Invest · February 2000 Glycogen-targeting subunits of protein phosphatase-1, such as protein targeting to glycogen (PTG), direct the phosphatase to the glycogen particle, where it stimulates glycogenesis. We have investigated the metabolic impact of overexpressing PTG in liver o ... Full text Link to item Cite

Increased glucose disposal induced by adenovirus-mediated transfer of glucokinase to skeletal muscle in vivo.

Journal Article FASEB J · December 1999 In non-insulin-dependent diabetes mellitus, insulin-stimulated glucose uptake is impaired in muscle, contributing in a major way to development of hyperglycemia. We previously showed that expression of the glucose phosphorylating enzyme glucokinase (GK) in ... Full text Link to item Cite

Glucokinase overexpression restores glucose utilization and storage in cultured hepatocytes from male Zucker diabetic fatty rats.

Journal Article J Biol Chem · November 5, 1999 Zucker diabetic fatty rats develop type 2 diabetes concomitantly with peripheral insulin resistance. Hepatocytes from these rats and their control lean counterparts have been cultured, and a number of key parameters of glucose metabolism have been determin ... Full text Link to item Cite

Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia.

Journal Article Diabetes · October 1999 The balance between hepatic glucose uptake and production is perturbed in both major forms of diabetes. It has been suggested that pharmacologic or genetic methods for enhancing glucokinase (GK) enzymatic activity in liver might be a means of increasing gl ... Full text Link to item Cite

Sparing effect of leptin on liver glycogen stores in rats during the fed-to-fasted transition.

Journal Article Am J Physiol · September 1999 The effect of moderate hyperleptinemia ( approximately 20 ng/ml) on liver and skeletal muscle glycogen metabolism was examined in Wistar rats. Animals were studied approximately 90 h after receiving recombinant adenoviruses encoding rat leptin (AdCMV-lepti ... Full text Link to item Cite

Glucose-6-phosphatase overexpression lowers glucose 6-phosphate and inhibits glycogen synthesis and glycolysis in hepatocytes without affecting glucokinase translocation. Evidence against feedback inhibition of glucokinase.

Journal Article J Biol Chem · August 27, 1999 In hepatocytes glucokinase (GK) and glucose-6-phosphatase (Glc-6-Pase)(1) have converse effects on glucose 6-phosphate (and fructose 6-phosphate) levels. To establish whether hexose 6-phosphate regulates GK binding to its regulatory protein, we determined ... Full text Link to item Cite

Snare protein expression and adenoviral transfection of amphicrine AR42J.

Journal Article Biochem Biophys Res Commun · July 14, 1999 The amphicrine AR42J acinar cell line is an excellent model to study both exocrine and neuroendocrine exocytotic mechanisms. As a first step toward this goal, we determined the specific isoforms of the v- and t-SNARE and Munc18 families expressed in these ... Full text Link to item Cite

Increase in PDX-1 levels suppresses insulin gene expression in RIN 1046-38 cells.

Journal Article Endocrinology · July 1999 RIN1046-38 cells (RIN-38) exhibit a passage-dependent reduction in both basal and glucose-regulated insulin secretion, accompanied by decreased insulin content. In an attempt to explain the mechanism of the gradual decrease in insulin production in culture ... Full text Link to item Cite

Overexpression of G11alpha and isoforms of phospholipase C in islet beta-cells reveals a lack of correlation between inositol phosphate accumulation and insulin secretion.

Journal Article Diabetes · May 1999 It has been suggested that insulin secretion from pancreatic islets may be mediated in part by activation of phospholipases C (PLCs) and phosphoinositide hydrolysis. The purpose of this study was to determine whether the relatively modest fuel-stimulated i ... Full text Link to item Cite

Adenovirus-mediated overexpression of uncoupling protein-2 in pancreatic islets of Zucker diabetic rats increases oxidative activity and improves beta-cell function.

Journal Article Diabetes · May 1999 The discovery of uncoupling protein (UCP)-2, a ubiquitously expressed protein homologous to UCP-1, has raised the possibility that energy balance of cells might be regulated in tissues other than brown adipocytes. In normal pancreatic islets, UCP-2 is upre ... Full text Link to item Cite

Reversing adipocyte differentiation: implications for treatment of obesity.

Journal Article Proc Natl Acad Sci U S A · March 2, 1999 Conventional treatment of obesity reduces fat in mature adipocytes but leaves them with lipogenic enzymes capable of rapid resynthesis of fat, a likely factor in treatment failure. Adenovirus-induced hyperleptinemia in normal rats results in rapid nonketot ... Full text Link to item Cite

Metabolic engineering with recombinant adenoviruses.

Journal Article Annu Rev Nutr · 1999 Fuel homeostasis in mammals is accomplished by the interplay between tissues and organs with distinct metabolic roles. These regulatory mechanisms are disrupted in obesity and diabetes, leading to a renewed emphasis on discovery of molecular and pharmacolo ... Full text Link to item Cite

Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression.

Journal Article J Biol Chem · December 4, 1998 We reported that the lipoapoptosis of beta-cells observed in fat-laden islets of obese fa/fa Zucker Diabetic Fatty (ZDF) rats results from overproduction of ceramide, an initiator of the apoptotic cascade and is induced by long-chain fatty acids (FA). Wher ... Full text Link to item Cite

Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats.

Journal Article J Biol Chem · November 20, 1998 The terminal step in hepatic gluconeogenesis is catalyzed by glucose-6-phosphatase, an enzyme activity residing in the endoplasmic reticulum and consisting of a catalytic subunit (glucose-6-phosphatase (G6Pase)) and putative accessory transport proteins. W ... Full text Link to item Cite

Overexpression of protein targeting to glycogen (PTG) in rat hepatocytes causes profound activation of glycogen synthesis independent of normal hormone- and substrate-mediated regulatory mechanisms.

Journal Article J Biol Chem · October 9, 1998 Protein targeting to glycogen (PTG), also known as PPP1R5, is a widely expressed member of a growing family of proteins that target protein phosphatase-1 (PP-1) to glycogen particles. Because PTG also binds to glycogen synthase and phosphorylase kinase, it ... Full text Link to item Cite

Overexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion.

Journal Article Proc Natl Acad Sci U S A · September 29, 1998 The high-Km glucose transporter, GLUT-2, and the high-Km hexokinase of beta cells, glucokinase (GK), are required for glucose-stimulated insulin secretion (GSIS). GLUT-2 expression in beta cells of Zucker diabetic fatty (ZDF) rats is profoundly reduced at ... Full text Link to item Cite

The repression of hormone-activated PEPCK gene expression by glucose is insulin-independent but requires glucose metabolism.

Journal Article J Biol Chem · September 11, 1998 Phosphoenolpyruvate carboxykinase (PEPCK) is a rate-controlling enzyme in hepatic gluconeogenesis, and it therefore plays a central role in glucose homeostasis. The rate of transcription of the PEPCK gene is increased by glucagon (via cAMP) and glucocortic ... Full text Link to item Cite

Expression of glucokinase in cultured human muscle cells confers insulin-independent and glucose concentration-dependent increases in glucose disposal and storage.

Journal Article Diabetes · September 1998 Insulin resistance, as is found in skeletal muscle of individuals with obesity and NIDDM, appears to involve a reduced capacity of the hormone to stimulate glucose uptake and/or phosphorylation. The glucose phosphorylation step, as catalyzed by hexokinase ... Full text Link to item Cite

Resistance to adenovirally induced hyperleptinemia in rats. Comparison of ventromedial hypothalamic lesions and mutated leptin receptors.

Journal Article J Clin Invest · August 15, 1998 Leptin regulates appetite and body weight via hypothalamic targets, but it can act directly on cultured pancreatic islets to regulate their fat metabolism. To obtain in vivo evidence that leptin may act peripherally as well as centrally, we compared the ef ... Full text Link to item Cite

Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression.

Journal Article Proc Natl Acad Sci U S A · August 4, 1998 Obesity causes its complications through functional and morphologic damage to remotely situated tissues via undetermined mechanisms. In one rodent model of obesity, the Zucker diabetic fatty fa/fa rat, overaccumulation of triglycerides in the pancreatic is ... Full text Link to item Cite

Role of peroxisome proliferator-activated receptor alpha in disease of pancreatic beta cells.

Journal Article Proc Natl Acad Sci U S A · July 21, 1998 Expression of peroxisome proliferator-activated receptor alpha (PPARalpha) and enzymes of fatty acid (FA) oxidation is markedly reduced in the fat-laden, dysfunctional islets of obese, prediabetic Zucker diabetic fatty (fa/fa) rats with mutated leptin rece ... Full text Link to item Cite

Molecular or pharmacologic perturbation of the link between glucose and lipid metabolism is without effect on glucose-stimulated insulin secretion. A re-evaluation of the long-chain acyl-CoA hypothesis.

