Journal ArticleNat Rev Endocrinol · March 7, 2025
The pancreatic islets of Langerhans are central to fine-tuning metabolism to ensure metabolic homeostasis during the transition between fasting and feeding. Insulin and glucagon, the principal hormones generated and secreted by islets, exert powerful contr ...
Full textLink to itemCite
Journal ArticlePeptides · May 2024
Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are transmembrane receptors involved in insulin, glucagon and somatostatin secretion from the pancreatic islet. Therapeutic targeting of GLP1R and GIP ...
Full textLink to itemCite
Journal ArticleCell Metab · September 5, 2023
The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1), which have cogn ...
Full textLink to itemCite
Journal ArticleMol Metab · June 2023
OBJECTIVE: Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RA) and fibroblast growth factor-21 (FGF21) confer similar metabolic benefits. GLP-1RA induce FGF21, leading us to investigate mechanisms engaged by the GLP-1RA liraglutide to increase FGF ...
Full textLink to itemCite
Journal ArticleNat Metab · June 2023
The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance1. The GLP-1 receptor (GLP-1R) is an established drug ta ...
Full textLink to itemCite
Journal ArticleCell Metab · November 1, 2022
The evolution of glucagon has seen the transition from an impurity in the preparation of insulin to the development of glucagon receptor agonists for use in type 1 diabetes. In type 2 diabetes, glucagon receptor antagonists have been explored to reduce gly ...
Full textLink to itemCite
Journal ArticleMol Metab · April 2021
BACKGROUND: Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP's biology was quick ...
Full textLink to itemCite
Journal ArticleSci Adv · March 2021
Glucose-dependent insulinotropic polypeptide (GIP) communicates nutrient intake from the gut to islets, enabling optimal levels of insulin secretion via the GIP receptor (GIPR) on β cells. The GIPR is also expressed in α cells, and GIP stimulates glucagon ...
Full textLink to itemCite
Journal ArticleAm 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 textLink to itemCite
Journal ArticleJCI Insight · September 3, 2020
Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outco ...
Full textLink to itemCite
Journal ArticleJ Biol Chem · August 14, 2020
The insulinotropic actions of glucagon-like peptide 1 receptor (GLP-1R) in β-cells have made it a useful target to manage type 2 diabetes. Metabolic stress reduces β-cell sensitivity to GLP-1, yet the underlying mechanisms are unknown. We hypothesized that ...
Full textLink to itemCite
Journal ArticleSci Adv · August 2020
There is great interest in identifying a glucagon-like peptide-1 (GLP-1)-based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplore ...
Full textLink to itemCite
Journal ArticleCell Metab · May 5, 2020
Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enz ...
Full textLink to itemCite
Journal ArticleDiabetes · May 2020
Glucagon is classically described as a counterregulatory hormone that plays an essential role in the protection against hypoglycemia. In addition to its role in the regulation of glucose metabolism, glucagon has been described to promote ketosis in the fas ...
Full textLink to itemCite
Journal ArticleDiabetes · April 2020
Glucagon is historically described as the counterregulatory hormone to insulin, induced by fasting/hypoglycemia to raise blood glucose through action mediated in the liver. However, it is becoming clear that the biology of glucagon is much more complex and ...
Full textLink to itemCite
Journal ArticlePeptides · March 2020
Glucose-dependent insulinotropic polypeptide (GIP) is an intestinally derived peptide that is secreted in response to feeding. The GIP receptor (GIPR) is expressed in many cell types involved in the regulation of metabolism, including α- and β-cells. Gluca ...
Full textLink to itemCite
Journal ArticleMol Metab · February 2020
OBJECTIVE: Glucose-dependent insulinotropic polypeptide is an intestinally derived hormone that is essential for normal metabolic regulation. Loss of the GIP receptor (GIPR) through genetic elimination or pharmacological antagonism reduces body weight and ...
Full textLink to itemCite
Journal ArticleExp Physiol · February 2020
What is the central question of the study? Does the action of l-citrulline, which has been shown to augment performance in animals and athletes, possibly via increasing mitochondrial function, translate to obese animals, and does this improve glycaemia? Wh ...
