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

Horm Metab Res. 2002 Apr;34(4):217-21. doi: 10.1055/s-2002-26714.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Blood Glucose
  • Carbonates
  • Glucosides
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • Monosaccharide Transport Proteins
  • T 1095
  • Arginine
  • Calcium