Prolongation of the insulinotropic action of glucagon-like peptide 1 by the dimethyl ester of succinic acid in an animal model of type-2 diabetes.
Adult rats, that had been injected with streptozotocin during the neonatal period, received a primed constant infusion of succinic acid dimethyl ester (SAD; 0.5 micromol followed by 0.25 micromol x min(-1), both per g body wt.) in saline for 15 min and, at the 5th min of such an infusion, an intravenous injection of GLP-1 (5 pmol per g body wt.). Within 2 min, the ester increased the plasma insulin concentration by 0.33+/-0.05 nM. Likewise, within 2 min, GLP-1 provoked a marked increase in plasma insulin concentration; such an increase was comparable in rats infused with either saline or SAD, with an overall mean value of 0.93+/-0.07 nM. In the rats infused with SAD, however, the secretory response to GLP-1 appeared more sustained than in the saline-infused animals. For instance, the paired ratio for the insulinogenic index at 10/2 min after GLP-1 injection averaged 30.5+/-4.0% in SAD-infused rats, as compared (P<0.025) to only 17.0+/-2.5% in saline-infused animals. These findings suggest that succinic acid esters could be used to prolong the insulinotropic action of GLP-1 in the treatment of type-2 diabetes.
Garcia-Martinez
J A
JA
Fundacion Jimenez Diaz, Madrid, Spain.
Cancelas
J
J
Villanueva-Peñacarrillo
M L
ML
Valverde
I
I
Malaisse
W J
WJ
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D007328:Insulin / Q000097:blood*; D008297:Male; D010179:Pancreas / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D013386:Succinates / Q000494:pharmacology*
D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D013386:Succinates; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C056451:dimethyl succinate