IMPAIRED CYTOSOLIC CA2-INHIBITORY POLYPEPTIDE IN PANCREATIC BETA-CELLS FROM TRIPHENYLTIN-INDUCED DIABETIC HAMSTER( RESPONSE TO GLUCOSE AND GASTRIC)

Oral administration of a single dose of triphenyltin compounds induces diabetes with decreased insulin secretion in rabbits and hamsters aft er 2-3 days without any morphological changes in pancreatic islets. In the present study, to test the possibility that the impaired insulin secretion induced by triphenyltin compounds could result from an impai red Ca2+ response in pancreatic beta-cells, we investigated the effect of triphenyltin-chloride (TPTCl) administration on the changes in the cytoplasmic Ca2+ concentration ([Ca2+](i)) induced by secretagogues, such as glucose, high K+, gastric inhibitory polypeptide (GIP), and ac etylcholine (ACh) in hamster pancreatic beta-cells. TPTCl administrati on caused partial suppression in 10 mM K+-induced rise in [Ca2+](i) wi thout suppressing the increase in [Ca2+](i) evoked by 20-50 mM K+. Adm inistration of TPTCl strongly inhibited the rises in [Ca2+](i) induced by 27.8 mM glucose, 100 mu M ACh in the presence of 5.5 mM glucose, a nd by 100 nM GIP in the presence of 5.5 mM glucose. In the ACh-induced response, TPTCl administration strongly suppressed the late sustained phase, while weakly suppressing the initial rise in [Ca2+](i). TPTCl administration significantly suppressed the rise of cAMP content in is let cells induced by 100 nM GIP with 1 mM 3-isobutyl-1-methylxanthine in the presence of 5.5 mM glucose (P < 0.01, N = 5-11). TPTCl administ ration also impaired the insulin secretion in islet cells induced by 2 7.8 mM glucose, 100 nM GIP in the presence of 5.5 mM glucose, and 100 mu M ACh in the presence of 5.5 mM glucose (P < 0.05, N = 9-16). We co nclude that the pathology of triphenyltin-induced diabetes in hamsters involves a defect in cellular Ca2+ response due to a reduced Ca2+-inf lux through voltage-gated Ca2+ channels.