Journal
EUROPEAN JOURNAL OF ENDOCRINOLOGY
Volume 152, Issue 4, Pages 671-677Publisher
BIOSCIENTIFICA LTD
DOI: 10.1530/eje.1.01885
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Objective: To assess the significance of protein kinase A (PKA) in glucose triggering of ATP-sensitive K+ (K-ATP(+)) channel-dependent insulin secretion and in glucose amplification of K-ATP(+) channel-independent insulin secretion. Methods: Insulin release from cultured perifused mouse pancreatic islets was determined by radioimmunoassay. Results: In islets cultured at 5.5mmol/l glucose, and then perifused in physiological Krebs-Ringer medium. the PKA inhibitors, H89 (10 mu mol/l) and PKI 6-22 amide (30 mu mol/l) did not inhibit glucose (16.7 mu mol/l)-induced insulin secretion, but inhibited stimulation by the adenylyl cyclase activator. forskolin (10 mu mol/l). In the presence of 60 mu mol/l K+ and 250 mu mol/l diazoxide. which stimulates maximum Ca2+ influx independently of K-ATP(+) channels, H89 (10 mu mol/l) inhibited Ca2+-evoked insulin secretion, but failed to prevent glucose amplification of K+ channel-independent insulin secretion. In the presence of 1 mmol/l ouabain and 250 mu mol/l diazoxide. which cause modest Ca2+ influx, glucose amplification of K-ATP(+) channel-independent insulin secretion was Observed without concomitant Ca2+ stimulation of PKA activity. In islets cultured at 16.7 mmol/l glucose, glucose (16.7 mmol/l)-induced insulin secretion in physiological Krebs-Ringer medium was augmented and now inhibited by H89 (10 mu mol/l), implicating that culture at 16.7 mmol/l glucose may increase Ca2+-sensitive adenylyl cyclase activity and hence PKA activity. In accordance, Ca2+-evoked insulin secretion at 60 mmol/l K+ and 250 mu mol/l diazoxide was improved, whereas glucose amplification of K-ATP(+) channel-independent insulin secretion was unaffected. Conclusions: Glucose may activate PKA through triggering of the K-ATP(+) channel-dependent pathway. Glucose amplification of K-ATP(+) channel-independent insulin secretion, on the other hand, occurs by PKA-independent mechanisms.
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