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.
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.
Yasuda
K
K
Laboratory of Metabolism, Faculty of Integrated Human Studies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. yasuda@tom.life.h.kyoto-u.ac.jp
Okamoto
Y
Y
Nunoi
K
K
Adachi
T
T
Shihara
N
N
Tamon
A
A
Suzuki
N
N
Mukai
E
E
Fujimoto
S
S
Oku
A
A
Tsuda
K
K
Seino
Y
Y
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002254:Carbonates / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D005960:Glucosides / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D001120:Arginine; D001786:Blood Glucose; D002118:Calcium; D002254:Carbonates; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D009004:Monosaccharide Transport Proteins; C121396:T 1095