Mk. Gutniak et al., GLUCAGON-LIKE PEPTIDE-I ENHANCES THE INSULINOTROPIC EFFECT OF GLIBENCLAMIDE IN NIDDM PATIENTS AND IN THE PERFUSED RAT PANCREAS, Diabetes care, 19(8), 1996, pp. 857-863
Citations number
29
Categorie Soggetti
Endocrynology & Metabolism","Medicine, General & Internal
OBJECTIVE - To investigate the acute effects of glibenclamide and gluc
agon-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 experime
nts, GLP-I (0.75 pmol . kg(-1) . min(-1)) was given as a continuous in
fusion 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 in
fusion administered by an artificial pancreas (Biostator). RESULTS - G
LP-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 b
asal 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 re
mained unchanged. GLP-I markedly decreased total integrated glucose re
sponse 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 glibencla
mide had no effect (598 +/- 101 mmol . l(-1) . min(-1), AUC [-30-180 m
in], 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 (contro
l 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 b
ut not postprandial glucagon responses. Using paracetamol as a marker
for gastric emptying rate of the test meal, treatment with GLP-I decre
ased gastric emptying at 180 min by similar to 50% compared with the c
ontrol subjects (P < 0.01). CONCLUSIONS - In acute experiments on over
weight patients with NIDDM, GLP-I exerted a marked antidiabetogenic ac
tion on the basal and postprandial state. The peptide stimulated insul
in, suppressed basal glucagon release, and prolonged gastric emptying.
The glucose-lowering effect of GLP-I was further enhanced by glibencl
amide. This action may be at least partially accounted for by a synerg
istic 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.