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

Abstract

The therapeutic effects of an orally active inhibitor of Na+‐glucose cotransporter (SGLT), T‐1095 (a derivative of phlorizin; 3‐(benzo[b]furan‐5‐yl)‐2′,6′‐dihydroxy‐4′‐methylpropiophenone 2′‐O‐(6‐O‐methoxycarbonyl‐β‐D‐glycopyranoside)) were examined in C57BL/KsJ‐db/db (db/db) mice, a genetic animal model of obese type 2 diabetes. The higher renal SGLT activity in db/db mice than normoglycaemic C57BL/KsJ‐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 metabolite, T‐1095A, which had approximately 10 times more potency, effectively inhibited renal SGLT activity of these mice in vitro. 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 concomitant increase in glucose excretion into urine. In contrast, T‐1095 only slightly affected blood glucose levels in db/+m mice. Chronic administration of T‐1095 (0.1% w w−1 pellet chow, for 12 weeks) decreased blood glucose and haemoglobin A 1C levels, and improved glucose intolerance 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 content in the pancreas of T‐1095‐treated db/db mice. Food consumption was not changed, while impaired body weight gain was ameliorated by T‐1095 treatment. Both the development of albuminuria and the expansion of glomerular mesangial area in db/db mice were significantly suppressed by chronic T‐1095 treatment, indicating the prevention of the progression of diabetic nephropathy. These results demonstrate that the SGLT inhibitor T‐1095 is able to improve the metabolic abnormalities and inhibit the development of diabetic complications in db/db mice. Thus, T‐1095 can be used for therapy of type 2 diabetic patients. British Journal of Pharmacology (2001) 132, 578–586; doi:10.1038/sj.bjp.0703829