Glucagon-like peptide 1 increases insulin sensitivity in depancreatized dogs.

Abstract

To determine whether glucagon-like peptide (GLP)-1 increases insulin sensitivity in addition to stimulating insulin secretion, we studied totally depancreatized dogs to eliminate GLP-1's incretin effect. Somatostatin was infused (0.8 microg x kg(-1) x min(-1)) to inhibit extrapancreatic glucagon in dogs, and basal glucagon was restored by intraportal infusion (0.65 ng x kg(-1) x min(-1)). To simulate the residual intraportal insulin secretion in type 2 diabetes, basal intraportal insulin infusion was given to obtain plasma glucose concentrations of approximately 10 mmol/l. Glucose was clamped at this level for the remainder of the experiment, which included peripheral insulin infusion (high dose, 5.4 pmol x kg(-1) x min(-1), or low dose, 0.75 pmol x kg(-1) x min(-1)) with or without GLP-1(7-36) amide (1.5 pmol x kg(-1) x min(-1)). Glucose production and utilization were measured with 3-[3H]glucose, using radiolabeled glucose infusates. In 12 paired experiments with six dogs at the high insulin dose, GLP-1 infusion resulted in higher glucose requirements than saline (60.9+/-11.0 vs. 43.6+/-8.3 micromol x kg(-1) x min(-1), P< 0.001), because of greater glucose utilization (72.6+/-11.0 vs. 56.8+/-9.7 micromol x kg(-1) x min(-1), P<0.001), whereas the suppression of glucose production was not affected by GLP-1. Free fatty acids (FFAs) were significantly lower with GLP-1 than saline (375.3+/-103.0 vs. 524.4+/-101.1 micromol/l, P<0.01), as was glycerol (77.9+/-17.5 vs. 125.6+/-51.8 micromol/l, P<0.05). GLP-1 receptor gene expression was found using reverse transcriptase-polymerase chain reaction of poly(A)-selected RNA in muscle and adipose tissue, but not in liver. Low levels of GLP-1 receptor gene expression were also found in adipose tissue using Northern blotting. In 10 paired experiments with five dogs at the low insulin dose, GLP-1 infusion did not affect glucose utilization or FFA and glycerol suppression when compared with saline, suggesting that GLP-1's effect on insulin action was dependent on the insulin dose. In conclusion, in depancreatized dogs, GLP-1 potentiates insulin-stimulated glucose utilization, an effect that might be contributed in part by GLP-1 potentiation of insulin's antilipolytic action.

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].…”

Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones

“…Several studies have indicated that GLP-1 might have an insulin-independent effect on glucose homeostasis [26][27][28][29][30][31][32], while other researchers suggested that GLP-1 did not acutely affect glucose metabolism independently of insulin [33][34][35][36][37]. These conflicting results may be a consequence of the large variability in the model and methods used: healthy vs diabetic, diabetic hyperglycaemic vs diabetic maintained euglycaemic, clamp vs IVGTT etc.…”

Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans

“…In contrast, results from in vivo studies have been less consistent. GLP-1 (7-36) has been reported to increase glucose uptake during hyperglycaemia and hyperinsulinaemia in diabetic rats [17], pancreatectomized dogs [18] and in Type I (insulin-dependent) diabetic patients [19,20]. In contrast, GLP-1 (7-36) has been reported to have no effect on the insulin action in non-diabetic human subjects [21], in dogs [22] or Type II diabetic patients [23].…”

“…Repeated measures ANOVA was used to Several factors could account for these discordant results. A positive but small effect on insulin action has most consistently been observed in severely insulin deficient animals or Type I diabetic patients [18,20]. The methods used to assess insulin action also have differed ranging from clamps, to frequently sampled intravenous glucose tolerance tests to prandial infusions of glucose [17,18,19,20,21,22,23].…”