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 μumol/l glibenclamide. In human experiments, GLP-I (0.75 pmol. kg−1 · 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 ± 2.7 years, BMI 28.7 ± 1.5 kg/m2, mean ± 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 ± 0.4 and 4.5 ± 0.1 vs. 6.0 ± 0.3 mmol/l, P < 0.01), while with only glibenclamide, glucose concentrations remained unchanged. GLP-I markedly decreased total integrated glucose response to the meal (353 ± 60 vs. 724 ± 91 mmol μ l−1 · min−1, area under the curve [AUC] [–30–180 min], P < 0.02), whereas glibenclamide had no effect (598 ± 101 mmol · l−1 · min−1, AUC [–30–180 min], NS). The combined treatment further enhanced the glucose lowering effect of GLP-I (138 ± 24 mmol · l−1 · min, AUC [–30–180 min], P < 0.001). GLP-I, glibenclamide, and combined treat-stimulated meal-induced insulin release as reflected by insulinogenic indexes (control 1.44 ± 0.4; GLP-I 6.3 ± 1.6, P < 0.01; glibenclamide 6.8 ± 2.1, P < 0.01; combination 20.7 ± 5.0, P < 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 ∼50% compared with the control subjects (P < 0.01).
In acute experiments on 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 on insulin release. Glibenclamide per se enhanced postprandial but not basal insulin release and exerted a less pronounced antidiabetogenic effect compared with GLP-I.