Glucagon-like peptide I enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas

被引:74
作者
Gutniak, MK
Guenifi, A
Berggren, LJ
Holst, JJ
Hellstrom, PM
Efendic, S
机构
[1] KAROLINSKA HOSP,DEPT MED,GASTROENTEROL UNIT,S-10401 STOCKHOLM,SWEDEN
[2] UNIV COPENHAGEN,PANUM INST,DEPT MED PHYSIOL,DK-2200 COPENHAGEN N,DENMARK
关键词
D O I
10.2337/diacare.19.8.857
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
OBJECTIVE - 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. RESEARCH DESIGN AND METHODS - Rat islets were perfused with 10 nmol/l GLP-I in combination with 2 mu mol/l glibenclamide. In human experiments, GLP-I (0.75 pmol . kg(-1) . min(-1)) was given as a continuous infusion during was administered orally. Eight patients participated in the study (age 57.6 +/- 2.7 years, BMI 28.7 +/- 1.5 kg/m(2), mean +/- SE). In all subjects, blood glucose was first normalized by insulin infusion administered by an artificial pancreas (Biostator). RESULTS - GLP-I increased the insulinotropic effect of glibenclamide fourfold in the per fused 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 . 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 treatment 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 similar to 50% compared with the control subjects (P < 0.01). CONCLUSIONS - 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.
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页码:857 / 863
页数:7
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