Glucagon-Like Peptide I Enhances the Insulinotropic Effect of Glibenclamide in NIDDM Patients and in the Perfused Rat Pancreas


    loading  Checking for direct PDF access through Ovid

Abstract

OBJECTIVETo investigate the acute effects of glibenclamide and glucagon-like peptide I (GLP-I) and their combination in perfused isolated rat pancreas and in patients with secondary failure to sulfonylureas.RESEARCH DESIGN AND METHODSRat islets were perfused with 10 nmol/l GLP-I in combination with 2 micromole/l glibenclamide. In human experiments, GLP-I (0.75 [bullet] pmol [bullet] kg-1 [bullet] min-1) was given as a continuous infusion during 240 min, while glibenclamide (3.5 mg) was administered orally. Eight patients participated in the study (age 57.6 plus/minus 2.7 years, BMI 28.7 plus/minus 1.5 kg/m2, mean plus/minus SE). In all subjects, blood glucose was first normalized by insulin infusion administered by an artificial pancreas (Biostator).RESULTSGLP-I increased the insulinotropic effect of glibenclamide fourfold in the perfused rat pancreas. In human experiments, treatment with GLP-I alone and in combination with glibenclamide significantly decreased basal glucose levels (5.1 plus/minus 0.4 and 4.5 plus/minus 0.1 vs. 6.0 plus/minus 0.3 mmol/l, P less than 0.01), while with only glibenclamide, glucose concentrations remained unchanged. GLP-I markedly decreased total integrated glucose response to the meal (353 plus/minus 60 vs. 724 plus/minus 91 mmol/l [bullet] l-1 [bullet] min-1, area under the curve [AUC] [-30-180 min], P less than 0.02), whereas glibenclamide had no effect (598 plus/minus 101 mmol [bullet] l-1 [bullet] min-1, AUC [-30-l80 min], NS). The combined treatment further enhanced the glucose lowering effect of GLP-I (138 plus/minus 24 mmol [bullet] l-1 [bullet] min, AUC [-30-180 min], P less than 0.001). GLP-I, glibenclamide, and combined treatment stimulated meal-induced insulin release as reflected by insulinogenic indexes (control 1.44 plus/minus 0.4; GLP-I 6.3 plus/minus 1.6, P less than 0.01; glibenclamide 6.8 plus/minus 2.1, P less than 0.01; combination 20.7 plus/minus 5.0, P less than 0.001). GLP-I inhibited basal but not postprandial glucagon responses. Using paracetamol as a marker for gastric emptying rate of the test meal, treatment with GLP-I decreased gastric emptying at 180 min by approximately 50 percent compared with the control subjects (P less than 0.01).CONCLUSIONSIn acute experiments no overweight patients with NIDDM, GLP-I exerted a marked antidiabetogenic action on the basal and postprandial state. The peptide stimulated insulin, suppressed basal glucagon release, and prolonged gastric emptying. The glucose-lowering effect of GLP-I was further enhanced by glibenclamide. This action may be at least partially accounted for by a synergistic effect of these two compounds insulin release and exerted a less pronounced antidiabetogenic effect compared with GLP-I.

    loading  Loading Related Articles