title: Cholesterol elevation impairs glucose-stimulated Ca(2+) signaling in mouse pancreatic β-cells.
abstract: Recent studies have demonstrated that cholesterol elevation in pancreatic islets is associated with a reduction in glucose-stimulated insulin secretion, but the underlying cellular mechanisms remain elusive. Here, we show that cholesterol enrichment dramatically reduced the proportion of mouse β-cells that exhibited a Ca(2+) signal when stimulated by high glucose. When cholesterol-enriched β-cells were challenged with tolbutamide, there was a decrease in the amplitude of the Ca(2+) signal, and it was associated with a reduction in the cell current density of voltage-gated Ca(2+) channels (VGCC). Although the cell current densities of the ATP-dependent K(+) channels and the delayed rectifier K(+) channels were also reduced in the cholesterol-enriched β-cells, glucose evoked only a small depolarization in these cells. In cholesterol-enriched cells, the glucose-mediated increase in cellular ATP content was dramatically reduced, and this was related to a decrease in glucose uptake via glucose transporter 2 and an impairment of mitochondrial metabolism. Thus, cholesterol enrichment impaired glucose-stimulated Ca(2+) signaling in β-cells via two mechanisms: a decrease in the current density of VGCC and a reduction in glucose-stimulated mitochondrial ATP production, which in turn led to a smaller glucose-evoked depolarization. The decrease in VGCC-mediated extracellular Ca(2+) influx in cholesterol-enriched β-cells was associated with a reduction in the amount of exocytosis. Our findings suggest that defect in glucose-stimulated Ca(2+) signaling is an important mechanism underlying the impairment of glucose-stimulated insulin secretion in islets with elevated cholesterol level.
authors.affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
authors.forename: Andy K
authors.initials: AK
authors.lastname: Lee
authors.forename: Valerie
authors.initials: V
authors.lastname: Yeung-Yam-Wah
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Tse
authors.forename: Amy
authors.initials: A
authors.lastname: Tse
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism*; D004594:Electrophysiology; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice
chemical_list: D015220:Calcium Channels; D007328:Insulin; D002784:Cholesterol; D005947:Glucose; D002118:Calcium