Full textLink to itemCite
Journal ArticleMol Metab · October 2019
OBJECTIVE: Bariatric surgery acutely improves glucose control, an effect that is generally sustained for years in most patients. The acute postoperative glycemic reduction is at least partially mediated by enhanced incretin secretion and islet function, an ...
Full textLink to itemCite
Journal ArticleMol Metab · October 2019
OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) is secreted from the gut in response to nutrient ingestion and promotes meal-dependent insulin secretion and lipid metabolism. Loss or attenuation of GIP receptor (GIPR) action leads to resistan ...
Full textLink to itemCite
Journal ArticleJ Clin Invest · October 1, 2019
Genome-wide association studies (GWAS) have provided a wealth of information on potential disease-associated genes in the human population. In particular, several loci have been associated with type 2 diabetes (T2D). However, due to the complexity of the d ...
Full textLink to itemCite
Journal ArticleDiabetes · September 2019
Exogenous ghrelin reduces glucose-stimulated insulin secretion and endogenous ghrelin protects against hypoglycemia during starvation. Islet ε-cells produce ghrelin and δ-cells express growth hormone secretagogue receptor (GHSR), suggesting the possibility ...
Full textLink to itemCite
Journal ArticleJCI Insight · July 23, 2019
Glucagon and insulin are commonly believed to have counteracting effects on blood glucose levels. However, recent studies have demonstrated that glucagon has a physiologic role to activate β-cells and enhance insulin secretion. To date, the actions of gluc ...
Full textLink to itemCite
Journal ArticleMol Metab · April 2019
OBJECTIVE: Administration of glucagon (GCG) or GCG-containing co-agonists reduces body weight and increases energy expenditure. These actions appear to be transduced by multiple direct and indirect GCG receptor (GCGR)-dependent mechanisms. Although the can ...
Full textLink to itemCite
Journal ArticleJCI Insight · March 21, 2019
Bariatric surgeries including vertical sleeve gastrectomy (VSG) ameliorate obesity and diabetes. Weight loss and accompanying increases to insulin sensitivity contribute to improved glycemia after surgery; however, studies in humans also suggest weight-ind ...
Full textLink to itemCite
Journal ArticleJCI Insight · March 7, 2019
Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α to β cell communication and con ...
Full textLink to itemCite
Journal ArticleCell Metab · February 5, 2019
Dipeptidyl peptidase-4 (DPP-4) controls glucose homeostasis through enzymatic termination of incretin action. We report that plasma DPP-4 activity correlates with body weight and fat mass, but not glucose control, in mice. Genetic disruption of adipocyte D ...
Full textLink to itemCite
Journal ArticleEndocr Rev · October 1, 2018
Glucagonlike peptide 1 (GLP-1) receptor agonists have been efficacious for the treatment of type 2 diabetes due to their ability to reduce weight and attenuate hyperglycemia. However, the activity of glucagonlike peptide 1 receptor-directed strategies is s ...
Full textLink to itemCite
Journal ArticleDiabetes · August 2018
Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in ...
Full textLink to itemCite
Journal ArticleDiabetologia · August 2018
AIMS/HYPOTHESIS: Cre-loxP systems are frequently used in mouse genetics as research tools for studying tissue-specific functions of numerous genes/proteins. However, the expression of Cre recombinase in a tissue-specific manner often produces undesirable c ...
Full textLink to itemCite
Journal ArticleCell 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 textLink to itemCite
Journal ArticleCell Metab · February 6, 2018
Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impai ...
Full textLink to itemCite
Journal ArticleDiabetes · June 2017
GPR119 was originally identified as an orphan β-cell receptor; however, subsequent studies demonstrated that GPR119 also regulates β-cell function indirectly through incretin hormone secretion. We assessed the importance of GPR119 for β-cell function in Gp ...
Full textLink to itemCite
Journal ArticleCell Metab · April 4, 2017
Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control h ...
