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- Buschard, Karsten, et al.
(författare)
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C16:0 sulfatide inhibits insulin secretion in rat beta-cells by reducing the sensitivity of KATP channels to ATP inhibition
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:10, s. 2826-34
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Tidskriftsartikel (refereegranskat)abstract
- Sulfatide (3'-sulfo-beta-galactosyl ceramide) is a glycosphingolipid present in mammalians in various fatty acid isoforms of which the saturated 16 carbon-atom length (C16:0) is more abundant in pancreatic islets than in neural tissue, where long-chain sulfatide isoforms dominate. We previously reported that sulfatide isolated from pig brain inhibits glucose-induced insulin secretion by activation of ATP-sensitive K+ channels (K(ATP) channels). Here, we show that C16:0 sulfatide is the active isoform. It inhibits glucose-stimulated insulin secretion by reducing the sensitivity of the K(ATP) channels to ATP. (The half-maximal inhibitory concentration is 10.3 and 36.7 micromol/l in the absence and presence of C16:0 sulfatide, respectively.) C16:0 sulfatide increased whole-cell K(ATP) currents at intermediate glucose levels and reduced the ability of glucose to induce membrane depolarization, reduced electrical activity, and increased the cytoplasmic free Ca2+ concentration. Recordings of cell capacitance revealed that C16:0 sulfatide increased Ca2+-induced exocytosis by 215%. This correlated with a stimulation of insulin secretion by C16:0 sulfatide in intact rat islets exposed to diazoxide and high K+. C24:0 sulfatide or the sulfatide precursor, beta-galactosyl ceramide, did not affect any of the measured parameters. C16:0 sulfatide did not modulate glucagon secretion from intact rat islets. In betaTC3 cells, sulfatide was expressed (mean [+/-SD] 0.30 +/- 0.04 pmol/microg protein), and C16:0 sulfatide was found to be the dominant isoform. No expression of sulfatide was detected in alphaTC1-9 cells. We conclude that a major mechanism by which the predominant sulfatide isoform in beta-cells, C16:0 sulfatide, inhibits glucose-induced insulin secretion is by reducing the K(ATP) channel sensitivity to the ATP block.
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