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

Br J Pharmacol. 2001 Jan;132(2):578-86. doi: 10.1038/sj.bjp.0703829.


1. 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-beta-D-glycopyranoside)) were examined in C57BL/KsJ-db/db (db/db) mice, a genetic animal model of obese type 2 diabetes. 2. 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. 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 concomitant 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 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. 5. 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. 6. 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.

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Carbonates / therapeutic use*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control
  • Glucagon / metabolism
  • Glucose Tolerance Test
  • Glucosides / therapeutic use*
  • Glycosuria / metabolism
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / metabolism
  • Kidney Glomerulus / pathology
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Microvilli / drug effects
  • Microvilli / metabolism
  • Monosaccharide Transport Proteins / antagonists & inhibitors*
  • Pancreas / metabolism
  • Phenotype
  • Sodium-Glucose Transporter 1


  • Blood Glucose
  • Carbonates
  • Glucosides
  • Hypoglycemic Agents
  • Insulin
  • Membrane Glycoproteins
  • Monosaccharide Transport Proteins
  • Slc5a1 protein, mouse
  • Sodium-Glucose Transporter 1
  • T 1095
  • Glucagon