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Impaired Cytosolic Ca²⁺ Response to Glucose and Gastric Inhibitory Polypeptide in Pancreatic ß-Cells from Triphenyltin-Induced Diabetic Hamster

Department of Hygiene (Y.M., H.M.), Dokkyo University School of Medicine, Mibu, Tochigi 321–02, Japan; Department of Physiology I (M.K.), Nippon Medical School, Sendagi 1, Bunkyo, Tokyo 113 Japan; Department of Medicine (K.O.), Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Saitama 343, Japan

Address all correspondence and requests for reprints to: Yoshikazu Miura, Ph.D., Department of Hygiene, Dokkyo University School of Medicine, 880, Mibu, Tochigi 321–02, Japan.

Oral administration of a single dose of triphenyltin compounds induces diabetes with decreased insulin secretion in rabbits and hamsters after 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 impaired Ca²⁺ response in pancreatic ß-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 acetylcholine (ACh) in hamster pancreatic ß-cells. TPTCl administration caused partial suppression in 10 mM K⁺-induced rise in [Ca²⁺]_i without suppressing the increase in [Ca²⁺]_i evoked by 20–50 mM K⁺. Administration of TPTCl strongly inhibited the rises in [Ca²⁺]_i induced by 27.8 mM glucose, 100 µM ACh in the presence of 5.5 mM glucose, and 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 islet 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 administration also impaired the insulin secretion in islet cells induced by 27.8 mM glucose, 100 nM GIP in the presence of 5.5 mM glucose, and 100 µM ACh in the presence of 5.5 mM glucose (P < 0.05, N = 9–16). We conclude that the pathology of triphenyltin-induced diabetes in hamsters involves a defect in cellular Ca²⁺ response due to a reduced Ca²⁺-influx through voltage-gated Ca²⁺ channels.

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