Inhibition of Fructose 1,6-Bisphosphatase Reduces Excessive Endogenous Glucose Production and Attenuates Hyperglycemia in Zucker Diabetic Fatty Rats

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 6; pp. 1747 - 1754
• Main Authors: van Poelje, Paul D., Potter, Scott C., Chandramouli, Visvanathan C., Landau, Bernard R., Dang, Qun, Erion, Mark D.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2006
• Subjects: Alanine - analogs & derivatives; Alanine - chemistry; Alanine - pharmacology; Alanine - therapeutic use; Animals; Biological and medical sciences; Blood Glucose - metabolism; Body Weight - drug effects; Care and treatment; Cholesterol - metabolism; Dehydrogenases; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes research; Diabetes. Impaired glucose tolerance; Diet; Eating - drug effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Fructose-Bisphosphatase - antagonists & inhibitors; Genetic aspects; Glucagon; Gluconeogenesis - drug effects; Glucose; Glucose - biosynthesis; Hyperglycemia; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Insulin - blood; Insulin resistance; Ketone Bodies - metabolism; Kinases; Laboratory animals; Lactic Acid - metabolism; Male; Medical sciences; Metabolism; Molecular Structure; Nutrition research; Organophosphonates; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Organophosphorus Compounds - therapeutic use; Pancreas - drug effects; Pancreas - metabolism; Rats; Rats, Zucker; Triglycerides - metabolism; Type 2 diabetes; Endocrinopathy; Vertebrata; Hyperglycemia; Mammalia; Rat; Animal; Diabetes mellitus; Rodentia; Glucose; Inhibition; Fructose
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db05-1443

Inhibition of Fructose 1,6-Bisphosphatase Reduces Excessive Endogenous Glucose Production and Attenuates Hyperglycemia in Zucker Diabetic Fatty Rats Paul D. van Poelje 1 , Scott C. Potter 1 , Visvanathan C. Chandramouli 2 , Bernard R. Landau 2 , Qun Dang 1 and Mark D. Erion 1 1 From the Departments of Biochemistry and Medicinal Chemistry, Metabasis Therapeutics, La Jolla, California 2 Division of Clinical and Molecular Endocrinology, Case Western Reserve University School of Medicine, Cleveland, Ohio Address correspondence and reprint requests to Dr. Paul D. van Poelje, c/o Metabasis Therapeutics, 11119 North Torrey Pines Rd., La Jolla, CA 92037. E-mail: paulv{at}mbasis.com Abstract Gluconeogenesis is increased in type 2 diabetes and contributes significantly to fasting and postprandial hyperglycemia. We recently reported the discovery of the first potent and selective inhibitors of fructose 1,6-bisphosphatase (FBPase), a rate-controlling enzyme of gluconeogenesis. Herein we describe acute and chronic effects of the lead inhibitor, MB06322 (CS-917), in rodent models of type 2 diabetes. In fasting male ZDF rats with overt diabetes, a single dose of MB06322 inhibited gluconeogenesis by 70% and overall endogenous glucose production by 46%, leading to a reduction in blood glucose of >200 mg/dl. Chronic treatment of freely feeding 6-week-old male Zucker diabetic fatty (ZDF) rats delayed the development of hyperglycemia and preserved pancreatic function. Elevation of lactate (∼1.5-fold) occurred after 4 weeks of treatment, as did the apparent shunting of precursors into triglycerides. Profound glucose lowering (∼44%) and similar metabolic ramifications were associated with 2-week intervention therapy of 10-week-old male ZDF rats. In high-fat diet–fed female ZDF rats, MB06322 treatment for 2 weeks fully attenuated hyperglycemia without evidence of metabolic perturbation other than a modest reduction in glycogen stores (∼20%). The studies confirm that excessive gluconeogenesis plays an integral role in the pathophysiology of type 2 diabetes and suggest that FBPase inhibitors may provide a future treatment option. FBPase, fructose 1,6-bisphosphatase NEFA, nonesterified free fatty acid Footnotes DOI: 10.2337/db05-1443 The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted March 8, 2006. Received November 4, 2005. DIABETES