title: Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice.
abstract: The sodium-glucose cotransporter 2 (SGLT2) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the therapeutic effects of SGLT2 selective inhibitor ipragliflozin were examined in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice which exhibit impaired insulin secretion, insulin resistance, hyperlipidemia, hepatic steatosis, and obesity. Single administration of ipragliflozin dose-dependently increased urinary glucose excretion, reduced blood glucose and plasma insulin levels, and improved glucose intolerance. Four-week repeated administration of ipragliflozin improved not only glucose tolerance, hyperglycemia, and hyperinsulinemia but also impaired insulin secretion, hyperlipidemia, hepatic steatosis, and obesity with a concomitant increase in urinary glucose excretion. In addition, ipragliflozin reduced plasma and liver levels of oxidative stress biomarkers (thiobarbituric acid reactive substances and protein carbonyl) and inflammatory markers (interleukin 6, tumor necrosis factor α, monocyte chemotactic protein-1, and c-reactive protein), and improved liver injury as assessed by plasma levels of aminotransferases. These results demonstrate that SGLT2 selective inhibitor ipragliflozin improves not only hyperglycemia but also diabetes/obesity-associated metabolic abnormalities in type 2 diabetic mice and suggest that ipragliflozin may be useful in treating type 2 diabetes with metabolic syndrome.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Ibaraki, 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: Qun
authors.initials: Q
authors.lastname: Li
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; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000652:urine; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000150:complications / Q000188:drug therapy; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006029:Glycosuria / Q000188:drug therapy; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000150:complications / Q000188:drug therapy; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D009765:Obesity / Q000150:complications / Q000188:drug therapy; D018384:Oxidative Stress / Q000187:drug effects*; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C572941:ipragliflozin
keywords: Diabetes; Hyperglycemia; Ipragliflozin; SGLT2; Urinary glucose excretion