Full textLink to itemCite
Journal ArticleJ Clin Invest · March 1, 2017
Glucagon-like peptide 1 receptor (GLP-1R) signaling in the CNS has been linked to reduced food intake, lower body weight, improved glucose homeostasis, and activation of CNS stress axes. GLP-1 is produced by cells that express proglucagon (GCG); however, t ...
Full textLink to itemCite
Journal ArticleCell Metab · January 10, 2017
Pharmacological inhibition of the dipeptidyl peptidase-4 (DPP4) enzyme potentiates incretin action and is widely used to treat type 2 diabetes. Nevertheless, the precise cells and tissues critical for incretin degradation and glucose homeostasis remain unk ...
Full textLink to itemCite
Journal ArticleDiabetes · March 2016
Dipeptidyl peptidase-4 (DPP4) inhibitors used for the treatment of type 2 diabetes are cardioprotective in preclinical studies; however, some cardiovascular outcome studies revealed increased hospitalization rates for heart failure (HF) among a subset of D ...
Full textLink to itemCite
Journal ArticleNat Med · January 2016
The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabet ...
Full textLink to itemCite
Journal ArticleCardiovascular Endocrinology · January 1, 2016
The gut incretin hormone, glucagon-like peptide 1 (GLP-1), regulates islet hormone secretion, circulating glucose levels, and body weight, making it an attractive agent for the treatment of type 2 diabetes. As cardiovascular disease represents the leading ...
Full textCite
Journal ArticleDiabetes · November 2015
There is growing concern over confounding artifacts associated with β-cell-specific Cre-recombinase transgenic models, raising questions about their general usefulness in research. The inducible β-cell-specific transgenic (MIP-CreERT(1Lphi)) mouse was desi ...
Full textLink to itemCite
Journal ArticleNat Rev Endocrinol · June 2015
Glucagon is secreted from islet α cells and controls blood levels of glucose in the fasting state. Impaired glucagon secretion predisposes some patients with type 1 diabetes mellitus (T1DM) to hypoglycaemia; whereas hyperglycaemia in patients with T1DM or ...
Full textLink to itemCite
Journal ArticleDiabetes · March 2015
Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mec ...
Full textLink to itemCite
Journal ArticleNat Med · January 2015
We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucos ...
Full textLink to itemCite
Journal ArticleMol Metab · August 2014
GLP-1R agonists improve outcomes in ischemic heart disease. Here we studied GLP-1R-dependent adaptive and cardioprotective responses to ventricular injury. Glp1r (-/-) hearts exhibited chamber-specific differences in gene expression, but normal mortality a ...
Full textLink to itemCite
Journal ArticleCell Metab · June 4, 2013
Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and immune function, providing a scientific basis for utilizing incretin-based therapies in th ...
Full textLink to itemCite
Journal ArticleEndocrinology · January 2013
Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce lipid accumulation in peripheral tissues, attenuating atherosclerosis and hepatic steatosis in preclinical studies. We examined whether GLP-1R activation decreases atherosclerosis progression in hig ...
Full textLink to itemCite
Journal ArticleDis Model Mech · September 2012
Glucocorticoids (GCs) are potent pharmacological agents used to treat a number of immune conditions. GCs are also naturally occurring steroid hormones (e.g. cortisol, corticosterone) produced in response to stressful conditions that are thought to increase ...
Full textLink to itemCite
Journal ArticleDiabetes · January 2012
Glucose-dependent insulinotropic polypeptide (GIP) promotes glucose-dependent insulin secretion. However, GIP also enhances glucocorticoid secretion and promotes adiposity. Because obesity and diabetes are glucocorticoid dependent, we examined whether the ...
Full textLink to itemCite
Journal ArticleAm J Physiol Endocrinol Metab · June 2011
Optimal skeletal muscle mass is vital to human health, because defects in muscle protein metabolism underlie or exacerbate human diseases. The mammalian target of rapamycin complex 1 is critical in the regulation of mRNA translation and protein synthesis. ...
