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 beta-cells as a result of Ca2+-induced exocytosis. Recent experiments have shown that chronic palmitate exposure results in the loss of localised Ca2+-influx and impaired exocytosis of insulin secretory granules in beta-cells. In the present study, the roles of Ca2+-channel clustering disruption, and dissociation of granules from Ca2+-channels, in the impaired exocytotic and secretory responses from palmitate-treated beta-cells, are investigated using mathematical models of Ca2+ dynamics, granule pools, exocytosis and secretion. It is shown that either disruption of Ca2+-channel clusters or dissociation of granules from Ca2+-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 Ca2+-channels is the most likely explanation for the experimental findings from beta-cells exposed chronically to palmitate.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

HCSP

palmitate

insulin secretion

beta-cells

mathematical modelling

Publikations- och innehållstyp

art (ämneskategori)

ref (ämneskategori)