Tirmenstein, Mark, Horvath, Joseph, Mangipudy, Raja, Dorr, Thomas, Colman, Karyn, Zinker, B, Kirby, M, Cheng, P, Patrone, Laura, Reilly, Timothy, Wang, Veronica and Janovitz, Evan (2015) Hyperglycemic Zucker diabetic fatty rats are resistant to the adverse effects of a potent glucokinase activator. Toxicologic Pathology. pp. 1-13. ISSN 0192-6233 print / 1533-1601 online

Abstract

Glucokinase, which catalyzes the initial step in glycolysis (glucose-6-phosphate formation), is a key regulator of glucose homeostasis. As a result, glucokinase activators have been in development for the treatment of type 2 diabetes. Daily administration of a Bristol-Myers Squibb glucokinase activator (BMS-GKa) to healthy euglycemic Sprague Dawley (SD) rats and beagle dogs in 1-month studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures that were comparable to those expected at therapeutic clinical exposures. A subsequent study was conducted in markedly hyperglycemic, insulin-resistant Zucker diabetic fatty (ZDF) rats. Daily oral administration of BMS-GKa to male ZDF rats for 1 month did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1-month SD rat study at exposures that exceeded those observed in SD rats. This confirmed that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GKa activation and would not occur in diabetics where baseline glucose levels would be much higher providing a compelling justification to proceed to early clinical studies in diabetic patients.

Item Type:	Article
Keywords:	Glucokinase activator, Hypoglycemia, Zucker diabetic rats, ZDF, Diabetes, Type 2 diabetes
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/23570