title: Antidiabetic effects of SGLT2-selective inhibitor ipragliflozin in streptozotocin-nicotinamide-induced mildly diabetic mice.
abstract: Sodium-glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption, and inhibition of renal SGLT2 activity represents an innovative strategy for the treatment of hyperglycemia in diabetic patients. The present study investigated the antidiabetic effects of ipragliflozin, a SGLT2-selective inhibitor, in streptozotocin-nicotinamide-induced mildly diabetic mice, which exhibited a mild decline in glucose tolerance associated with the loss of early-phase insulin secretion. Oral administration of ipragliflozin increased urinary glucose excretion in a dose-dependent manner, an effect which was significant at doses of 0.3 mg/kg or higher and lasted over 12 h. In addition, ipragliflozin dose-dependently improved hyperglycemia and glucose intolerance with concomitant decreases in plasma insulin levels without causing hypoglycemia. Once-daily dosing of ipragliflozin (0.1 - 3 mg/kg) for 4 weeks attenuated hyperglycemia, glucose intolerance, and impaired insulin secretion. These results suggest that the SGLT2-selective inhibitor ipragliflozin increases urinary glucose excretion by inhibiting renal glucose reabsorption, improves hyperglycemia in streptozotocin-nicotinamide-induced mildly diabetic mice, and may be useful for treating type 2 diabetes.
authors.affiliation: Drug Discovery Research, Astellas Pharma, Inc., Ibaraki 305-8585, Japan. atsuo.tahara@jp.astellas.com
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tahara
authors.forename: Eiji
authors.initials: E
authors.lastname: Kurosaki
authors.forename: Masanori
authors.initials: M
authors.lastname: Yokono
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamajuku
authors.forename: Rumi
authors.initials: R
authors.lastname: Kihara
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hayashizaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takasu
authors.forename: Masakazu
authors.initials: M
authors.lastname: Imamura
authors.forename: Li
authors.initials: L
authors.lastname: Qun
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomiyama
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Noda
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000494:pharmacology / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009536:Niacinamide; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013311:Streptozocin; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D009536:Niacinamide; C572941:ipragliflozin; D013311:Streptozocin; D005947:Glucose