Glucagon-like Peptide 1 -- Part I

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Scrocchi LA, Brown TJ, MacLusky N, et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med. 1996;2:1254-1258. Abstract
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Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycemia by endogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741-744. Abstract
Drucker D, Phillippe J, Mojsov S, Chick W, Habener J. Glucagon-like peptide 1 stimulates insulin gene expression and increases cyclic AMP levels in rat islet cell line. Proc Natl Acad Sci U S A. 1987;84:3434-3438. Abstract
Fehmann H-C, Habener J. Insulinotropic hormone glucagon-like peptide-1 (7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma bTC-1 cells. Endocrinology. 1992;130:159-166. Abstract
Buteau J, Roduit R, Susini S, Prentki M. 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. Diabetologia. 1999;42:856-864. Abstract
Drucker DJ. Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol Endocrinol. 2003;17:161-171. Abstract
Vahl T, D'Alessio D. Enteroinsular signaling: perspectives on the role of the gastrointestinal hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in normal and abnormal glucose metabolism. The regulatory role of leptin in food intake. Curr Opin Clin Nutr Metab Care. 2003;6:461-468. Abstract
Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999;48:2270-2276. Abstract
Zhou J, Wang X, Pineyro MA, Egan JM. Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells. Diabetes. 1999;48:2358-2366. Abstract
Hui H, Wright C, Perfetti R. Glucagon-like peptide 1 induces differentiation of islet duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells. Diabetes. 2001;50:785-796. Abstract
Wang Q, Brubaker PL. Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia. 2002;45:1263-1273. Abstract
Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87:1239-1246. Abstract
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Fehmann H-C, Goke R, Goke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulin releasing polypeptide. Endocr Rev. 1995;16:390-410. Abstract
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Creutzfeldt W, Orskov C, Kleine N, Holst JJ, Willms B, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I (7-36) amide in type I diabetic patients. Diabetes Care. 1996;19:580-586. Abstract
Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: Effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab. 1996;81:327-332. Abstract
Meier JJ, Gallwitz B, Salmen S, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:2719-2725. Abstract
Imeryuz N, Yegen BC, Bozkurt A, Coskun T, Villanueva-Penacarrillo ML, Ulusoy NB. Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol. 1997;273:G920-G927. Abstract
Dupre J, Behme MT, Hramiak IM, McDonald TJ. Subcutaneous glucagon-like peptide I combined with insulin normalizes postcibal glycemic excursions in IDDM. Diabetes Care. 1997;20:381-384. Abstract
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Physiologic Effects of GLP-1 Receptor Activation

GLP-1 is an incretin hormone and by definition stimulates the release of insulin from pancreatic beta cells in conjunction with carbohydrates that are absorbed from the gut. Accordingly, the most important physiologic effect of GLP-1 is the regulation of postprandial glucose homeostasis. This notion is supported by studies demonstrating that competitive antagonism of GLP-1 receptor signaling in rats caused impaired glucose tolerance.^[1] Subsequent experiments in mice with a disruption of the GLP-1 receptor gene demonstrated fasting hyperglycemia as well as impaired oral glucose tolerance associated with decreased insulin secretion.^[2] Findings analogous to the studies in rodents were observed in nonhuman primates as well as in human subjects. Administration of a GLP-1 receptor antagonist or immunoneutralization of circulating GLP-1 resulted in hyperglycemia during glucose ingestion.^[3,4] This body of information indicates that GLP-1 is necessary for normal glucose tolerance.

