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To 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.Rat 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).GLP-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).In 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.