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J Biol Chem. 2011 Nov 25;286(47):40857-66. doi: 10.1074/jbc.M111.232801. Epub 2011 Oct 7.

Involvement of ATP-sensitive potassium (K(ATP)) channels in the loss of beta-cell function induced by human islet amyloid polypeptide.

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  • 1Diabetes and Obesity Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic de Barcelona, 08036 Barcelona, Spain.

Abstract

Islet amyloid polypeptide (IAPP) is a major component of amyloid deposition in pancreatic islets of patients with type 2 diabetes. It is known that IAPP can inhibit glucose-stimulated insulin secretion; however, the mechanisms of action have not yet been established. In the present work, using a rat pancreatic beta-cell line, INS1E, we have created an in vitro model that stably expressed human IAPP gene (hIAPP cells). These cells showed intracellular oligomers and a strong alteration of glucose-stimulated insulin and IAPP secretion. Taking advantage of this model, we investigated the mechanism by which IAPP altered beta-cell secretory response and contributed to the development of type 2 diabetes. We have measured the intracellular Ca(2+) mobilization in response to different secretagogues as well as mitochondrial metabolism. The study of calcium signals in hIAPP cells demonstrated an absence of response to glucose and also to tolbutamide, indicating a defect in ATP-sensitive potassium (K(ATP)) channels. Interestingly, hIAPP showed a greater maximal respiratory capacity than control cells. These data were confirmed by an increased mitochondrial membrane potential in hIAPP cells under glucose stimulation, leading to an elevated reactive oxygen species level as compared with control cells. We concluded that the hIAPP overexpression inhibits insulin and IAPP secretion in response to glucose affecting the activity of K(ATP) channels and that the increased mitochondrial metabolism is a compensatory response to counteract the secretory defect of beta-cells.

PMID:
21984830
[PubMed - indexed for MEDLINE]
PMCID:
PMC3220453
Free PMC Article

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