title: Sphingosine 1-phosphate (S1P) regulates glucose-stimulated insulin secretion in pancreatic beta cells.
abstract: Recent studies suggest that sphingolipid metabolism is altered during type 2 diabetes. Increased levels of the sphingolipid ceramide are associated with insulin resistance. However, a role for sphingolipids in pancreatic beta cell function, or insulin production, and release remains to be established. Our studies in MIN6 cells and mouse pancreatic islets demonstrate that glucose stimulates an intracellular rise in the sphingolipid, sphingosine 1-phosphate (S1P), whereas the levels of ceramide and sphingomyelin remain unchanged. The increase in S1P levels by glucose is due to activation of sphingosine kinase 2 (SphK2). Interestingly, rises in S1P correlate with increased glucose-stimulated insulin secretion (GSIS). Decreasing S1P levels by treatment of MIN6 cells or primary islets with the sphingosine kinase inhibitor reduces GSIS. Moreover, knockdown of SphK2 alone results in decreased GSIS, whereas knockdown of the S1P phosphatase, Sgpp1, leads to a rise in GSIS. Treatment of mice with the sphingosine kinase inhibitor impairs glucose disposal due to decreased plasma insulin levels. Altogether, our data suggest that glucose activates SphK2 in pancreatic beta cells leading to a rise in S1P levels, which is important for GSIS.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Cantrell Stanford
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Popa
authors.forename: Kara L
authors.initials: KL
authors.lastname: Larson
authors.forename: Sabire
authors.initials: S
authors.lastname: Özcan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D018149:Glucose Intolerance / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007340:Insulinoma; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D005947:Glucose; D007328:Insulin; D008246:Lysophospholipids; D010744:Phosphoric Monoester Hydrolases; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate