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The Effects of GLP-1 Analogs in the Portal System

Under normal conditions, the liver plays a critical role in disposing of orally or enterally delivered carbohydrate and therefore in limiting postprandial hyperglycemia. We often think that this response involves only a decrease in hepatic glucose production however there are many studies showing that there is also a stimulation of hepatic glucose uptake.1

The latter is dependent on a number of inputs: circulating concentrations of glucose, nonesterified fatty acids, and amino acids; hormones (insulin); and neural mediators (NO and norepinephrine)2. The route of glucose delivery is responsible for determining as much as 50% of NHGU (net hepatic glucose uptake). The oral, enteral, or portal vein route of delivery brings about a negative arterial-portal vein glucose gradient that elicits a coordinated response of liver and muscle in glucose disposal such that NHGU is enhanced and muscle glucose uptake is suppressed. The portal glucose signal appears to be associated with a change in afferent signaling from the liver to the brain, resulting in a modification of efferent signaling to the liver, likely via sympathetic and/or nitrergic innervation. These signals apparently alleviate a tonic inhibition of NHGU. It appears that in type 2 diabetes, both hepatic glucose production and glucose uptake in the postprandial period are abnormal, in association with a defect in hepatic glucokinase (GK)3,4,5.

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Since glucagon-like peptide-1 (GLP-1) analogs have a profound and well known effect on hepatic glucose production and decrease in postprandial glucose levels, many researchers are studying whether the positive effects of these analogs are also associated with increasing hepatic glucose uptake.

To begin with, there is substantial evidence that there is a portal signal for the release of GLP-1 and the associated glucose-lowering effects6. In related studies, several of the same scientists made the intriguing observation that GLP-1(7-36amide) activated afferent fiber firing from the hepatic vagal nerve and the effect of GLP-1 was not blocked by the GLP-1R antagonist exendin(9-39)7.

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 implicating 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.8

Intraportal infusion of GLP-1 in dogs was subsequently shown to increase primarily non-hepatic glucose disposal9,10 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 secretion11,12. 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 response13

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.14

Could consumption of certain 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.15,16 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.17

These and numerous other studies point to the value of GLP-1 analogs in increasing hepatic glucose uptake as well as decreasing hepatic glucose production in diabetes patients. It will be interesting to see if in the future, we will be able to differentiate between the NHGU effect of GLP-1 analogs, and if prescribing habits will include a consideration of this factor.

References:
  1. Cherrington AD. Banting Lecture 1997. Control of glucose uptake and release by the liver in vivo. Diabetes. 1999;48:1198–214
  2. Adkins-Marshall B, Pagliassotti MJ, Asher JR, Connolly CC, Neal DW, Williams PE, Myers SR, Hendrick GK, Adkins RB Jr., Cherrington AD. Role of hepatic nerves in response of liver to intraportal glucose delivery in dogs. Am J Physiol. 1992;262:E679–86
  3. Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism: evidence for a defect in hepatic glucokinase activity. Diabetes. 2000;49:272–83
  4. Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism: evidence for a defect in hepatic glucokinase activity. Diabetes. 2000;49:272–83.
  5. Hyperglycemia acutely lowers the postprandial excursions of glucagon-like Peptide-1 and gastric inhibitory polypeptide in humans. J Clin Endocrinol Metab. 2009;94:1379–85
  6. Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP-1. Am J Physiol. 1996 Nov;271(5 Pt 1):E808-13.
  7. 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
  8. 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
  9. Effect of intraportal glucagon-like peptide-1 on glucose metabolism in conscious dogs. Am J Physiol Endocrinol Metab. 2003 May;284(5):E1027-36
  10. Am J Physiol Endocrinol Metab. 2007 Aug 7; [Epub ahead of print]
  11. 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
  12. Exenatide can reduce glucose independent of islet hormones or gastric emptying. Am J Physiol Endocrinol Metab. 2008 May 20.
  13. Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones. Diabetologia. 2005 May;48(5):967-75.
  14. 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
  15. Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like Peptide-1. Obes Res. 2005 Jun;13(6):1000-7
  16. 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
  17. Improvement of Glucose Tolerance and Hepatic Insulin Sensitivity by Oligofructose Requires a Functional Glucagon-Like Peptide 1 Receptor,Diabetes 2006 55: 1484-1490