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

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.

Type 2 Diabetes - Insulin Secretion - Fura-2 AM - Pancreatic Beta-Cell - Phlorizin

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