Journal Article J Biol Chem · June 26, 1998 The mechanism by which glucose stimulates insulin secretion from the pancreatic islets of Langerhans is incompletely understood. It has been suggested that malonyl-CoA plays a regulatory role by inhibiting fatty acid oxidation and promoting accumulation of ... Full text Link to item Cite

Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta- induced cytotoxicity and reduces nitric oxide production.

Journal Article J Clin Invest · May 1, 1998 The fact that insulin-producing islet beta-cells are susceptible to the cytotoxic effects of inflammatory cytokines represents a potential hinderance to the use of such cells for transplantation therapy of insulin-dependent diabetes mellitus (IDDM). In the ... Full text Link to item Cite

Fundamental metabolic differences between hepatocytes and islet beta-cells revealed by glucokinase overexpression.

Journal Article Biochemistry · March 31, 1998 Adenovirus-mediated overexpression of the glucose phosphorylating enzyme glucokinase causes large changes in glycolytic flux and glucose storage in isolated rat hepatocytes, but not in pancreatic islets. We have used the well-differentiated insulinoma cell ... Full text Link to item Cite

OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype.

Journal Article Proc Natl Acad Sci U S A · January 20, 1998 In obese Zucker diabetic fatty (ZDF) rats with mutant leptin receptors, pancreatic islets have an approximately 50-fold increase in fat (TG), overproduce nitric oxide (NO), and lack a normal proinsulin mRNA response to fatty acids. We overexpressed the wil ... Full text Link to item Cite

Metabolic impact of adenovirus-mediated overexpression of the glucose-6-phosphatase catalytic subunit in hepatocytes.

Journal Article J Biol Chem · October 24, 1997 Glucose-6-phosphatase (G6Pase) catalyzes the hydrolysis of glucose 6-phosphate (Glu-6-P) to free glucose and, as the last step in gluconeogenesis and glycogenolysis in liver, is thought to play an important role in glucose homeostasis. G6Pase activity appe ... Full text Link to item Cite

Adenovirus-mediated expression of the catalytic subunit of glucose-6-phosphatase in INS-1 cells. Effects on glucose cycling, glucose usage, and insulin secretion.

Journal Article J Biol Chem · October 3, 1997 Glucose-6-phosphatase (Glu-6-Pase) catalyzes the terminal step of gluconeogenesis, the conversion of glucose 6-phosphate (Glu-6-P) to free glucose. This enzyme activity is thought to be conferred by a complex of proteins residing in the endoplasmic reticul ... Full text Link to item Cite

Evidence that potentiation of insulin secretion is mediated by free rather than CoA-activated fatty acids

Journal Article Experimental and Clinical Endocrinology and Diabetes · September 24, 1997 Cite

beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy.

Journal Article Diabetes · August 1997 Leptin was overexpressed in the liver of normal Wistar rats by infusing recombinant adenovirus containing the cDNA encoding leptin. Plasma leptin levels rose to 12-24 ng/ml (vs. <2 ng/ml in control rats), and food intake and body weight fell. Visible fat d ... Full text Link to item Cite

Engineering of glycerol-stimulated insulin secretion in islet beta cells. Differential metabolic fates of glucose and glycerol provide insight into mechanisms of stimulus-secretion coupling.

Journal Article J Biol Chem · July 25, 1997 Insulin secretion from beta cells in the islets of Langerhans can be stimulated by a number of metabolic fuels, including glucose and glyceraldehyde, and is thought to be mediated by metabolism of the secretagogues and an attendant increase in the ATP:ADP ... Full text Link to item Cite

Engineered cell lines for insulin replacement in diabetes: current status and future prospects.

Journal Article Diabetologia · July 1997 The recently completed diabetes complications and control trial has highlighted the need for improvement of insulin delivery systems for treatment of insulin-dependent diabetes mellitus. Despite steady improvement in methods for islet and whole pancreas tr ... Full text Link to item Cite

Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation.

Journal Article Proc Natl Acad Sci U S A · June 10, 1997 We have studied mechanisms by which leptin overexpression, which reduces body weight via anorexic and thermogenic actions, induces triglyceride depletion in adipocytes and nonadipocytes. Here we show that leptin alters in pancreatic islets the mRNA of the ... Full text Link to item Cite

Regulation of insulin secretion from novel engineered insulinoma cell lines.

Journal Article Diabetes · June 1997 In the accompanying article, we describe the creation of novel cell lines derived from RIN 1046-38 rat insulinoma cells by stable transfection with combinations of genes encoding human insulin, GLUT2, and glucokinase. Herein we describe the regulation of i ... Full text Link to item Cite

Novel insulinoma cell lines produced by iterative engineering of GLUT2, glucokinase, and human insulin expression.

Journal Article Diabetes · June 1997 Cellular engineering studies in our group are directed at creating insulin-secreting cell lines that simulate the performance of the normal islet beta-cell. The strategy described in this article involves the stepwise stable introduction of genes relevant ... Full text Link to item Cite

Stimulation of glucose-6-phosphatase gene expression by glucose and fructose-2,6-bisphosphate.

Journal Article J Biol Chem · May 9, 1997 Glucose-6-phosphatase, a key enzyme in the homeostatic regulation of blood glucose concentration, catalyzes the terminal step in gluconeogenesis and glycogenolysis. Glucose, the product of the glucose-6-phosphatase reaction, dramatically increases the leve ... Full text Link to item Cite

Structural domains that contribute to substrate specificity in facilitated glucose transporters are distinct from those involved in kinetic function: studies with GLUT-1/GLUT-2 chimeras.

Journal Article Biochemistry · May 6, 1997 GLUT-2 differs from other members of the facilitated glucose transporter family because it transports a wider range of substrates and exhibits a higher Km for transport of glucose analogs such as 2-deoxyglucose (2-DOG). In order to investigate the structur ... Full text Link to item Cite

Direct antidiabetic effect of leptin through triglyceride depletion of tissues.

Journal Article Proc Natl Acad Sci U S A · April 29, 1997 Leptin is currently believed to control body composition largely, if not entirely, via hypothalamic receptors that regulate food intake and thermogenesis. Here we demonstrate direct extraneural effects of leptin to deplete fat content of both adipocytes an ... Full text Link to item Cite

Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy.

Journal Article Proc Natl Acad Sci U S A · December 10, 1996 Sustained hyperleptinemia of 8 ng/ml was induced for 28 days in normal Wistar rats by infusing a recombinant adenovirus containing the rat leptin cDNA (AdCMV-leptin). Hyperleptinemic rats exhibited a 30-50% reduction in food intake and gained only 22 g ove ... Full text Link to item Cite

Insulinsezernierende Zellen zur Therapie des Diabetes mellitus

Journal Article Naturwissenschaften · December 1, 1996 Even with intensive insulin therapy it is impossible to reach physiological blood glucose levels in insulin-dependent diabetes mellitus. Because of the high costs and technical problems involved in islet cell transplantation broad applicability of this the ... Cite

Adenoviral-mediated glucokinase overexpression in rat primary hepatocytes increases the efficiency of glycogen accumulation and lactate production at physiologic glucose concentrations

Journal Article FASEB Journal · December 1, 1996 Glucokinase (GK) catalyses the conversion of glucose to glucose-6-phosphate, and is vital to the liver's role in maintaining glucose homeostasis. To address the effects of altered GK expression on liver carbohydrate metabolism, rat primary hepatocytes were ... Cite

Evidence for a role of glucose-induced translocation of glucokinase in the control of hepatic glycogen synthesis.

Journal Article J Biol Chem · November 29, 1996 Glucokinase reversibly partitions between a bound and a free state in the hepatocyte in response to the metabolic status of the cell. Maximum binding occurs at low [glucose] (<5 mM) and minimum binding at high [glucose] or in the presence of sorbitol or fr ... Full text Link to item Cite

Glucose 6-phosphate produced by glucokinase, but not hexokinase I, promotes the activation of hepatic glycogen synthase.

Journal Article J Biol Chem · September 27, 1996 In a previous study (O'Doherty, R. M., Lehman, D. L., Seoane, J., Gómez-Foix, A. M., Guinovart, J. J., and Newgard, C.B. (1996) J. Biol. Chem. 271, 20524-20530), we demonstrated that adenovirus-mediated overexpression of glucokinase but not hexokinase I ha ... Full text Link to item Cite

A novel leptin receptor isoform in rat.

