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

Abstract.

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 identified that stimulate insulin secretion in a more glucose-dependent way. In agreement with this, our aim was to generate imidazoline derivatives with a potential for the treatment of type 2 diabetic patients. We developed the compound 2-[4-(4-chlorophenyl)-3-(2-methoxyethoxy)-2-naphthalenyl]-4,5-dihydro-1-H-imidazole monohydrochloride (LY389382) with an imidazoline moiety and investigated its effects on glucose-dependent insulin secretion in a β-cell line, isolated rat islets and in vivo. We could demonstrate that LY389382 induces insulin secretion in MIN6 cells and rat islets in a glucose-dependent manner (EC₅₀=1.1 µM and 0.3 µM, respectively). Furthermore during hyperglycaemia LY389382 increased insulin secretion in a dose-dependent manner in healthy rats, whereas the compound had no effect at euglycemia in a tenfold 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 glucose concentration was reduced from 22.7±1.7 mM to 16.6±2.3 mM. During 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 glucose-dependent insulin secretion only within a limited range of concentrations, LY389382 stimulates insulin secretion over a concentration range of at least two log units in a glucose-dependent manner. These data suggest that this imidazoline compound has a potential for the treatment of type 2 diabetes.