Reduction of renal transport maximum for glucose by inhibition of NA(+)-glucose cotransporter suppresses blood glucose elevation in dogs.
T-1095, an orally active inhibitor of Na(+)-glucose cotransporter (SGLT), excretes excess plasma glucose into urine, lowers blood glucose levels, and thus has therapeutic potential for treatment of diabetes mellitus. To elucidate the correlation between threshold for renal glucose reabsorption and blood glucose levels, we evaluated the effects of T-1095 on transport maximum for glucose (TmG) in dogs. Intravenous infusion of T-1095A (0.25-2.0 microg/kg/min), an active metabolite of T-1095, dose-dependently increased fractional glucose excretion induced by a hyper-amount of glucose infusion in anesthetized dogs. Calculated TmG was decreased by T-1095A in a dose dependent manner, and plasma concentration of T-1095A correlated well with the reduction of TmG (R2=0.704). Then, oral glucose tolerance tests (OGTT) were carried out in dogs. T-1095 at a dose of 3 mg/kg (p.o.) slightly increased urinary glucose excretion without affecting blood glucose levels. Ten mg/kg (p.o.) of T-1095 suppressed the elevation of blood glucose levels by excreting a large quantity urinary glucose. The estimated TmG reduction by 3 and 10 mg/kg of T-1095 was about 50% and more than 80%, respectively. In conclusion, this study clarified that more than 80% reduction of TmG by inhibition of SGLT was necessary for suppressing postprandial hyperglycemia in normoglycemic dogs.