Mechanism

Receptor agonism and antagonism:
The actions of GLP-1 are mediated by receptors that are expressed in the pancreatic islet, the parietal cells of the stomach, lung, and neural tissue. Endocrinology. 1996 Jul;137(7):2968-78.   Presence of GLP-1 receptors in liver and skeletal  muscle have not yet been demonstrated. GLP-1 receptors are found in high concentrations in the blood brain barrier deficient areas as the floor of the fourth ventricle, as well as hypothalamic and pituitary areas. Mice with a null mutation in the GLP-1 receptor gene develop glucose intolerance. Nat Med. 1996 Nov;2(11):1254-8.   GLP-1 receptor antagonist or GLP-1 antisera have been shown to reduce meal-stimulated insulin secretion in animals and humans.  Diabetes. 1999 Jan;48(1):86-93      Competitive antagonism of GLP-1 receptor signalling in rats causes impaired glucose tolerance. Diabetes. 2002;44:16-19.  Disrupting the GLP-1 receptor gene in mice produced fasting hyperglycaemia as well as impaired oral glucose tolerance with decreased insulin secretion. Nat Med. 1996 Nov;2(11):1254-8. Body weight and feeding were not affected in these GLP1R-/- mice.

Brain Effects:
 GLP-1 is an incretin hormone in the gut and a Neuropeptide in the brain. GLP-1 in the brain is mainly located in the cells of the nucleus of tractus solitarius and the area postrema. J Comp Neurol. 1988 May 22;271(4):519-32.   GLP-1 reduces caloric intake in the rat possibly via a direct action on the satiety centre in the brain. Activation of GLP-1 receptors after acute intra-cerebroventricular GLP-1 administration to rats resulted in a reduction of food intake.  GLP-1 penetrates the BBB poorly, and hence neurohumoral signals from the gut may be conveyed to the NTS via the BBB-free area postrema and gastric vagal afferents which impinge on central preproglucagon expressing neurones. The anorectic effect of GLP-1 appears to be mediated by the PVN, as direct injections of GLP-1 into this nucleus cause anorexia. Am J Physiol. 1996 Oct;271(4 Pt 2):R848-56    Gastric distension with saline has also been shown to activate GLP 1 and 2 immunoreactive neurones of the NTS  in rats. Interestingly, cerebral GLP-1 agonist or antagonist administration has been shown to have an influence on whole body glucose disposal during hyperglycaemia in rodents. Utilisation of glucose by the muscle seems to be modulated by intracerebral infusions of exendin 4 (agonist) or Exendin 9 (antagonist). J Clin Invest. 2005 Dec;115(12):3554-63.  ICV infusion of Exendin4  in the presence of intravenously-induced hyperglycaemia reduces insulin-stimulated utilisation of glucose by the muscle, with concomitant increased hepatic glycogen storage associated with a four fold increase in insulin secretion. [On the other hand, Exendin 9 increases muscle glucose utilisation in an insulin-independent fashion as was demonstrable even in insulin receptor knock out mice.]  These results have been interpreted to suggest the possibility of GLP-1 facilitating replenishment of the hepatic glycogen stores in the postprandial state.    GLP-1 also seems to have autonomic effects  J Clin Invest. 2002 Jul;110(1):43-52.  since cerebral GLP-1 receptor activation produces catecholamine secretion which influences sympathetic preganglionic neurones.

Pancreatic effects:
GLP-1 receptor activation has been shown to inhibit beta-cell apoptosis which would have major implications in humans from a therapeutic point of view. Diabetologia. 2002;45:1263-1273.  GLP-1 has the potential to protect rodent islet cells from cytokine induced apoptosis and necrosis via a protein kinase B-dependent signalling pathway.   Diabetologia. 2005 Jul;48(7):1339-49    In rodents, GLP-1 and GLP-1 receptor agonists promote the differentiation of pancreatic duct cells into insulin-secreting cells. Diabetes. 1999 Dec;48(12):2358-66  In contrast to sulphonylureas, GLP-1 stimulates not only insulin release but also insulin biosynthesis  (it enhances all steps of insulin biosynthesis and potentiates glucose-induced secretion) and gene expression  Proc Natl Acad Sci U S A. 1987 May;84(10):3434-8,  although it should be noted that GLP-1 action is not imperative for insulin synthesis as shown by normal proinsulin gene transcription even in GLP-1 receptor knock out mice.  Diabetes. 1998 Apr;47(4):632-9. GLP-1 may have a tonic inhibitory effect on the pancreatic alpha cells suppressing fasting glucagon levels. J Clin Invest. 1998 Apr 1;101(7):1421-30.   GLP-1 stimulates the transcription of Glucokinase and the GLUT 2 transporter genes as well as B-cell neogenesis. Endocrinology. 1995 Nov;136(11):4910-7.  The glucose dependent effect of GLP-1 on the pancreas to decrease glucagon levels post prandially might well be due to GLP-1 receptors on pancreatic alpha cells,   Diabetes. 1997 May;46(5):785-91    although a paracrine effect via somatostatin  is also possible. Am J Physiol. 1995 Dec;269(6 Pt 1):G852-60.

GLP-1 closes ATP-dependent potassium channels  in a glucose dependent fashion via protein kinase A, Nature. 1993 Jan 28;361(6410):362-5.  and augments insulin secretion through actions further downstream, in the form of direct  stimulatory effects on calcium influx    J Biol Chem. 1995 Jul 28;270(30):17749-57.  and secretory granule exocytosis.   Pflugers Arch. 1998 Apr;435(5):583-94 ;   Diabetes. 1998 Jan;47(1):57-65.    The insulinotropic effect of GLP-1 is glucose dependent, (needing a blood glucose level of about 4.3 mmol/L ),  J Clin Endocrinol Metab. 2002 Mar;87(3):1239-46   which ensures that insulin secretion is not stimulated in the presence of hypoglycaemia. This glucose dependent insulinotropism is attributable to the mechanism of action of GLP1 at the pancreas which is distinct from that of sulphonylureas. Sulphonylureas open the ATP dependent potassium channel in cell membranes of beta cells at even low glucose levels, while GLP-1 requires a permissive degree of hyperglycaemia.      Diabetes. 1998 Jan;47(1):57-65. GLP1 increases insulin secretion by activating protein kinase A, leading to increased intracellular calcium concentrations like sulphonylureas, but does not produce depolarisation of the membrane by closing the potassium channel unlike sulphonylureas.

Effects on gastric emptying and gastric acid secretion seem to be vagally mediated and in keeping with this, vagally denervated rats Am J Physiol. 1997 Oct;273(4 Pt 1):G920-7.    do not show slowing of gastric emptying while vagotomised humans   Gut. 1997 May;40(5):597-601.  do not show reduction in gastric acid secretion with GLP-1 administration.

 Although GLP-1 has direct effects on the pancreas to stimulate insulin, only a small proportion of GLP-1 produced in the intestine reaches the pancreas in the active form, as DPP-IV inactivates up to 50% of the GLP-1, Endocrinology. 1999 Nov;140(11):5356-63 while most of the remainder is inactivated in the portal circulation. Hence neural mechanisms may be important in the insulinotropic actions of GLP-1.

  .

    This page was last updated on: 07/03/2007

 Copyright and Terms of use