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.