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.