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 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.
Mest
H J
HJ
Lilly Research Laboratories, Department of Pharmacology, Hamburg, Germany. mest_hans-juergen@lilly.com
Raap
A
A
Schloos
J
J
Treinies
I
I
Paal
M
M
Giese
U
U
Koivisto
V
V
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000032:analysis / Q000378:metabolism* / Q000627:therapeutic use; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects*; D008297:Male; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker
C450501:2-(4-(4-chlorophenyl)-3-(2-methoxyethoxy)-2-naphthalenyl)-4,5-dihydro-1-H-imidazole monohydrochloride; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007328:Insulin; D009281:Naphthalenes; C032368:midaglizole