Long-term treatment with sergliflozin etabonate improves disturbed glucose metabolism in KK-A(y) mice

Eur J Pharmacol. 2009 Sep 15;618(1-3):98-104. doi: 10.1016/j.ejphar.2009.07.001. Epub 2009 Jul 15.

Abstract

Sergliflozin etabonate, a novel oral selective low-affinity sodium glucose cotransporter (SGLT2) inhibitor, improves hyperglycemia by suppressing renal glucose reabsorption, in which SGLT2 participates as a dominant transporter. In the present study, we examined the antidiabetic profile of sergliflozin etabonate in a diabetic model, KK-A(y) mice, with symptoms of obesity and hyperinsulinemia. The blood glucose level was monitored in non-fasted female KK-A(y) mice after a single oral administration of sergliflozin etabonate. The non-fasting blood glucose level was reduced in a dose-dependent manner after a single oral administration of sergliflozin etabonate (39% reduction at 2 h after a dose of 30 mg/kg). The effects of long-term administration of sergliflozin etabonate on the blood glucose level were assessed in female KK-A(y) mice in several studies (4-day, 8-week, and 9-week administration study), in which sergliflozin etabonate was administered in the diet. The non-fasting blood glucose and plasma insulin were both lowered dose-dependently in the 4-day administration study. Long-term treatment with sergliflozin etabonate dose-dependently improved the hyperglycemia and prevented body weight gain in the 8-week study. In addition to the improvement in glycemic control, fatty liver and pancreatic beta-cell abnormalities were ameliorated in mice fed sergliflozin etabonate in the 9-week study. These data indicate that SGLT2 inhibitors could be useful to improve hyperglycemia resulting from insulin resistance without pancreatic beta-cell abuse or body weight gain. SGLT2 inhibitors may simultaneously realize both a systemic negative energy balance and correction of hyperglycemia.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzhydryl Compounds / administration & dosage*
  • Benzhydryl Compounds / pharmacology*
  • Benzhydryl Compounds / therapeutic use
  • Drug Administration Schedule
  • Female
  • Glucose / metabolism*
  • Glucosides / administration & dosage*
  • Glucosides / pharmacology*
  • Glucosides / therapeutic use
  • Hyperinsulinism / complications
  • Hyperinsulinism / drug therapy
  • Hyperinsulinism / metabolism
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Mice
  • Mice, Inbred Strains
  • Obesity / complications
  • Obesity / drug therapy
  • Obesity / metabolism
  • Time Factors

Substances

  • Benzhydryl Compounds
  • Glucosides
  • Hypoglycemic Agents
  • sergliflozin etabonate
  • Glucose