Glucose-insensitivity induced by Ca(2+) toxicity in islet beta-cells and its prevention by PACAP.
The present study examined whether a sustained increase in cytosolic Ca(2+) concentration ([Ca(2+)](i)) causes glucose-insensitivity in beta-cells and whether it could be modulated by pituitary adenylate cyclase-activating polypeptide (PACAP), a pancreatic insulinotropin. Rat single beta-cells were cultured for 2 days with sustained increases in [Ca(2+)](i), followed by determination of the [Ca(2+)](i) response to glucose (8.3 mM) as monitored with fura-2. High K(+) (25 mM) produced sustained increases in [Ca(2+)](i) in beta-cells, which were inhibited by nifedipine, a Ca(2+) channel blocker. After culture with high K(+), the incidence and amplitude of [Ca(2+)](i) responses to glucose were markedly reduced. This glucose-insensitivity was prevented by the presence of nifedipine or PACAP-38 (10(-13) M and 10-9) M) in high K(+) culture. PACAP-38 attenuated high K(+)-induced [Ca(2+)](i) increases. In conclusion, sustained increases in [Ca(2+)](i) induce glucose-insensitivity (Ca(2+) toxicity in beta-cells) and it is prevented by PACAP possibly in part due to its Ca(2+)-reducing capacity.
Yanagida
Kazuhiro
K
Department of Physiology, Kagoshima University School of Medicine, 8-35-1 Sakuragaoka, 890-8520, Kagoshima, Japan.
Yaekura
Kazuro
K
Arima
Terukatsu
T
Yada
Toshihiko
T
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004396:Coloring Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes / Q000494:pharmacology; D016257:Fura-2 / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011188:Potassium / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
C495403:Adcyap1 protein, rat; D004396:Coloring Agents; D005456:Fluorescent Dyes; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014665:Vasodilator Agents; D005947:Glucose; D011188:Potassium; D002118:Calcium; D016257:Fura-2