title: Utilization of the Zucker Diabetic Fatty (ZDF) Rat Model for Investigating Hypoglycemia-related Toxicities.
abstract: Glucokinase (GK) catalyzes the initial step in glycolysis and is a key regulator of glucose homeostasis. Therefore, glucokinase activators (GKa) have potential benefit in treating type 2 diabetes. Administration of a Bristol-Myers Squibb GKa (BMS-820132) to healthy euglycemic Sprague-Dawley (SD) rats and beagle dogs in 1 mo toxicology 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 comparable to those expected at therapeutic clinical exposures. To investigate whether these adverse effects were secondary to exaggerated pharmacology (prolonged hypoglycemia), BMS-820132 was administered daily to male Zucker diabetic fatty (ZDF) rats for 1 mo. ZDF rats are markedly hyperglycemic and insulin resistant. BMS-820132 did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1 mo toxicology studies at exposures that exceeded those observed in SD rats and dogs. This indicates that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GK activation. This study indicates that ZDF rats, with conventional toxicity studies, are a useful disease model for testing antidiabetic agents and determining toxicities that are independent of prolonged hypoglycemia.
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, New Jersey, USA mark.tirmenstein@bms.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Tirmenstein
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, New Jersey, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Horvath
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, Princeton, New Jersey, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Graziano
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, New Jersey, USA.
authors.forename: Raja
authors.initials: R
authors.lastname: Mangipudy
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, New Jersey, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dorr
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, New Jersey, USA Present affiliation: Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA.
authors.forename: Karyn
authors.initials: K
authors.lastname: Colman
authors.affiliation: Bristol-Myers Squibb, Discovery Biology, Pennington, New Jersey, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Zinker
authors.affiliation: Bristol-Myers Squibb, Discovery Biology, Pennington, New Jersey, USA Present affiliation: Lilly China Research and Development Center, Shanghai, China.
authors.forename: Mark
authors.initials: M
authors.lastname: Kirby
authors.affiliation: Bristol-Myers Squibb, Discovery Chemistry, Pennington, New Jersey, USA.
authors.forename: Peter T W
authors.initials: PT
authors.lastname: Cheng
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, New Jersey, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Patrone
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, New Jersey, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kozlosky
authors.affiliation: Bristol-Myers Squibb, Exploratory Clinical and Translational Research, Princeton, New Jersey, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Reilly
authors.affiliation: Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, New Jersey, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Wang
authors.affiliation: Bristol-Myers Squibb, Discovery Toxicology, Pennington, New Jersey, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Janovitz
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D004435:Eating / Q000187:drug effects; D020536:Enzyme Activators / Q000493:pharmacokinetics / Q000633:toxicity*; D005941:Glucokinase / Q000235:genetics; D007003:Hypoglycemia / Q000139:chemically induced* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051381:Rats; D011924:Rats, Zucker / Q000378:metabolism*; D013045:Species Specificity; D066007:Toxicokinetics
chemical_list: D001786:Blood Glucose; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007328:Insulin; D005941:Glucokinase
keywords: ZDF; Zucker diabetic rats; diabetes; glucokinase activator; hypoglycemia; type 2 diabetes