What is the role of GLP-1 in the portal system?
The importance of a portal signal for the glucose-lowering effects of GLP-1 was demonstrated in Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP-1. Am J Physiol. 1996 Nov;271(5 Pt 1):E808-13.
In related studies, several of the same scientists made the intriguing observation that GLP-1(7-36amide) but not exendin-4, activated afferent fibre firing from the hepatic vagal nerve and the effect of GLP-1 was not blocked by theGLP-1R antagonist exendin(9-39) as described in The hepatic vagal reception of intraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor. J Auton Nerv Syst. 2000 Apr 12;80(1-2):14-21
Subsequent experiments demonstrated that intraportal GLP-1 makedly augmented insulin secretion and glucose clearance and the effects of portal GLP-1 on insulin secretion were blocked by the ganglionic blocker chlorisondamine as shown in Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. Am J Physiol Regul Integr Comp Physiol. 2000 Oct;279(4):R1449-54.
The portal glucose sensor represents an incompletely understood entity that contributes to the sensing of ambient circulating glucose in the hepatoportal region. The molecular identity of the portal glucose sensor remains a subject of intense interest. Using a combination of +/+ mice and the GLP-1 Receptor antagonist exendin (9-39), and GLP-1R-/- knockout mice, Remy Burcelin, and colleagues provided new evidence implication a role for basal levels of portal GLP-1 in the enhanced glucose clearance seen after portal glucose entry. Pharmacological or genetic disruption of GLP-1 receptor signaling completely abrogated the enhanced glucose clearance seen after portal glucose challenge. These findings expand our knowledge of GLP-1 action, and the GLP-1 receptor now appears to function as at least one component of an integrated physiologically relevant glucose sensor. See Glucose Competence of the Hepatoportal Vein Sensor Requires the Presence of an Activated Glucagon-Like Peptide-1 Receptor. Diabetes. 2001 Aug;50(8):1720-8
Intraportal infusion of GLP-1 in dogs was subsequently shown to increase primarily non-hepatic glucose disposal as demonstrated in Effect of intraportal glucagon-like peptide-1 on glucose metabolism in conscious dogs. Am J Physiol Endocrinol Metab. 2003 May;284(5):E1027-36 and Intraportal GLP-1 Infusion Increases Non-Hepatic Glucose Utilization without Changing Pancreatic Hormone Levels. Am J Physiol Endocrinol Metab. 2007 Aug 7; [Epub ahead of print] wherein intraportal GLP-1 enhanced non-hepatic glucose disposal without detectable changes in plasma levels of insulin or glucagon. Hence, several studies have shown that GLP-1, administered intraportally or systemically, increased glucose disposal in the liver independently of insulin secretion. See Insulin-independent effects of GLP-1 on canine liver glucose metabolism: duration of infusion and involvement of hepatoportal region. Am J Physiol Endocrinol Metab. 2004 Jul;287(1):E75-81 and EXENATIDE CAN REDUCE GLUCOSE INDEPENDENT OF ISLET HORMONES OR GASTRIC EMPTYING. Am J Physiol Endocrinol Metab. 2008 May 20. [Epub ahead of print]
Consistent with data from rodent studies, intraportal GLP-1 also promotes glucose clearance in dogs beyond simply stimulation of insulin secretion, in association with a marked induction of a counterregulatory hormone response as shown in Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones. Diabetologia. 2005 Diabetologia. 2005 May;48(5):967-75.
Notably however, peripheral infusion of glucose together with simultaneous intraportal GLP-1 infusion did not enhance whole body glucose clearance, emphasizing the importance of a simultaneous increase in both portal glucose and endogenous GLP-1 for triggering the portal glucose sensor. See Intraportally Delivered GLP-1, in the Presence of Hyperglycemia Induced via Peripheral Glucose Infusion, Does Not Change Whole Body Glucose Utilization Am J Physiol Endocrinol Metab. 2007 Dec 4;
Can nutrients exert anti-diabetic actions via enhancement of GLP-1 secretion and potentiation of the portal GLP-1 signal? Several studies correlate an antidiabetic effect of oligofructose (OF), together with reduced weight gain with an increase in portal and/or plasma levels of GLP-1 in rodents, as described in Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like Peptide-1. Obes Res. 2005 Jun;13(6):1000-7 and Involvement of endogenous glucagon-like peptide-1(7-36) amide on glycaemia-lowering effect of oligofructose in streptozotocin-treated rats. J Endocrinol. 2005 Jun;185(3):457-65. The central role of GLP-1 receptor signaling as an essential element for the anti-diabetic actions of oligofructose has been demonstrated in high fat fed mice. Administration of the GLP-1R antagonist exendin(9-39) completely blocks the therapeutic benefit of oligofructose, and OF does not exert glucose-lowering actions in GLP-1R-/- mice. See Improvement of Glucose Tolerance and Hepatic Insulin Sensitivity by Oligofructose Requires a Functional Glucagon-Like Peptide 1 Receptor Diabetes 2006 55: 1484-1490