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C16:0 Sulfatide Inhibits Insulin Secretion in Rat ß-Cells by Reducing the Sensitivity of K_ATP Channels to ATP Inhibition

¹ Bartholin Instituttet, Rigshospitalet, Copenhagen, Denmark
² Institute of Clinical Neuroscience, The Sahlgrenska Academy at Göteborg University, Mölndal Hospital, Mölndal, Sweden
³ Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado
⁴ Lilly Research Laboratories, Hamburg, Germany

Address correspondence and reprint requests to Dr. Karsten Buschard, Bartholin Instituttet, Rigshospitalet, 2100 Copenhagen, Denmark. E-mail: buschard{at}dadlnet.dk

Abbreviations: [Ca²⁺]_i, cytoplasmic free Ca²⁺ concentration; ELISA, enzyme-linked immunosorbent assay; GalCer, galactosyl ceramide; HPTLC, high-performance thin-layer chromatography; K_ATP channel, ATP-sensitive K⁺ channel; KRBH, Krebs-Ringer bicarbonate HEPES buffer; PIP, phosphatidylinositol phosphate; SulfLacCer, sulfated lactosyl ceramide; TLC, thin-layer chromatography

Sulfatide (3'-sulfo-ß-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 µmol/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, ß-galactosyl ceramide, did not affect any of the measured parameters. C16:0 sulfatide did not modulate glucagon secretion from intact rat islets. In ßTC3 cells, sulfatide was expressed (mean [±SD] 0.30 ± 0.04 pmol/µg protein), and C16:0 sulfatide was found to be the dominant isoform. No expression of sulfatide was detected in TC1-9 cells. We conclude that a major mechanism by which the predominant sulfatide isoform in ß-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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