Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice.

Glucagon-like peptide-1 (GLP-1) circulates at low levels and acts as an incretin hormone, potentiating glucose-dependent insulin secretion from islet β cells. GLP-1 also modulates gastric emptying and engages neural circuits in the portal region and CNS that contribute to GLP-1 receptor-dependent (GLP-1R-dependent) regulation of glucose homeostasis. To elucidate the importance of pancreatic GLP-1R signaling for glucose homeostasis, we generated transgenic mice that expressed the human GLP-1R in islets and pancreatic ductal cells (Pdx1-hGLP1R:Glp1r-/- mice). Transgene expression restored GLP-1R-dependent stimulation of cAMP and Akt phosphorylation in isolated islets, conferred GLP-1R-dependent stimulation of β cell proliferation, and was sufficient for restoration of GLP-1-stimulated insulin secretion in perifused islets. Systemic GLP-1R activation with the GLP-1R agonist exendin-4 had no effect on food intake, hindbrain c-fos expression, or gastric emptying but improved glucose tolerance and stimulated insulin secretion in Pdx1-hGLP1R:Glp1r-/- mice. i.c.v. GLP-1R blockade with the antagonist exendin(9-39) impaired glucose tolerance in WT mice but had no effect in Pdx1-hGLP1R:Glp1r-/- mice. Nevertheless, transgenic expression of the pancreatic GLP-1R was sufficient to normalize both oral and i.p. glucose tolerance in Glp1r-/- mice. These findings illustrate that low levels of endogenous GLP-1 secreted from gut endocrine cells are capable of augmenting glucoregulatory activity via pancreatic GLP-1Rs independent of communication with neural pathways.

[1]  J. Holst,et al.  Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice. , 2011, Endocrinology.

[2]  H. Raybould,et al.  Effect of ghrelin receptor antagonist on meal patterns in cholecystokinin type 1 receptor null mice , 2011, Physiology & Behavior.

[3]  D. Drucker,et al.  Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis. , 2011, The Journal of clinical investigation.

[4]  D. Drucker,et al.  GPR119 regulates murine glucose homeostasis through incretin receptor-dependent and independent mechanisms. , 2011, Endocrinology.

[5]  D. Drucker,et al.  Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice , 2011, Diabetologia.

[6]  T. Lam,et al.  Intestinal cholecystokinin controls glucose production through a neuronal network. , 2009, Cell metabolism.

[7]  Diana L. Williams,et al.  Minireview: finding the sweet spot: peripheral versus central glucagon-like peptide 1 action in feeding and glucose homeostasis. , 2009, Endocrinology.

[8]  D. Drucker,et al.  Glucagon-Like Peptide-1 Receptor Activation Modulates Pancreatitis-Associated Gene Expression But Does Not Modify the Susceptibility to Experimental Pancreatitis in Mice , 2009, Diabetes.

[9]  S. Woods,et al.  Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity , 2009, The Journal of Neuroscience.

[10]  J. Kushner,et al.  Adaptive β-Cell Proliferation Is Severely Restricted With Advanced Age , 2009, Diabetes.

[11]  T. Gurlo,et al.  Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice , 2009, Diabetes.

[12]  D. Drucker,et al.  Brain Glucagon-Like Peptide-1 Regulates Arterial Blood Flow, Heart Rate, and Insulin Sensitivity , 2008, Diabetes.

[13]  S. Woods,et al.  Arcuate Glucagon-Like Peptide 1 Receptors Regulate Glucose Homeostasis but Not Food Intake , 2008, Diabetes.

[14]  R. Bergman,et al.  Exenatide can reduce glucose independent of islet hormones or gastric emptying. , 2008, American journal of physiology. Endocrinology and metabolism.

[15]  R. Seeley,et al.  Role of Central Nervous System Glucagon-Like Peptide-1 Receptors in Enteric Glucose Sensing , 2008, Diabetes.

[16]  D. Drucker,et al.  An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis. , 2008, Gastroenterology.

[17]  R. Seeley,et al.  The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. , 2008, Annual review of physiology.

[18]  M. Lazar,et al.  Adipokines and the peripheral and neural control of energy balance. , 2008, Molecular endocrinology.

[19]  D. Drucker,et al.  Differential Antidiabetic Efficacy of Incretin Agonists Versus DPP-4 Inhibition in High Fat–Fed Mice , 2008, Diabetes.

[20]  S. Woods,et al.  Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats. , 2007, Endocrinology.

[21]  L. Sheu,et al.  Interaction Between Munc13-1 and RIM Is Critical for Glucagon-Like Peptide-1–Mediated Rescue of Exocytotic Defects in Munc13-1–Deficient Pancreatic β-Cells , 2007, Diabetes.

[22]  J. Holst,et al.  Exendin-4, but not dipeptidyl peptidase IV inhibition, increases small intestinal mass in GK rats. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[23]  D. Cummings,et al.  Gastrointestinal regulation of food intake. , 2007, The Journal of clinical investigation.

[24]  Tanya Hansotia,et al.  Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. , 2007, The Journal of clinical investigation.

[25]  D. Drucker,et al.  The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes , 2006, The Lancet.

[26]  P. Scherer.  Adipose Tissue , 2006, Diabetes.

