Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor.

Activation of the hepatoportal glucose sensors by portal glucose infusion leads to increased glucose clearance and induction of hypoglycemia. Here, we investigated whether glucagon-like peptide-1 (GLP-1) could modulate the activity of these sensors. Mice were therefore infused with saline (S-mice) or glucose (P-mice) through the portal vein at a rate of 25 mg/kg. min. In P-mice, glucose clearance increased to 67.5 +/- 3.7 mg/kg. min as compared with 24.1 +/- 1.5 mg/kg. min in S-mice, and glycemia decreased from 5.0 +/- 0.1 to 3.3 +/- 0.1 mmol/l at the end of the 3-h infusion period. Coinfusion of GLP-1 with glucose into the portal vein at a rate of 5 pmol/kg. min (P-GLP-1 mice) did not increase the glucose clearance rate (57.4 +/- 5.0 ml/kg. min) and hypoglycemia (3.8 +/- 0.1 mmol/l) observed in P-mice. In contrast, coinfusion of glucose and the GLP-1 receptor antagonist exendin-(9-39) into the portal vein at a rate of 0.5 pmol/kg. min (P-Ex mice) reduced glucose clearance to 36.1 +/- 2.6 ml/kg. min and transiently increased glycemia to 9.2 +/- 0.3 mmol/l at 60 min of infusion before it returned to the fasting level (5.6 +/- 0.3 mmol/l) at 3 h. When glucose and exendin-(9-39) were infused through the portal and femoral veins, respectively, glucose clearance increased to 70.0 +/- 4.6 ml/kg. min and glycemia decreased to 3.1 +/- 0.1 mmol/l, indicating that exendin-(9-39) has an effect only when infused into the portal vein. Finally, portal vein infusion of glucose in GLP-1 receptor(-/-) mice failed to increase the glucose clearance rate (26.7 +/- 2.9 ml/kg. min). Glycemia increased to 8.5 +/- 0.5 mmol/l at 60 min and remained elevated until the end of the glucose infusion (8.2 +/- 0.4 mmol/l). Together, our data show that the GLP-1 receptor is part of the hepatoportal glucose sensor and that basal fasting levels of GLP-1 sufficiently activate the receptor to confer maximum glucose competence to the sensor. These data demonstrate an important extrapancreatic effect of GLP-1 in the control of glucose homeostasis.

[1]  Xia Li,et al.  Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[2]  R. Burcelin,et al.  Portal glucose infusion in the mouse induces hypoglycemia: evidence that the hepatoportal glucose sensor stimulates glucose utilization. , 2000, Diabetes.

[3]  R. Burcelin,et al.  Glucose sensing by the hepatoportal sensor is GLUT2-dependent: in vivo analysis in GLUT2-null mice. , 2000, Diabetes.

[4]  A. Niijima,et al.  The hepatic vagal reception of intraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor. , 2000, Journal of the autonomic nervous system.

[5]  J. Holst,et al.  Glucagon-Like Peptide-1-(7-36)Amide Is Transformed to Glucagon-Like Peptide-1-(9-36)Amide by Dipeptidyl Peptidase IV in the Capillaries Supplying the L Cells of the Porcine Intestine1. , 1999, Endocrinology.

[6]  D. Drucker,et al.  Exendin-(9-39) Is an Inverse Agonist of the Murine Glucagon-Like Peptide-1 Receptor: Implications for Basal Intracellular Cyclic Adenosine 3',5'-Monophosphate Levels and β-Cell Glucose Competence* *This work was supported by Grant 31-46958.96 from the Swiss National Science Foundation (to B.T.). , 1998, Endocrinology.

[7]  R. Bergman,et al.  Novel Glucosensor for Hypoglycemic Detection Localized to the Portal Vein , 1997, Diabetes.

[8]  K. Jungermann,et al.  Sensing by intrahepatic muscarinic nerves of a portal‐arterial glucose concentration gradient as a signal for insulin‐dependent glucose uptake in the perfused rat liver , 1997, FEBS letters.

[9]  A. Niijima,et al.  The hepatic vagal nerve is receptive to incretin hormone glucagon-like peptide-1, but not to glucose-dependent insulinotropic polypeptide, in the portal vein. , 1996, Journal of the autonomic nervous system.

[10]  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.

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

[12]  L. Rossetti,et al.  Neural and pancreatic influences on net hepatic glucose uptake and glycogen synthesis. , 1996, The American journal of physiology.

[13]  A. Niijima.  Afferent impulse discharges from glucoreceptors in the liver of the guinea pig. , 1996, Nutrition.

[14]  M. Moore,et al.  The nerves, the liver, and the route of feeding: an integrated response to nutrient delivery. , 1996, Nutrition.

[15]  F M Matschinsky,et al.  A Lesson in Metabolic Regulation Inspired by the Glucokinase Glucose Sensor Paradigm , 1996, Diabetes.

[16]  B. Göke,et al.  Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. , 1993, The Journal of biological chemistry.

[17]  G. Waeber,et al.  Glucagon-Like Peptide-I and the Control of Insulin Secretion in the Normal State and in NIDDM , 1993, Diabetes.

[18]  Dawson Ly.  Proposed Medicare changes not favorable for individuals with diabetes. , 1993 .

[19]  A. Cherrington,et al.  Magnitude of Negative Arterial-Portal Glucose Gradient Alters Net Hepatic Glucose Balance in Conscious Dogs , 1991, Diabetes.

[20]  K. Jungermann,et al.  A portal‐arterial glucose concentration gradient as a signal for an insulin‐dependent net glucose uptake in perfused rat liver , 1986, FEBS letters.

[21]  A. Niijima.  Blood glucose levels modulate efferent activity in the vagal supply to the rat liver. , 1985, The Journal of physiology.

[22]  Y. Oomura,et al.  Convergence of hepatoportal glucose-sensitive afferent signals to glucose-sensitive units within the nucleus of the solitary tract , 1984, Neuroscience Letters.

[23]  Y. Oomura,et al.  Functional correlations between lateral hypothalamic glucose-sensitive neurons and hepatic portal glucose-sensitive units in rat , 1983, Brain Research.

[24]  H. Berthoud,et al.  Evidence for a role of the gastric, coeliac and hepatic branches in vagally stimulated insulin secretion in the rat. , 1983, Journal of the autonomic nervous system.

[25]  M. Schmitt.  Influences of hepatic portal receptors on hypothalamic feeding and satiety centers. , 1973, The American journal of physiology.

[26]  R. Bergman,et al.  Portal vein afferents are critical for the sympathoadrenal response to hypoglycemia. , 2000, Diabetes.

[27]  C. Orskov,et al.  Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. , 1999, Endocrinology.

[28]  W. Dolci,et al.  Exendin-(9-39) is an inverse agonist of the murine glucagon-like peptide-1 receptor: implications for basal intracellular cyclic adenosine 3',5'-monophosphate levels and beta-cell glucose competence. , 1998, Endocrinology.

[29]  A. Cherrington,et al.  Comparison of the time courses of insulin and the portal signal on hepatic glucose and glycogen metabolism in the conscious dog. , 1996, The Journal of clinical investigation.

[30]  W. Creutzfeldt.  Entero-insular axis and diabetes mellitus. , 1992, Hormone and metabolic research. Supplement series.