Inhibition of fructose 1,6-bisphosphatase reduces excessive endogenous glucose production and attenuates hyperglycemia in Zucker diabetic fatty rats.
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.
van Poelje
Paul D
PD
Department of Biochemistry, Metabasis Therapeutics, 11119 North Torrey Pines Rd., La Jolla, CA 92037, USA. paulv@mbasis.com
Potter
Scott C
SC
Chandramouli
Visvanathan C
VC
Landau
Bernard R
BR
Dang
Qun
Q
Erion
Mark D
MD
D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D005260:Female; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors*; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000096:biosynthesis*; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007657:Ketone Bodies / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D007657:Ketone Bodies; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D014280:Triglycerides; D019344:Lactic Acid; C502805:N,N'-((5-(2-amino-5-(2-methylpropyl)-4-thiazolyl)-2-furanyl)phosphinylidene)bis(alanine) diethyl ester; D002784:Cholesterol; D006597:Fructose-Bisphosphatase; D005947:Glucose; D000409:Alanine