Full textLink to itemCite
Journal ArticleAm J Physiol Cell Physiol · January 2011
Glucocorticoids have been proposed to be both adipogenic and lipolytic in action within adipose tissue, although it is unknown whether these actions can occur simultaneously. Here we investigate both the in vitro and in vivo effects of corticosterone (Cort ...
Full textLink to itemCite
Journal ArticlePLoS One · November 17, 2010
This present study investigated the temporal effects of type 1 diabetes mellitus (T1DM) on adolescent skeletal muscle growth, morphology and contractile properties using a 90% partial pancreatecomy (Px) model of the disease. Four week-old male Sprague-Dawl ...
Full textLink to itemCite
Journal ArticleAm J Physiol Regul Integr Comp Physiol · July 2010
We determined the effects of voluntary wheel running on the hypothalamic-pituitary-adrenal (HPA) axis, and the peripheral determinants of glucocorticoids action, in male Zucker diabetic fatty (ZDF) rats. Six-week-old euglycemic ZDF rats were divided into B ...
Full textLink to itemCite
Journal ArticleAm J Physiol Endocrinol Metab · March 2010
Stress-activated systems and oxidative stress are involved in insulin resistance, which, along with beta-cell failure, contribute to the development of type 2 diabetes mellitus (T2DM). Exercise improves insulin resistance and glucose tolerance, and these a ...
Full textLink to itemCite
Journal ArticleMetabolism · May 2009
Glucocorticoids (GCs) have long been thought to be lipolytic in nature. Recently, however, increased exposure to GCs in insulin-sensitive tissues has been associated with lipid accumulation and metabolic complications, regardless of plasma concentrations. ...
Full textLink to itemCite
Journal ArticleJ Appl Physiol (1985) · January 2009
Although exercise is a common and potent activator of the hypothalamic-pituitary adrenal (HPA) axis, the effects of exercise on the acute stress response are not well understood. Here, we investigated the effects of short- (2 wk) and long-term (8 wk) volun ...
Full textLink to itemCite
Journal ArticleAm J Physiol Cell Physiol · March 2007
Streptozotocin (STZ) is used extensively to induce pancreatic beta-cell death and ultimately diabetes mellitus in animal models. However, the direct effects of STZ on muscle are largely unknown. To delineate the effects of STZ from the effects of hypoinsul ...
Full textLink to itemCite
Journal ArticleDiabetes Technol Ther · December 2006
BACKGROUND: Hypoglycemia is the most common and serious side effect of insulin therapy in type 1 diabetes (T1DM), frequently occurring both during and after vigorous exercise. Late-onset hypoglycemia (LOH) is of great concern, occurring 1-36 h after exerci ...
Full textLink to itemCite
Journal ArticleJ Appl Physiol (1985) · June 2006
Adaptations of the hypothalamic-pituitary-adrenal (HPA) axis to voluntary exercise in rodents are not clear, because most investigations use forced-exercise protocols, which are associated with psychological stress. In the present study, we examined the ef ...
Full textLink to itemCite
Journal ArticleJ Appl Physiol (1985) · May 2006
Recent findings indicate that elevated levels of glucocorticoids (GC), governed by the expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and GC receptors (GR), in visceral adipose tissue and skeletal muscle lead to increased insulin re ...
Full textLink to itemCite
Journal ArticlePhysiol Behav · February 28, 2006
To explore the metabolic effects of high volume wheel running in the Syrian golden hamster, 6-week old (YOUNG) and 6-month old (OLD) male animals were randomly divided into sedentary (i.e., YOUNG-S or OLD-S) or running wheel (i.e., YOUNG-RW or OLD-RW) grou ...
Full textLink to itemCite
Journal ArticleJ Immunol · January 15, 2004
Numerous studies have demonstrated the role of regulatory T (Treg) cells in peripheral tolerance. Nevertheless, how the survival and death of Treg cells is controlled is largely unknown. In this study, we investigated the mechanisms involved in regulating ...
Full textLink to itemCite