Glucagon-Like Peptide 1 Increases Insulin Sensitivity in Depancreatized Dogs

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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 micro g [centered dot] kg-1 [centered dot] min-1) to inhibit extrapancreatic glucagon in dogs, and basal glucagon was restored by intraportal infusion (0.65 ng [centered dot] kg-1 [centered dot] 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 [centered dot] kg-1 [centered dot] min-1, or low dose, 0.75 pmol [centered dot] kg-1 [centered dot] min-1) with or without GLP-1(7-36) amide (1.5 pmol [centered dot] kg-1 [centered dot] min-1). Glucose production and utilization were measured with 3-[(3) H]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 micro mol [centered dot] kg-1 [centered dot] min-1, P < 0.001), because of greater glucose utilization (72.6 +/- 11.0 vs. 56.8 +/- 9.7 micro mol [centered dot] kg-1 [centered dot] 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 micro mol/l, P < 0.01), as was glycerol (77.9 +/- 17.5 vs. 125.6 +/- 51.8 micro mol/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 of 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. Diabetes 48:1045-1053, 1999

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