title: C16:0 sulfatide inhibits insulin secretion in rat beta-cells by reducing the sensitivity of KATP channels to ATP inhibition.
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.
authors.affiliation: Bartholin Instituttet, Rigshospitalet, 2100 Copenhagen, Denmark. buschard@dadlnet.dk
authors.forename: Karsten
authors.initials: K
authors.lastname: Buschard
authors.forename: Maria
authors.initials: M
authors.lastname: Blomqvist
authors.forename: Jan-Eric
authors.initials: JE
authors.lastname: Månsson
authors.forename: Pam
authors.initials: P
authors.lastname: Fredman
authors.forename: Kirstine
authors.initials: K
authors.lastname: Juhl
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005089:Exocytosis / Q000187:drug effects; D005947:Glucose / Q000037:antagonists & inhibitors; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007340:Insulinoma / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D009844:Oligosaccharides / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew; D013433:Sulfoglycosphingolipids / Q000494:pharmacology*
chemical_list: C514726:C16-0 sulfatide; C112785:FD6 compound; D007328:Insulin; D009844:Oligosaccharides; D015221:Potassium Channels; D013433:Sulfoglycosphingolipids; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium