title: Induction of insulin secretion by apolipoprotein M, a carrier for sphingosine 1-phosphate.
abstract: BACKGROUND
  High-density lipoprotein (HDL) has been proposed to enhance β-cell functions. Clinical studies have suggested that apolipoprotein M (apoM), which rides mainly on HDL, is involved in diabetes; however, the underlying mechanism has not yet been elucidated. Recently, apoM was shown to be a carrier for sphingosine 1-phosphate (S1P), a bioactive lipid mediator. In the present study, we investigated the modulation of insulin secretion by apoM through the action of S1P.
  
  
  RESULTS
  We overexpressed apoM in the livers of C57BL6 mice using adenovirus gene transfer and found that the blood glucose levels under ad libitum feeding conditions were lower in the apoM-overexpressing mice. While an insulin tolerance test revealed that insulin sensitivity was not significantly affected, a glucose tolerance test revealed that apoM-overexpressing mice had a better glucose tolerance because of enhanced insulin secretion, a phenomenon that was reversed by treatment with VPC 23019, an antagonist against S1P1 and S1P3 receptor. In vitro experiments with MIN6 cells also revealed that apoM-containing lipoproteins enhanced insulin secretion, which was again inhibited by VPC 23019. ApoM retarded the degradation of S1P, and an increase in Pdx1 expression, the attenuation of endoreticulum stress, and the phosphorylation of Akt, AmpK, and Erk were observed as possible underlying mechanisms for the effect of S1P, maintained at a high concentration by apoM, on the increase in insulin secretion.
  
  
  CONCLUSIONS
  ApoM augmented insulin secretion by maintaining the S1P concentration under both in vivo and in vitro conditions.
authors.affiliation: Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: kurano-tky@umin.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurano
authors.affiliation: The Fourth Department of Internal Medicine, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan. Electronic address: masumihara-tky@umin.ac.jp.
authors.forename: Masumi
authors.initials: M
authors.lastname: Hara
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. Electronic address: ktsune@med.u-toyama.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: hsakoda-tky@umin.ac.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.affiliation: Tsukuba Research Institute, Research & Development Division, Sekisui Medical Co., Ltd., Ibaraki, Japan. Electronic address: shimizu154@sekisui.com.
authors.forename: Tomo
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Fukushima, Japan. Electronic address: kazut@fmu.ac.jp.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Tsukamoto
authors.affiliation: Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan; Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan. Electronic address: ikeda-1im@h.u-tokyo.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan; Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan. