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

Abstract

1 The therapeutic e ects 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-b-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, e ectively inhibited renal SGLT activity of these mice in vitro.3 Single oral administration of T-1095 (10, 30, 100 mg kg 71 , p.o.) to db/db mice caused a dosedependent reduction in blood glucose levels and a concomitant increase in glucose excretion into urine. In contrast, T-1095 only slightly a ected blood glucose levels in db/+m mice. 4 Chronic administration of T-1095 (0.1% w w 71 pellet chow, for 12 weeks) decreased blood glucose and haemoglobin A 1C levels, and improved glucose intolerance in db/db mice. The agerelated 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 signi®cantly 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.

SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models

“…Two weeks of treatment with dapagliflozin improved glucose utilization and was accompanied by reduced glucose production and enhanced glucose influx into liver tissue, but the treatment showed no effect on glucose uptake in skeletal muscle and adipose tissue [13] . Similar results have been described for other SGLT-2 inhibitors, for example, T-1095 and empagliflozin [14,15] . Gluco-or lipotoxicity contributes to the decline of β-cell function and mass [16] .…”

“…As the first rate-limiting step in skeletal muscle glucose metabolism, glucose uptake is markedly impaired under diabetic conditions [33] . A few studies have demonstrated that long-term treatment with SGLT2 inhibitors could enhance insulin sensitivity in the livers of type 2 diabetic animal models, but did not effect insulin sensitivity in muscle and adipose tissue [13][14][15] . In this study, a significant decrease in serum insulin levels www.chinaphar.com Yan PK et al Acta Pharmacologica Sinica npg was observed after chronic treatment with SHR3824 that was accompanied by decreased fasting blood glucose and HbA1c levels, suggesting that whole-body insulin sensitivity was improved.…”

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

“…In Akita and streptozotocin-induced animal models of insulin-deficient diabetes, SGLT2 inhibition reduced albuminuria [18][19][20]. SGLT2 inhibition has similar anti-albuminuric effects in animal models of type 2 diabetes [21], including recent evidence that empagliflozin reduced albuminuria, independent of effects on BP or hyperglycaemia, in BTBR ob/ob mouse models of type 2 diabetes [22]. Previous clinical studies in type 2 diabetes patients with and without CKD have shown that SGLT2 inhibition is associated with an acute but modest decline in eGFR within 3-6 weeks of treatment initiation, followed by a period of stable renal function for 52-104 weeks; this change is reversible after drug cessation for 2 weeks [17,23,24].…”

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

“…There are already examples of the clinical use of glucose transporter inhibitors. An oral inhibitor of sodium-glucose cotransporters, T-1095, has been administered to diabetic mice (Arakawa et al, 2001). Higher levels of these transporters are present in the kidneys of diabetic mice than in normal mice and treatment with the inhibitor decreased blood glucose levels by promoting glycosuria.…”