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 mu mol followed by 0.25 mu mol . 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.