Glucose concentration-dependent potentiation of insulin secretion by a new chemical entity, KCP256.

Abstract

The insulinotropic activity of KCP256 [(R)-8-benzyl-2-cyclopentyl-7, 8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride] was examined using MIN6 cells (a pancreatic beta-cell line) and pancreatic islets isolated from rats. Unlike sulfonylurea anti-diabetic drugs, KCP256 dose-dependently (0.1-10 microM) enhanced insulin secretion from MIN6 cells and its insulinotropic effect was exerted only at high concentrations of glucose (8.3-22 mM) but not at low concentrations of glucose (3.3-5.5 mM). Furthermore, the action mechanism of KCP256 was different because, unlike sulfonylurea drugs, KCP256 did not displace the binding of [3H]glibenclamide, and did not inhibit the 86Rb+ efflux nor K(ATP) channel activity. In isolated islets, KCP256 also enhanced insulin secretion in a dose- and a glucose-concentration-dependent manner. Plasma levels of insulin after glucose challenge in KCP256-administrated rats were higher than those in vehicle-administrated animals, indicating that KCP256 can enhance insulin secretion in vivo. Since the insulinotropic activity of KCP256 only occurs at high concentrations of glucose, this novel drug may exhibit a decreased risk of drug-induced hypoglycemia compared with sulfonylurea drugs when treating patients with diabetes.

• Authors: Kiyotoshi Mori, Kotaro Takasaki, Yoshimitsu Katoh, Hiroshi Yano, Kimihisa Ueno, Michiaki Ichimura, Hideaki Kusaka, Yuji Nomoto, Katsuya Higo, Satoshi Nakanishi
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 528 Issue 1-3 Pg. 176-82 (Dec 28 2005) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16316644 (Publication Type: Journal Article)

Chemical References

• (R)-8-benzyl-2-cyclopentyl-7, 8-dihydro-4-propyl-1H-imidazo(2,1-i)purin-5(4H)-one hydrochloride
• Blood Glucose
• Hypoglycemic Agents
• Imidazoles
• Insulin
• Purines
• Purinones
• Glucose

Topics

• Animals
• Blood Glucose (drug effects)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Synergism
• Glucose (pharmacology)
• Glucose Tolerance Test
• Hypoglycemic Agents (administration & dosage, pharmacology)
• Imidazoles (pharmacology)
• In Vitro Techniques
• Insulin (blood, metabolism)
• Islets of Langerhans (drug effects, metabolism)
• Male
• Purines (pharmacology)
• Purinones (administration & dosage, pharmacology)
• Rats
• Rats, Wistar