Insulin Secretory Granules Enter a Highly Calcium‐Sensitive State following Palmitate‐Induced Dissociation from Calcium Channels: A Theoretical Study

Impaired insulin secretion is a major contributor to diabetes. Obesity is a known risk factor for the development of diabetes, and prolonged exposure of pancreatic islets to lipids results in impaired insulin secretion. Insulin is released from pancreatic β‐cells as a result of Ca 2+ ‐induced exocytosis. Recent experiments have shown that chronic palmitate exposure results in the loss of localised Ca 2+ ‐influx and impaired exocytosis of insulin secretory granules in β‐cells. In the present study, the roles of Ca 2+ ‐channel clustering disruption, and dissociation of granules from Ca 2+ ‐channels, in the impaired exocytotic and secretory responses from palmitate‐treated β‐cells, are investigated using mathematical models of Ca 2+ dynamics, granule pools, exocytosis and secretion. It is shown that either disruption of Ca 2+ ‐channel clusters or dissociation of granules from Ca 2+ ‐channels with a shift to a highly calcium‐sensitive pool can explain the recent experimental findings of palmitate‐induced defects of exocytosis and insulin secretion. On the basis of imaging results, it is argued that a shift to a highly calcium‐sensitive state after dissociation of granules from Ca 2+ ‐channels is the most likely explanation for the experimental findings from β‐cells exposed chronically to palmitate.