Journal Article FEBS Lett · August 26, 1996 Five mouse and human leptin receptors (Ob-R) have recently been identified, a long isoform (Ob-Rb), preferentially expressed in hypothalamus, and 4 short isoforms, Ob-Ra, Ob-Rc, Ob-Rd, and Ob-Re. We have identified a new short isoform in the rat, r-OB-Rf, ... Full text Link to item Cite

Differential metabolic effects of adenovirus-mediated glucokinase and hexokinase I overexpression in rat primary hepatocytes.

Journal Article J Biol Chem · August 23, 1996 The first step of glucose metabolism is the phosphorylation of glucose, catalyzed by the hexokinase family of enzymes. To address the metabolic impact of increasing glucose phosphorylation capacity in liver, rat primary hepatocytes were treated with recomb ... Full text Link to item Cite

Differential effects of overexpressed glucokinase and hexokinase I in isolated islets. Evidence for functional segregation of the high and low Km enzymes.

Journal Article J Biol Chem · January 5, 1996 Glucose-stimulated insulin secretion is believed to require metabolism of the sugar via a high Km pathway in which glucokinase (hexokinase IV) is rate-limiting. In this study, we have used recombinant adenoviruses to overexpress the liver and islet isoform ... Full text Link to item Cite

[Insulin producing cells as therapy in diabetes mellitus].

Journal Article Naturwissenschaften · January 1996 Even with intensive insulin therapy it is impossible to reach physiological blood glucose levels in insulin-dependent diabetes mellitus. Because of the high costs and technical problems involved in islet cell transplantation broad applicability of this the ... Link to item Cite

Regulatory role of glucose transport and phosphorylation in pancreatic islet β-cells

Journal Article Diabetes Reviews · January 1, 1996 Insulin secretion is largely controlled by the level of circulating glucose. The mechanism by which glucose stimulates insulin release from pancreatic islet β-cells has been an important but difficult area of investigation. In recent years, the tools of mo ... Cite

Adenovirus-mediated overexpression of liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in gluconeogenic rat hepatoma cells. Paradoxical effect on Fru-2,6-P2 levels.

Journal Article J Biol Chem · October 13, 1995 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase has been postulated to be a metabolic signaling enzyme, which acts as a switch between glycolysis and gluconeogenesis in mammalian liver by regulating the level of fructose 2,6-bisphosphate. The effect o ... Full text Link to item Cite

Pancreatic beta-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids.

Journal Article J Biol Chem · January 20, 1995 To elucidate the mechanism of the basal hyperinsulinemia of obesity, we perfused pancreata from obese Zucker and lean Wistar rats with substimulatory concentrations of glucose. Insulin secretion at 4.2 and 5.6 mM glucose was approximately 10 times that of ... Full text Link to item Cite

Metabolic coupling factors in pancreatic beta-cell signal transduction.

Journal Article Annu Rev Biochem · 1995 This chapter focuses on the biochemical mechanisms that mediate glucose-stimulated insulin secretion (GSIS) from beta-cells of the islets of Langerhans and the potentiating role played by fatty acids. We summarize evidence supporting the idea that glucose ... Full text Link to item Cite

Adenovirus-mediated delivery into myocytes of muscle glycogen phosphorylase, the enzyme deficient in patients with glycogen-storage disease type V.

Journal Article Biochem J · December 15, 1994 The feasibility of using adenovirus as a vector for the introduction of glycogen phosphorylase activity into myocytes has been examined. We used the C2C12 myoblast cell line to assay the impact of phosphorylase gene transfer on myocyte glycogen metabolism ... Full text Link to item Cite

Glucose-stimulated insulin secretion in cell lines

Journal Article Diabetes, Nutrition and Metabolism - Clinical and Experimental · December 1, 1994 Because islet β-cells are expensive and difficult to isolate, islet transplantation may have limited applicability for insulin replacement in insulin-dependent diabetes mellitus. Knowledge of glucose sensing guides the development of clonal cell lines that ... Cite

STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells.

Journal Article Diabetes · November 1994 The glucose analog streptozotocin (STZ) has long been used as a tool for creating experimental diabetes because of its relatively specific beta-cell cytotoxic effect, but the mechanism by which systemic injection of STZ causes beta-cell destruction is not ... Full text Link to item Cite

Overexpression of hexokinase I in isolated islets of Langerhans via recombinant adenovirus. Enhancement of glucose metabolism and insulin secretion at basal but not stimulatory glucose levels.

