Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na+-glucose cotransporter inhibitor T-1095

1 The therapeutic effects of an orally active inhibitor of Na+-glucose cotr ansporter (SGLT), T-1095 (a derivative of phlorizin; 3-(benzo[b]furan-5-yl) -2',6'-dihydroxy-4 2'-O-(6-O-methoxycarbonyl-beta -D-glycopyranoside were e xamined in C57BL/KsJ-db/db (db/db) mice, a genetic animal model of obese ty pe 2 diabetes. 2 The higher renal SGLT activity in db/db mice than normoglycaemic C57BL/Ks J-db/+m (db/+m) mice may support the rationale for using an SGLT inhibitor in the treatment regimen for type 2 diabetes. Both T-1095 and its metabolit e, T-1095A, which had approximately 10 times more potency, effectively inhi bited renal SGLT activity of these mice in vitro. 3 Single oral administration of T-1095 (10, 30, 100 mg kg(-1), p.o.) to db/ db mice caused a dose-dependent reduction in blood glucose levels and a con comitant increase in glucose excretion into urine. In contrast, T-1095 only slightly affected blood glucose levels in db/+m mice. 4 Chronic administration of T-1095 (0.1% w w(-1) pellet chow, for 12 weeks) decreased blood glucose and haemoglobin At, levels, and improved glucose i ntolerance in db/db mice. The age-related decrease in plasma insulin levels was markedly inhibited and there was a 2.5 fold increase of insulin conten t in the pancreas of T-1095-treated db/db mice. Food consumption was not ch anged, while impaired body weight gain was ameliorated by T-1095 treatment. 5 Both the development of albuminuria and the expansion of glomerular mesan gial area in db/db mice were significantly suppressed by chronic T-1095 tre atment, indicating the prevention of the progression of diabetic nephropath y. 6 These results demonstrate that the SGLT inhibitor T-1095 is able to impro ve the metabolic abnormalities and inhibit the development of diabetic comp lications in db/db mice. Thus, T-1095 can be used for therapy of type 2 dia betic patients.