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.

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.

• Authors: K Yasuda, Y Okamoto, K Nunoi, T Adachi, N Shihara, A Tamon, N Suzuki, E Mukai, S Fujimoto, A Oku, K Tsuda, Y Seino
• Journal: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme (Horm Metab Res) Vol. 34 Issue 4 Pg. 217-21 (Apr 2002) ISSN: 0018-5043 [Print] Germany
• PMID: 11987033 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Arginine (metabolism)
• Blood Glucose (metabolism)
• Calcium (antagonists & inhibitors, metabolism)
• Carbonates (pharmacology)
• Diabetes Mellitus, Type 2 (blood, drug therapy, metabolism)
• Glucosides (pharmacology)
• Glycated Hemoglobin (metabolism)
• Hyperglycemia (drug therapy, metabolism)
• Hypoglycemic Agents (pharmacology)
• Insulin (metabolism)
• Insulin Secretion
• Islets of Langerhans (drug effects, metabolism)
• Male
• Monosaccharide Transport Proteins (antagonists & inhibitors, metabolism)
• Rats
• Rats, Wistar