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 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.
Arakawa
K
K
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
Ishihara
T
T
Oku
A
A
Nawano
M
M
Ueta
K
K
Kitamura
K
K
Matsumoto
M
M
Saito
A
A
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002254:Carbonates / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control; D005934:Glucagon / Q000378:metabolism; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000627:therapeutic use*; D006029:Glycosuria / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D010179:Pancreas / Q000378:metabolism; D010641:Phenotype; D051269:Sodium-Glucose Transporter 1
D001786:Blood Glucose; D002254:Carbonates; D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; C121396:T 1095; D005934:Glucagon