Glucose-induced insulin secretion is potentiated by a new imidazoline compound

Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration. This can lead to hypoglycaemia in type 2 diabetic patients. Over the last years a number of imidazoline derivatives have been identifie d that stimulate insulin secretion in a more glucose:dependent way. In agre ement with this, our aim was to generate imidazoline derivatives with a pot ential for the treatment of type 2 diabetic patients. We developed the comp ound 2-[4-(4-chlorophenyl)-3-(2-methoxyethoxy)-2-naphthalenyl]-4,5-dihydro- 1-H-imidazole monohydrochloride (LY389382) with an imidazoline moiety and i nvestigated its effects on glucose-dependent insulin secretion in a p-cell line, isolated rat islets and in vivo. We could demonstrate that LY389382 i nduces insulin secretion in MIN6 cells and rat islets in a glucose-dependen t manner (EC50=1.1 CIM and 0.3 muM, respectively). Furthermore during hyper glycaemia LY389382 increased insulin secretion in a dose-dependent manner i n healthy rats, whereas the compound had no effect at euglycemia in a tenfo ld higher dosage. After 7 days of treatment of Zucker Diabetic Fatty [ZDF/( Gmi/fa)] rats with LY389382 with a dose of 15 mg/kg twice daily the blood g lucose concentration was reduced from 22.7 +/-1.7 mM to 16.6 +/-2.3 mM. Dur ing the same time period the glucose concentration increased from 21.7 +/-1 .7 mM to 28.9 +/-1.3 mM in the vehicle-treated group (P <0.05). The drop of the insulin level was also inhibited by LY389382 in ZDF rats. In contrast to other well-characterised imidazolines that have been shown to induce a g lucose-dependent insulin secretion only within a limited range of concentra tions, LY389382 stimulates insulin secretion over a concentration range of at least two log units in a glucose:dependent manner. These data suggest th at this imidazoline compound has a potential for the treatment of type 2 di abetes.