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- Title
MB06322 (CS-917), but not Metformin, Lowers Blood Glucose by Inhibiting Gluconeogenesis in Zucker Diabetic Fatty Rats.
- Authors
Van Poelje, Paul D.; Potter, Scott C.; Haughey, Michael P.; Linemeyer, David L.; Erion, Mark D.
- Abstract
Increased gluconeogenesis is a major cause of hyperglycemia in patients with type 2 diabetes. We recently reported the discovery of MB06322 (CS-917), an orally available prodrug of a rationally designed inhibitor of fructose 1,6-bisphosphatase, a rate-controlling enzyme of gluconeogenesis. These studies further characterize MB06322 and compare its mechanism of action in male Sprague Dawley (SD) and Zucker diabetic fatty (ZDF) rats to that of metformin, a drug that inhibits gluconeogenesis in humans. MB06322 (10 mg/kg), but not metformin (1000 mg/kg), lowered blood glucose in overnight fasted SD rats, a model that depends solely on gluconeogenesis for maintenance of euglycemia. Intravenous infusion of the active metabolite of MB06322 at a rate of 1, 3 or 10 mg*kg[sup -1]*h[sup -1] inhibited glucose production in SD rats as assessed by euglycemic clamp. Approximately ∼95% inhibition was achieved at the highest infusion rate evaluated. Both metformin (100 and 1000 mg/kg) and MB06322 (30 and 300 mg/kg) lowered blood glucose acutely in postabsorptive ZDF rats, but only MB06322 inhibited gluconeogenesis and endogenous glucose production (EGP), as determined by [sup 14]C-bicarbonate and 6-[³H]-glucose tracer methods, respectively. Fourteen-day treatment of ZDF rats with metformin lowered blood glucose but did not reduce EGP. In contrast to MB06322, which potently inhibited gluconeogenesis from [sup 14]C-lactate in isolated ZDF rat bepatocytes (IC[sub 50]01.3 ± 0.1 µM), supra-pharmacological concentrations (> 1 mM) of metformin were required to inhibit gluconeogenesis in these cells. Furthermore, metformin altered cellular redox state, as indicated by an up to 3.7-fold increased lactate:pyruvate ratio, and increased lactate production. MB06322 demonstrated the expected in vitro and in vivo effects of a potent and selective inhibitor of gluconeogenesis. Metformin inhibited gluconeogenesis ∼ 1000-fold less potently than MB06322 in vitro and, at doses that lowered blood glucose, did not inhibit glucose production in vivo. The antihyperglycemic mechanism of metformin in ZDF rats differs from the primary mechanism ascribed to metformin in humans.
- Publication
Diabetes, 2007, Vol 56, pA145
- ISSN
0012-1797
- Publication type
Academic Journal