Scholars@Duke
Thomas Charles Becker

Thomas Charles Becker

Assistant Professor in Medicine
Medicine, Endocrinology, Metabolism, and Nutrition
thomas.becker@duke.edu
Duke Box 3813, Durham, NC 27710
Independence Park Facility, 4321 Medical Park Dr, Suite 200, Durham, NC 27704

Selected Publications

APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.

Journal Article J Clin Invest · January 16, 2024 Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and ... Full text Open Access Link to item Cite

Promises and Limitations of Current Models for Understanding Barrett's Esophagus and Esophageal Adenocarcinoma.

Journal Article Cell Mol Gastroenterol Hepatol · 2024 BACKGROUND & AIMS: This review was developed to provide a thorough and effective update on models relevant to esophageal metaplasia, dysplasia, and carcinogenesis, focusing on the advantages and limitations of different models of Barrett's esophagus (BE) a ... Full text Link to item Cite

HOPX+ injury-resistant intestinal stem cells drive epithelial recovery after severe intestinal ischemia.

Journal Article Am J Physiol Gastrointest Liver Physiol · November 1, 2021 Intestinal ischemia is a life-threatening emergency with mortality rates of 50%-80% due to epithelial cell death and resultant barrier loss. Loss of the epithelial barrier occurs in conditions including intestinal volvulus and neonatal necrotizing enteroco ... Full text Link to item Cite

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

Journal Article Cell Metab · April 6, 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 Link to item Cite

Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice.

Journal Article Biochim Biophys Acta Mol Basis Dis · March 1, 2019 Hexokinase domain containing 1, a recently discovered putative fifth hexokinase, is hypothesized to play key roles in glucose metabolism. Specifically, during pregnancy in a recent genome wide association study (GWAS), a strong correlation between HKDC1 an ... 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

Hepatic HKDC1 Expression Contributes to Liver Metabolism.

Journal Article Endocrinology · February 1, 2019 Glucokinase (GCK) is the principal hexokinase (HK) in the liver, operating as a glucose sensor to regulate glucose metabolism and lipid homeostasis. Recently, we proposed HK domain-containing 1 (HKDC1) to be a fifth HK with expression in the liver. Here, w ... Full text Link to item Cite

Syntaxin 4 Expression in Pancreatic β-Cells Promotes Islet Function and Protects Functional β-Cell Mass.

Journal Article Diabetes · December 2018 Syntaxin 4 (Stx4) enrichment in human and mouse islet grafts improves the success of transplants in reversing streptozotocin (STZ)-induced diabetes in mice, although the underlying molecular mechanisms remain elusive. Toward a further understanding of this ... Full text Link to item Cite

Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas.

Journal Article Nat Commun · October 3, 2017 Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the "genomic recipe" for beta cell expansion, we surveyed 38 human insulinomas to obt ... 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

The Brain-to-Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions.

Journal Article Diabetes · September 2016 The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been f ... 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

Aurora Kinase A is critical for the Nkx6.1 mediated β-cell proliferation pathway.

Journal Article Islets · 2015 Type 1 and type 2 diabetes are ultimately characterized by depleted β-cell mass. Characterization of the molecular pathways that control β-cell proliferation could be harnessed to restore these cells. The homeobox β-cell transcription factor Nkx6.1 induces ... 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

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

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

Relationship among brain and blood glucose levels and spontaneous and glucoprivic feeding.

Journal Article J Neurosci · May 27, 2009 Although several studies implicate small declines in blood glucose levels as stimulus for spontaneous meal initiation, no mechanism is known for how these dips might initiate feeding. To assess the role of ventromedial hypothalamus (VMH) (arcuate plus vent ... Full text Link to item Cite

Small interfering RNA-mediated suppression of proislet amyloid polypeptide expression inhibits islet amyloid formation and enhances survival of human islets in culture.

Journal Article Diabetes · November 2008 OBJECTIVE: Islet amyloid, formed by aggregation of the beta-cell peptide islet amyloid polypeptide (IAPP; amylin), is a pathological characteristic of pancreatic islets in type 2 diabetes. Toxic IAPP aggregates likely contribute to the progressive loss of ... 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

Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia.

Journal Article Diabetes · May 2008 OBJECTIVE: The counterregulatory response to insulin-induced hypoglycemia is mediated by the ventromedial hypothalamus (VMH), which contains specialized glucosensing neurons, many of which use glucokinase (GK) as the rate-limiting step in glucose's regulat ... 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

CCAAT/enhancer-binding protein beta deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice.

Journal Article J Biol Chem · May 25, 2007 CCAAT/enhancer-binding protein beta (C/EBPbeta) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBPbeta in hepatic lipogenesis remains undefined. Here we show that C/EBPbeta inactivation ... 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

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

p38 Mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis.

Journal Article J Biol Chem · December 30, 2005 Hepatic gluconeogenesis is essential for maintaining blood glucose levels during fasting and is the major contributor to postprandial and fasting hyperglycemia in diabetes. Gluconeogenesis is a classic cAMP/protein kinase A-dependent process initiated by g ... 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

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

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

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

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

Aminoimidazole carboxamide ribonucleoside toxicity: a model for study of pyrimidine starvation.

Journal Article J Cell Physiol · June 1981 Aminoimidazole carboxamide ribonucleoside (AIC-R), a purine precursor, has biphasic effects on the growth of Chinese hamster fibroblasts. At 200 microM AIC-R cell growth is almost completely arrested, while at 50 and 700 microM AIC-R cell growth is compara ... Full text Link to item Cite