Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

Abstract

. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab 285: E701-E707, 2003. First published May 28, 2003 10.1152/ ajpendo.00024.2003.-Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (R a) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [ 3 H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 Ϯ 14 vs. 113 Ϯ 11 pM; 0.153 Ϯ 0.029 vs. 0.156 Ϯ 0.026 nM; and 64.7 Ϯ 11.5 vs. 65.8 Ϯ 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steadystate levels of 4.8 Ϯ 0.2 to a nadir of 4.1 Ϯ 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in R a, from 22.6 Ϯ 2.8 to 19.1 Ϯ 2.8 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 (P Ͻ 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.incretin; glucose production; pancreatic clamp; gastrointestinal hormone; glucose tolerance GLUCAGON-LIKE PEPTIDE-1 (GLP-1; 7-36 amide) is an intestinal hormone that plays an important role in glucose homeostasis. GLP-1 is a potent insulinotropin that is secreted after meal ingestion, thereby contributing to the incretin effect (the greater insulin release occurring after oral compared with intravenous glucose administration; see Refs. 9, 28, and 35). GLP-1 also decreases glucagon release, either through direct interaction with the ␣-cell or indirectly via stimulation of insulin and somatostatin secretion (10, 47). Thus the overall effect of GLP-1 on pancreatic islet secretion is to decrease circulating glucose concentrations. In addition to the regulation of islet hormones, GLP-1 slows gastric emptying (49), another action that attenuates the rise in plasma glucose after meal ingestion. This broad range of acute effects on processes governing circulating levels of glucose has stimulated interest in using GLP-1 or GLP-1 analogs for the treatment of diabetes.Many investigators have also suggested that GLP-1 has effects on glucose metabolism beyond the regulation of pancreatic islet hormone secretion, e.g., extrapancreatic effects. The first report was from Gutniak and colleagues (20)...

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

“…In type 2 diabetes, liraglutide, a long-acting GLP-1 derivative, decreased fasting EGP as a result of reduced glycogenolysis [40], and increasing GLP-1 concentrations by dipeptidyl peptidase-4 inhibition with vildagliptin increased hepatic glucose disposal [41]. In healthy people, the infusion of GLP-1 decreased fasting EGP and tended to increase plasma glucose clearance independent of changes in insulin and glucagon concentrations [42].…”

Reduced plasma levels of glucagon-like peptide-1 in elderly men are associated with impaired glucose tolerance but not with coronary heart disease

“…The reason for the lack of association between ΔGLP-1 and M/I in the other groups remains elusive. GLP-1 might suppress hepatic glucose production directly [8] or indirectly by regulating glucagon secretion, which controls hepatic glucose production. The euglycaemic-hyperinsulinaemic clamp, used in the present study without infusion of radioactive-marked-glucose, cannot distinguish between hepatic vs skeletal muscle insulin sensitivity.…”

Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells

“…Although originally described as a potent stimulator of glucose-dependent insulin secretion, recent studies [1,2,3,4,5,6,7,8,10,11,12,13] have shown that the intestinal hormone GLP-1 also prevents the onset of diabetes and ameliorates existing diabetes through a mechanism that includes enhancement of beta-cell mass [16,17,18,19,20]. Despite limited evidence that GLP-1 can activate PKB [34], and that PKBα overexpression enhances beta-cell mass in vivo [27,28], no studies have shown whether PKB is essential for GLP-1-induced beta-cell proliferation and/or prevention of apoptosis.…”

“…It possesses a variety of anti-diabetic actions that are mediated at the level of the beta cell, as well as in peripheral tissues. These include not only the stimulation of glucose-dependent insulin secretion [3,4,5], but also the inhibition of glucagon release [6,7], gastric emptying [7,8] and food intake [9,10], and possibly also enhancement of insulin sensitivity [11,12]. Consistent with these biological actions, long-term treatment of Type 2 diabetic patients with GLP-1 decreases HbA 1c values and is associated with lower fasting and postprandial glucose concentrations and reduced body weight [13].…”