[27]  C. Kahn,et al.  Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. , 2005, The Journal of clinical investigation.

[28]  D. Dardevet,et al.  Insulin secretion-independent effects of GLP-1 on canine liver glucose metabolism do not involve portal vein GLP-1 receptors. , 2005, American journal of physiology. Gastrointestinal and liver physiology.

[29]  H. Friess,et al.  Delayed Gastric Emptying and Intestinal Hormones following Pancreatoduodenectomy , 2005, Pancreatology.

[30]  A. Pocai,et al.  Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism , 2005, Science.

[31]  R. Bergman,et al.  Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones , 2005, Diabetologia.

[32]  J. Bryan,et al.  Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis , 2005, Nature Medicine.

[33]  D. Drucker,et al.  A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. , 2004, Diabetes.

[34]  J. Holst,et al.  Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. , 2004, American journal of physiology. Endocrinology and metabolism.

[35]  D. Drucker,et al.  Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. , 2004, Gastroenterology.

[36]  J. Holst,et al.  Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. , 2004, Diabetes.

[37]  T. Kigoshi,et al.  Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells , 2004, Autonomic Neuroscience.

[38]  R. Seeley,et al.  CNS Glucagon-Like Peptide-1 Receptors Mediate Endocrine and Anxiety Responses to Interoceptive and Psychogenic Stressors , 2003, The Journal of Neuroscience.

[39]  A. Cherrington,et al.  Effect of intraportal glucagon-like peptide-1 on glucose metabolism in conscious dogs. , 2003, American journal of physiology. Endocrinology and metabolism.

[40]  D. Drucker,et al.  Glucagon-Like Peptide-1-Responsive Catecholamine Neurons in the Area Postrema Link Peripheral Glucagon-Like Peptide-1 with Central Autonomic Control Sites , 2003, The Journal of Neuroscience.

[41]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[42]  D. Drucker,et al.  Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor. , 2001, Diabetes.

[43]  S. Bustin.  Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. , 2000, Journal of molecular endocrinology.

[44]  S. Bonner-Weir,et al.  Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. , 1999, Diabetes.

[45]  M. Prentki,et al.  Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells , 1999, Diabetologia.

[46]  A. Cherrington,et al.  Banting Lecture 1997. Control of glucose uptake and release by the liver in vivo. , 1999, Diabetes.

[47]  A. Edvell,et al.  Initiation of Increased Pancreatic Islet Growth in Young Normoglycemic Mice (Umeå +/?). , 1999, Endocrinology.

[48]  M. Nauck.  Is glucagon-like peptide 1 an incretin hormone? , 1999, Diabetologia.

[49]  P. Shughrue,et al.  Distribution of pre‐pro‐glucagon and glucagon‐like peptide‐1 receptor messenger RNAs in the rat central nervous system , 1999, The Journal of comparative neurology.

[50]  P. J. Larsen,et al.  Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem , 1997, Neuroscience.

[51]  A. Joyner,et al.  Glucose intolerance but normal satiety in mice with a null mutation in the glucagon–like peptide 1 receptor gene , 1996, Nature Medicine.

[52]  A. Niijima,et al.  Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP-1. , 1996, The American journal of physiology.

[53]  D. Smith,et al.  A role for glucagon-like peptide-1 in the central regulation of feeding , 1996, Nature.

[54]  D. Drucker,et al.  Glucagon gene expression in vertebrate brain. , 1988, The Journal of biological chemistry.

[55]  J. Lauder,et al.  Distribution of glucagonlike peptide I (GLP‐I), glucagon, and glicentin in the rat brain: An immunocytochemical study , 1988, The Journal of comparative neurology.

[56]  K. Shima,et al.  Identification and localization of glucagon-like peptide-1 and its receptor in rat brain. , 1987, Endocrinology.

[57]  D. Drucker,et al.  Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[58]  D. Drucker,et al.  GPR 119 Regulates Murine Glucose Homeostasis Through Incretin Receptor-Dependent and Independent Mechanisms , 2010 .

[59]  J. Rosenstock,et al.  The Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes: A Randomized Controlled Trial Exploring Weekly, Biweekly, and Monthly Dosing Running title: Albiglutide dose regimen study , 2009 .

[60]  J. Kushner,et al.  ADAPTIVE BETA CELL PROLIFERATION IS SEVERELY RESTRICTED WITH ADVANCED AGE , 2009 .

[61]  D. Drucker,et al.  GLP-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice , 2009 .

[62]  P. Scherer.  From Lipid Storage Compartment to Endocrine Organ , 2006 .

[63]  C. Saper,et al.  Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. , 2002, The Journal of clinical investigation.

[64]  J. Habener,et al.  Developmental expression of the homeodomain protein IDX-1 in mice transgenic for an IDX-1 promoter/lacZ transcriptional reporter. , 1999, Endocrinology.

[65]  S. Bloom,et al.  Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. , 1999, Endocrinology.

[66]  S. Bloom,et al.  Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. , 1999, Diabetes.

[67]  B. Yeğen,et al.  Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. , 1997, The American journal of physiology.

[68]  清水 一郎.  Identification and localization of glucagon-like peptide-1 and its receptor in rat brain , 1987 .