Antidiabetic Effects of SGLT2-Selective Inhibitor Ipragliflozin in Streptozotocin–Nicotinamide-Induced Mildly Diabetic Mice

Atsuo Tahara; Eiji Kurosaki; Masanori Yokono; Daisuke Yamajuku; Rumi Kihara; Yuka Hayashizaki; Toshiyuki Takasu; Masakazu Imamura; Li Qun; Hiroshi Tomiyama; Yoshinori Kobayashi; Atsushi Noda; Masao Sasamata; Masayuki Shibasaki

doi:10.1254/jphs.12089FP

Full Paper

Antidiabetic Effects of SGLT2-Selective Inhibitor Ipragliflozin in Streptozotocin–Nicotinamide-Induced Mildly Diabetic Mice

Atsuo Tahara, Eiji Kurosaki, Masanori Yokono, Daisuke Yamajuku, Rumi Kihara, Yuka Hayashizaki, Toshiyuki Takasu, Masakazu Imamura, Li Qun, Hiroshi Tomiyama, Yoshinori Kobayashi, Atsushi Noda, Masao Sasamata, Masayuki Shibasaki

Author information

Atsuo Tahara
Drug Discovery Research, Astellas Pharma, Inc., Japan
Eiji Kurosaki
Drug Discovery Research, Astellas Pharma, Inc., Japan
Masanori Yokono
Drug Discovery Research, Astellas Pharma, Inc., Japan
Daisuke Yamajuku
Drug Discovery Research, Astellas Pharma, Inc., Japan
Rumi Kihara
Drug Discovery Research, Astellas Pharma, Inc., Japan
Yuka Hayashizaki
Drug Discovery Research, Astellas Pharma, Inc., Japan
Toshiyuki Takasu
Drug Discovery Research, Astellas Pharma, Inc., Japan
Masakazu Imamura
Drug Discovery Research, Astellas Pharma, Inc., Japan
Li Qun
Applied Pharmacology Research Laboratories, Astellas Pharma Europe B.V., The Netherlands
Hiroshi Tomiyama
Product Planning and Coordination Division, Research and Development Department, Kotobuki Pharmaceutical Co., Ltd., Japan
Yoshinori Kobayashi
Synthetic Division, Research Laboratories, Kotobuki Pharmaceutical Co., Ltd., Japan
Atsushi Noda
Synthetic Division, Research Laboratories, Kotobuki Pharmaceutical Co., Ltd., Japan
Masao Sasamata
Drug Discovery Research, Astellas Pharma, Inc., Japan
Masayuki Shibasaki
Drug Discovery Research, Astellas Pharma, Inc., Japan

Keywords: ipragliflozin, SGLT2, hyperglycemia, urinary glucose excretion, diabetes

JOURNAL FREE ACCESS

2012 Volume 120 Issue 1 Pages 36-44

DOI https://doi.org/10.1254/jphs.12089FP

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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.

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