Normalization of cytoplasmic calcium response in pancreatic beta-cells of spontaneously diabetic GK rat by the treatment with T-1095, a specific inhibitor of renal Na+-glucose co-transporters

• Published in: Hormone and metabolic research Vol. 34; no. 4; p. 217
• Main Authors: Yasuda, K, Okamoto, Y, Nunoi, K, Adachi, T, Shihara, N, Tamon, A, Suzuki, N, Mukai, E, Fujimoto, S, Oku, A, Tsuda, K, Seino, Y
• Format: Journal Article
• Language: English
• Published: Germany 01.04.2002
• Subjects: Animals; Arginine - metabolism; Blood Glucose - metabolism; Calcium - antagonists & inhibitors; Calcium - metabolism; Carbonates - pharmacology; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Glucosides - pharmacology; Glycated Hemoglobin A - metabolism; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Hypoglycemic Agents - pharmacology; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Male; Monosaccharide Transport Proteins - antagonists & inhibitors; Monosaccharide Transport Proteins - metabolism; Rats; Rats, Wistar
• ISSN: 0018-5043
• DOI: 10.1055/s-2002-26714

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 beta-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 [Ca(2+)]i response induced by 16.7 mM glucose in GK beta-cells was characterized by the loss of the steep first peak of [Ca(2+)]i elevation, and the lost first peak of [Ca(2+)]i reappeared in T-1095-treated beta-cells in 32 of 34 observations. In T-1095-treated beta-cells, the time lag to peak [Ca(2+)]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 beta-cell function by relieving [Ca(2+)]i response.