Horm Metab Res 2002; 34(4): 217-221
DOI: 10.1055/s-2002-26714
Original Clinical

© Georg Thieme Verlag Stuttgart · New York

Normalization of Cytoplasmic Calcium Response in Pancreatic β-Cells of Spontaneously Diabetic GK Rat by the Treatment with T-1095, a Specific Inhibitor of Renal Na+-Glucose Co-Transporters

K.  Yasuda 1, 2 , Y.  Okamoto 2 , K.  Nunoi 3 , T.  Adachi 3 , N.  Shihara 3 , A.  Tamon 3 , N.  Suzuki 3 , E.  Mukai 2 , S.  Fujimoto 2 , A.  Oku 4 , K.  Tsuda 1, 3 , Y.  Seino 2
  • 1 Laboratory of Metabolism, Faculty of Integrated Human Studies, Kyoto University, Kyoto, Japan
  • 2 Department of Metabolism and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  • 3 Laboratory of Metabolism, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan
  • 4 Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd., Saitama, Japan
K. Yasuda and Y. Okamoto equally contributed to this study.
Further Information

Publication History

25 June 2001

26 December 2001

Publication Date:
30 April 2002 (online)

Abstract

Chronic hyperglycemia is known to lead to a progressively further impaired insulin response and to hasten the development of complications in patients with type 2 diabetes, a notion referred as glucose toxicity. T-1095, a derivative of phlorizin, is a newly developed oral hypoglycemic agent that acts as a specific inhibitor of renal Na+-glucose co-transporters, reducing circulating blood glucose levels by promoting glucose excretion into urine. The effects of glycemic improvement by T-1095 on secretory function and cytoplasmic calcium response in pancreatic β-cells were investigated using spontaneously diabetic GK rats. After four weeks of treatment with T-1095 (age 4 to 8 week rats), serum glucose and HbA1c levels were significantly improved (serum glucose level, GK vs. GK T-1095, 277.3 ± 11.8 vs. 204.7 ± 6.4 mg/dl; HbA1c level, GK vs. GK T-1095, 6.2 ± 0.2 vs. 4.8 ± 0.1 %). Insulin secretion induced by 16.7 mM glucose was also significantly increased in the T-1095-treated group compared to the untreated group. The [Ca2+]i response induced by 16.7 mM glucose in GK β-cells was characterized by the loss of the steep first peak of [Ca2+]i elevation, and the lost first peak of [Ca2+]i reappeared in T-1095-treated β-cells in 32 of 34 observations. In T-1095-treated β-cells, the time lag to peak [Ca2+]i levels in the 16.7 mM glucose stimulation was significantly reduced (259.1 ± 15.3 sec, p < 0.01) compared to untreated GK rats (524.7 ± 52.9 sec). Thus, improvement of hyperglycemia by T-1095 ameliorates β-cell function by relieving [Ca2+]i response.

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K. Yasuda, M.D. Ph.D.

Laboratory of Metabolism · Faculty of Integrated Human Studies ·

Kyoto University, Sakyo-ku · Kyoto 606-8501 · Japan ·

Phone: + 81 (75) 753 66 88 ·

Fax: + 81 (75) 753 66 88

Email: yasuda@tom.life.h.kyoto-u.ac.jp

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