Journal Article J Biol Chem · August 19, 1994 Glucose metabolism and glucose-stimulated insulin secretion are thought to be controlled at the level of glucose phosphorylation in pancreatic islet beta-cells. In the current study we have investigated the importance of glucose phosphorylation by using re ... Link to item Cite

GLUT-2 gene transfer into insulinoma cells confers both low and high affinity glucose-stimulated insulin release. Relationship to glucokinase activity.

Journal Article J Biol Chem · April 15, 1994 The rat insulinoma cell line RIN 1046-38 loses glucose-stimulated insulin secretion as a function of time in culture. We found that the loss of glucose sensing in these cells was correlated with the loss of expression of GLUT-2 and glucokinase. Stable tran ... Link to item Cite

Molecular strategies for the treatment of diabetes.

Journal Article Transplant Proc · April 1994 Link to item Cite

Cellular engineering and gene therapy strategies for insulin replacement in diabetes.

Journal Article Diabetes · March 1994 In diabetes, insulin secretion is either completely absent (insulin-dependent diabetes mellitus [IDDM]) or inappropriately regulated (non-insulin-dependent diabetes mellitus [NIDDM]). In recent years, new insights into the molecular and biochemical mechani ... Full text Link to item Cite

Molecular engineering of the pancreatic beta-cell.

Journal Article J Lab Clin Med · October 1993 Link to item Cite

Transfection of AtT-20ins cells with GLUT-2 but not GLUT-1 confers glucose-stimulated insulin secretion. Relationship to glucose metabolism.

Journal Article J Biol Chem · July 15, 1993 Glucose is thought to stimulate insulin release from islet beta-cells through generation of metabolic signals. In the current study we have introduced the genes encoding the facilitated glucose transporters known as GLUT-1 and GLUT-2 into AtT-20ins cells t ... Link to item Cite

Autoantibodies to the GLUT-2 glucose transporter of beta cells in insulin-dependent diabetes mellitus of recent onset.

Journal Article Proc Natl Acad Sci U S A · February 15, 1993 Purified immunoglobulin G (IgG) from the serum of patients with insulin-dependent diabetes mellitus (IDDM) of recent onset inhibits high-Km uptake of 3-O-methyl-beta-D-glucose by rat pancreatic islets. To determine if the inhibition is the result of antibo ... Full text Link to item Cite

Adenovirus-mediated transfer of the muscle glycogen phosphorylase gene into hepatocytes confers altered regulation of glycogen metabolism.

Journal Article J Biol Chem · December 15, 1992 The muscle isozyme of glycogen phosphorylase is potently activated by the allosteric ligand AMP, whereas the liver isozyme is not. In this study we have investigated the metabolic impact of expression of muscle phosphorylase in liver cells. To this end, we ... Link to item Cite

Cellular engineering for the treatment of metabolic disorders: prospects for therapy in diabetes.

Journal Article Biotechnology (N Y) · October 1992 Significant advances in the areas of identification of disease susceptibility genes and gene transfer technologies have fueled new initiatives in cellular engineering as a means for treating metabolic disease. This article utilizes new findings from such w ... Full text Link to item Cite

Engineering of glucose-stimulated insulin secretion and biosynthesis in non-islet cells.

Journal Article Proc Natl Acad Sci U S A · January 15, 1992 The high-capacity glucose transporter known as GLUT-2 and the glucose phosphorylating enzyme glucokinase are thought to be key components of the "glucose-sensing apparatus" that regulates insulin release from the beta cells of the islets of Langerhans in r ... Full text Link to item Cite

Developmental expression of glycogenolytic enzymes in rabbit tissues: possible relationship to fetal lung maturation.

Journal Article Biochim Biophys Acta · November 11, 1991 Glycogen can be degraded in mammalian tissues by one of three isozymes of glycogen phosphorylase, termed muscle (M), liver (L) and brain (B) after the tissues in which they are preferentially expressed in adult animals, or by members of the family of alpha ... Full text Link to item Cite

An engineered liver glycogen phosphorylase with AMP allosteric activation.

