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

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 364; no. 1; pp. 47 - 52
• Main Authors: Mest, H J, Raap, A, Schloos, J, Treinies, I, Paal, M, Giese, U, Koivisto, V
• Format: Journal Article
• Language: English
• Published: Germany 01.07.2001
• Subjects: Animals; Blood Glucose - metabolism; Cell Line; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Glucose Tolerance Test; Hypoglycemic Agents - pharmacology; Imidazoles - chemistry; Imidazoles - metabolism; Imidazoles - pharmacology; Insulin - analysis; Insulin - metabolism; Insulin - therapeutic use; Insulin Secretion; Islets of Langerhans - drug effects; Male; Molecular Structure; Naphthalenes - chemistry; Naphthalenes - metabolism; Naphthalenes - pharmacology; Rats; Rats, Wistar; Rats, Zucker
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s002100100415

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 beta-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 microM and 0.3 microM, 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.