Triphenyltin impairs insulin secretion by decreasing glucose-induced NADP(H) and ATP production in hamster pancreatic β-cells.
Oral administration of triphenyltin chloride (TPT) (6 mg/100g body weight) inhibits insulin secretion by decreasing glucose-induced cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) in pancreatic β-cells of the hamster. To test the possibility that the abnormal level of the [Ca(2+)](i) induced by TPT administration could be due to a defect in the metabolic signal of glucose in the β-cells, we tested the effects of TPT administration on the glucose-induced NAD(P)H and ATP production, and on the changes of membrane potential and [Ca(2+)](i) by glucose and high K(+) in the β-cells. The [Ca(2+)](i) was measured in islet cells loaded with fura-2. TPT administration significantly reduced the NAD(P)H and ATP production, the depolarization of plasma membrane, and insulin secretion by 15 mM glucose in islet cells. TPT administration also reduced the insulin secretion by 10mM dihydroxyacetone and glyceraldehyde. However, TPT administration did not affect the increase of [Ca(2+)](i) and the insulin secretion by 30 mMK(+) or 100 μM tolbutamide, and the membrane potential by 30 mMK(+), and the insulin secretion by 10mM α-ketoisocaproic acid and 0.5mM formycin A, an analog of ATP in the presence of 15 mM glucose. These results suggested that the pathogenesis of TPT-induced hyperglycemia in hamster involves the reduction of [Ca(2+)](i) and insulin secretion in response to K(ATP) channel-dependent depolarization, which is related to the decrease of NAD(P)H and ATP production in pancreatic islet cells after glucose metabolism.
Laboratory of International Epidemiology, Dokkyo Medical University School of Medicine, 880 Mibu, Tochigi 321-0293, Japan. y-miura@dokkyomed.ac.jp
Yoshikazu
Y
Miura
Yuichi
Y
Hori
Shinzo
S
Kimura
Hiroyuki
H
Hachiya
Yuichirou
Y
Sakurai
Kenichi
K
Inoue
Tokihiko
T
Sawada
Keiichi
K
Kubota
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008647:Mesocricetus; D009249:NADP / Q000378:metabolism*; D009947:Organotin Compounds / Q000633:toxicity*; D018408:Patch-Clamp Techniques
D007328:Insulin; D009947:Organotin Compounds; D009249:NADP; D000255:Adenosine Triphosphate; C012594:triphenyltin chloride; D005947:Glucose; D002118:Calcium