Probably the primary component of the GLP-1-mediated regulation of postprandial glucose homeostasis is stimulation of insulin release.^[5,6] Of note, GLP-1-induced insulin release depends on elevated blood glucose levels,^[7,8] and GLP-1 causes only minimal stimulation of pancreatic beta cells at fasting glucose concentrations.^[6] Since the insulinotropic effect of GLP-1 is effectively tied to hyperglycemia, under normal circumstances this peptide does not cause hypoglycemia. GLP-1 stimulates not only insulin release but also insulin biosynthesis and gene expression.^[9,10] Consistent with a broad role in promoting beta-cell function, GLP-1 stimulates the transcription of glucokinase and the GLUT 2 transporter genes.^[11]

Beyond the acute insulinotropic effect of GLP-1, several studies support an important function of this hormone in the regulation of beta-cell mass.^[12,13] This novel area of GLP-1 research has received increasing attention after recent studies demonstrated that GLP-1 receptor activation directly stimulates beta-cell replication and neogenesis.^[14-16] In rodents, GLP-1 and GLP-1 receptor agonists promote the differentiation of pancreatic duct cells into insulin-secreting cells.^[15] Furthermore, GLP-1 receptor activation inhibits beta-cell apoptosis after streptozotocin administration as well as in animal models of obesity and hyperglycemia.^[17] This potentially important aspect of GLP-1 action has not yet been established in humans.

In addition to its actions on the beta cell, GLP-1 also regulates glucose homeostasis by inhibiting glucagon secretion from islet alpha cells.^[7] The glucagonostatic effect of GLP-1, which is also most pronounced when blood glucose is elevated,^[18] may be mediated by direct activation of GLP-1 receptors on alpha cells^[19] or by paracrine mechanisms due to insulin and somatostatin secretion.^[20] GLP-1 also seems to control glucagon secretion in the fasting state, because antagonism of GLP-1 receptor signaling results in elevated plasma glucagon concentrations.^[3,21] The importance of glucagon suppression by GLP-1 was demonstrated in a study of patients with type 1 diabetes in whom GLP-1 infusion significantly reduced fasting hyperglycemia.^[22]

Another mechanism by which GLP-1 is known to control glucose homeostasis in addition to the regulation of islet hormone secretion is by delaying gastric emptying.^[23,24] In this way GLP-1 controls the rate at which nutrients gain access to the absorptive surface of the intestine during the postprandial state. This effect is likely mediated by vagal afferent nerves.^[25] Notably, the delay in gastric emptying contributes considerably to the attenuated glycemic response in patients with type 1 diabetes treated subcutaneously with GLP-1.^[26] The observation that GLP-1 improves glucose control in patients without endogenous insulin secretion exemplifies the spectrum of physiologic effects by which GLP-1 contributes to postprandial glucose control and suggests that sites other than pancreatic beta cells play an important role in GLP-1 action.

GLP-1 is active in the brain, and activation of GLP-1 receptors after acute intracerebroventricular GLP-1 administration to rats resulted in a reduction of food intake.^[27,28] Furthermore, several studies have implicated GLP-1 in the promotion of satiety and regulation of food intake in humans (reviewed in Vahl and D'Alessio^[29]). While there is no good evidence that GLP-1 administration to obese patients will lead to a substantial reduction in body weight, the promise of an insulin secretagogue that does not promote weight gain is intriguing in itself. The current data raise the possibility that a GLP-1-mediated reduction in food intake is one of the mechanisms by which this gut hormone controls postprandial glucose homeostasis.

Several studies in humans have demonstrated that GLP-1 promotes a decrease in blood glucose concentrations independent of the islet hormones, although these findings have been disputed (reviewed in D'Alessio and Vahl^[30]). Several studies indicate that GLP-1 directly promotes glucose uptake in cultured cells, animals, and humans, although the bulk of evidence suggests that this does not occur by enhancement of insulin sensitivity. It has recently been reported that GLP-1 suppresses fasting glucose production while insulin and glucagon levels were fixed using a clamp technique.^[31] Overall, the islet-independent actions of GLP-1 to regulate glucose uptake and production are small -- when detected -- and this area remains controversial.

The central role of GLP-1 in glucose tolerance has raised questions about the possible involvement of this peptide in the pathogenesis of diabetes. In addition, the wide range of coordinated actions by which GLP-1 lowers blood glucose has launched a new wave of drug development centered on this peptide hormone. Part 2 of this column will address the clinical relevance of GLP-1 and its derivatives.