Journal Article J Biol Chem · August 25, 1991 Liver and muscle glycogen phosphorylases, which are products of distinct genes, are both activated by covalent phosphorylation, but in the unphosphorylated (b) state, only the muscle isozyme is efficiently activated by the allosteric activator AMP. The dif ... Link to item Cite

Analysis of the protein products encoded by variant glucokinase transcripts via expression in bacteria.

Journal Article FEBS Lett · March 11, 1991 Five variant transcripts of the single rat glucokinase gene have been described that are naturally expressed in islets of Langerhans, liver and anterior pituitary. Four of these were prepared as cDNA and expressed in bacteria in order to begin to address t ... Full text Link to item Cite

Expression of normal and novel glucokinase mRNAs in anterior pituitary and islet cells.

Journal Article J Biol Chem · March 5, 1991 The glucose-phosphorylating enzyme glucokinase likely plays an important role in regulating glucose-stimulated insulin secretion from the islets of Langerhans and has previously been thought to be expressed only in that tissue and in liver. In this study, ... Link to item Cite

Expression of reg/PSP, a pancreatic exocrine gene: relationship to changes in islet beta-cell mass.

Journal Article Mol Endocrinol · February 1991 A cDNA termed reg was recently isolated by differential screening of a library prepared from regenerating islets isolated from pancreatic remnants of rats subjected to 90% pancreatectomy and nicotinamide treatment. This led to speculation that this gene ma ... Full text Link to item Cite

Evidence that down-regulation of beta-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycemia.

Journal Article Proc Natl Acad Sci U S A · December 1990 Non-insulin-dependent diabetes mellitus (NIDDM) is attributed to a failure of pancreatic beta cells to maintain insulin secretion at a level sufficient to compensate for underlying insulin resistance. In the ZDF rat, a model of NIDDM that closely resembles ... Full text Link to item Cite

Underexpression of beta cell high Km glucose transporters in noninsulin-dependent diabetes.

Journal Article Science · October 26, 1990 The role of defective glucose transport in the pathogenesis of noninsulin-dependent diabetes (NIDDM) was examined in Zucker diabetic fatty rats, a model of NIDDM. As in human NIDDM, insulin secretion was unresponsive to 20 mM glucose. Uptake of 3-O-methylg ... Full text Link to item Cite

Regulation of beta-cell glucose transporter gene expression.

Journal Article Proc Natl Acad Sci U S A · June 1990 It has been postulated that a glucose transporter of beta cells (GLUT-2) may be important in glucose-stimulated insulin secretion. To determine whether this transporter is constitutively expressed or regulated, we subjected conscious unrestrained Wistar ra ... Full text Link to item Cite

The high Km glucose transporter of islets of Langerhans is functionally similar to the low affinity transporter of liver and has an identical primary sequence.

Journal Article J Biol Chem · April 25, 1990 The liver has been shown to contain a facilitated diffusion glucose transporter with high Km for glucose that is structurally distinct from the low Km glucose transporters found in most other tissues. We find that 3-O-methyl glucose is greater than 90% equ ... Link to item Cite

Differential expression and regulation of the glucokinase gene in liver and islets of Langerhans.

Journal Article Proc Natl Acad Sci U S A · October 1989 Glucokinase, a key regulatory enzyme of glucose metabolism in mammals, provides an interesting model of tissue-specific gene expression. The single-copy gene is expressed principally in liver, where it gives rise to a 2.4-kilobase mRNA. The islets of Lange ... Full text Link to item Cite

Rat amylin: cloning and tissue-specific expression in pancreatic islets.

Journal Article Proc Natl Acad Sci U S A · May 1989 Amyloid deposits in the islets of Langerhans of the pancreas are a common finding in non-insulin-dependent diabetes mellitus. The main protein constituent of these deposits is a 37-amino acid peptide known as amylin that resembles calcitonin gene-related p ... Full text Link to item Cite

The family of glycogen phosphorylases: structure and function.

Journal Article Crit Rev Biochem Mol Biol · 1989 Glycogen phosphorylase plays a central role in the mobilization of carbohydrate reserves in a wide variety of organisms and tissues. While rabbit muscle phosphorylase remains the most studied and best characterized of phosphorylases, recombinant DNA techni ... Full text Link to item Cite

Human brain glycogen phosphorylase. Cloning, sequence analysis, chromosomal mapping, tissue expression, and comparison with the human liver and muscle isozymes.

