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Inhibition of fructose 1,6-bisphosphatase reduces excessive endogenous glucose production and attenuates hyperglycemia in Zucker diabetic fatty rats.

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 ( approximately 1.5-fold) occurred after 4 weeks of treatment, as did the apparent shunting of precursors into triglycerides. Profound glucose lowering ( approximately 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 ( approximately 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.
AuthorsPaul D van Poelje, Scott C Potter, Visvanathan C Chandramouli, Bernard R Landau, Qun Dang, Mark D Erion
JournalDiabetes (Diabetes) Vol. 55 Issue 6 Pg. 1747-54 (Jun 2006) ISSN: 0012-1797 [Print] United States
PMID16731838 (Publication Type: Journal Article)
Chemical References
  • Blood Glucose
  • Insulin
  • Ketone Bodies
  • Organophosphonates
  • Organophosphorus Compounds
  • Triglycerides
  • Lactic Acid
  • N,N'-((5-(2-amino-5-(2-methylpropyl)-4-thiazolyl)-2-furanyl)phosphinylidene)bis(alanine) diethyl ester
  • Cholesterol
  • Fructose-Bisphosphatase
  • Glucose
  • Alanine
Topics
  • Alanine (analogs & derivatives, chemistry, pharmacology, therapeutic use)
  • Animals
  • Blood Glucose (metabolism)
  • Body Weight (drug effects)
  • Cholesterol (metabolism)
  • Diabetes Mellitus, Type 2 (drug therapy, metabolism)
  • Eating (drug effects)
  • Female
  • Fructose-Bisphosphatase (antagonists & inhibitors)
  • Gluconeogenesis (drug effects)
  • Glucose (biosynthesis)
  • Hyperglycemia (drug therapy, metabolism)
  • Insulin (blood)
  • Ketone Bodies (metabolism)
  • Lactic Acid (metabolism)
  • Male
  • Molecular Structure
  • Organophosphonates
  • Organophosphorus Compounds (chemistry, pharmacology, therapeutic use)
  • Pancreas (drug effects, metabolism)
  • Rats
  • Rats, Zucker
  • Triglycerides (metabolism)

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