Relative contribution of Ca 2+-dependent and Ca 2+-independent mechanisms to the regulation of insulin secretion by glucose

Although insulin secretion is usually regarded as a Ca 2+-dependent mechanism, recent studies have suggested the existence of a Ca 2+-independent pathway of regulation by glucose. Here, mouse islets were used to compare the contribution of Ca 2+-dependent and -independent pathways. Glucose increased insulin release in a concentration-dependent manner both in a control medium, when it depolarizes β cells and raises [Ca 2+] i(triggering signal), and in the presence of 30 mM K +and diazoxide, when it does not further raise [Ca 2+] ibut increases its efficacy on exocytosis. Both Ca 2+-dependent responses were amplified by glucagon-like peptide-1+acetylcholine, and were strongly potentiated by forskolin+PMA. Under conditions of mild or stringent Ca 2+deprivation, glucose had no effect either alone or with GLP-1 and acetylcholine, and was poorly effective even during pharmacological activation of protein kinases A and C. Similar results were obtained with rat islets. It is concluded that physiological regulation of insulin release by glucose is essentially achieved through the two Ca 2+-dependent pathways without significant contribution of a Ca 2+-independent mechanism.