Journal Article J Biol Chem · March 15, 1988 We have cloned the cDNA encoding a new isozyme of glycogen phosphorylase (1,4-D-glucan:orthosphosphate D-glucosyltransferase, EC 2.4.1.1) from a cDNA library prepared from a human brain astrocytoma cell line. Blot-hybridization analysis reveals that this m ... Link to item Cite

The polymorphic locus for glycogen storage disease VI (liver glycogen phosphorylase) maps to chromosome 14.

Journal Article Am J Hum Genet · April 1987 Human liver glycogen phosphorylase deficiency, also known as glycogen storage disease type VI (GSD VI) or Hers disease, is characterized by hepatomegaly and reduced or absent glycogenolytic response to the injection of glucagon. The recently isolated cDNA ... Link to item Cite

Modeling the biochemical differences between rabbit muscle and human liver phosphorylase.

Journal Article Proteins · 1987 Glycogen phosphorylases catalyze the regulated breakdown of glycogen to glucose-1-phosphate. In mammals, glycogen phosphorylase occurs in three different isozymes called liver, muscle, and brain after the tissues in which they are preferentially expressed. ... Full text Link to item Cite

Sequence analysis of the cDNA encoding human liver glycogen phosphorylase reveals tissue-specific codon usage.

Journal Article Proc Natl Acad Sci U S A · November 1986 We have cloned the cDNA encoding glycogen phosphorylase (1,4-alpha-D-glucan:orthophosphate alpha-D-glucosyl-transferase, EC 2.4.1.1) from human liver. Blot-hybridization analysis using a large fragment of the cDNA to probe mRNA from rabbit brain, muscle, a ... Full text Link to item Cite

The glucose-phosphorylating capacity of liver as measured by three independent assays. Implications for the mechanism of hepatic glycogen synthesis.

Journal Article J Biol Chem · July 5, 1986 In the fasted to fed transition liver glycogen derives mainly from gluconeogenic precursors. Why glucose is not used efficiently as a direct precursor of glycogen has become a controversial issue, in part because of disagreement over the question of how we ... Link to item Cite

Structure of Mammalian Isozymes of Glycogen Phosphorylase: Implications for Function

Journal Article Annals of the New York Academy of Sciences · January 1, 1986 Full text Cite

Time course and significance of changes in hepatic fructose-2,6-bisphosphate levels during refeeding of fasted rats.

Journal Article J Clin Invest · September 1984 The time course of changes in hepatic fructose-2,6-bisphosphate (F-2,6-P2) and glycogen content was examined in fasted rats infused with glucose intragastrically or allowed to eat a chow diet ad lib. Initial values for the two parameters were approximately ... Full text Link to item Cite

Efficient hepatic glycogen synthesis in refeeding rats requires continued carbon flow through the gluconeogenic pathway.

Journal Article J Biol Chem · June 10, 1984 Intragastric infusion of [1-14C]glucose into awake, fasted rats at rates that produced physiological increases in the circulating glucose concentration resulted in active glycogen deposition in liver. However, degradation of this glycogen revealed extensiv ... Link to item Cite

Evidence for suppression of hepatic glucose-6-phosphatase with carbohydrate feeding.

Journal Article Diabetes · February 1984 The mechanism by which exogenous glucose stimulates the incorporation of hepatic glucose-6-phosphate into glycogen in fasted rats has not been clearly delineated. We gave glucose intragastrically over a 3.5-h period during which liver glycogen was deposite ... Full text Link to item Cite

Studies on the mechanism by which exogenous glucose is converted into liver glycogen in the rat. A direct or an indirect pathway?

Journal Article J Biol Chem · July 10, 1983 To quantify the extent to which exogenous glucose is used directly or indirectly for hepatic glycogen synthesis, fasted rats were given [U-14C,3-3H] glucose intragastrically, intravenously, or as a component of a solid diet eaten ad libitum. In all cases l ... Link to item Cite

Heterogeneity of somatostatin like immunoreactivity (SLI) in extracts of porcine, canine and human pancreas.

Journal Article Acta Endocrinol (Copenh) · December 1981 Four different extraction procedure representative of methods commonly employed in the isolation of somatostatin like immunoreactivity (SLI) were tested for their ability to extract large MW forms of SLI from porcine, canine and human pancreas. The yield o ... Full text Link to item Cite