Long-term treatment with sergliflozin etabonate improves disturbed glucose metabolism in KK-A(y) mice.
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.
Katsuno
Kenji
K
Discovery Research Laboratory II, R&D, Kissei Pharmaceutical Co Ltd, Azumino, Japan. kenji_katsuno@pharm.kissei.co.jp
Fujimori
Yoshikazu
Y
Ishikawa-Takemura
Yukiko
Y
Isaji
Masayuki
M
D000284:Administration, Oral; D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005960:Glucosides / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D006946:Hyperinsulinism / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors
D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; C546025:sergliflozin etabonate; D005947:Glucose