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.
Pedersen
M G
MG
Department of Information Engineering, University of Padova, Padova, Italy. pedersen@dei.unipd.it
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D005089:Exocytosis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008962:Models, Theoretical; D019308:Palmitic Acid / Q000494:pharmacology*; D022142:Secretory Vesicles / Q000187:drug effects* / Q000378:metabolism
D015220:Calcium Channels; D007328:Insulin; D019308:Palmitic Acid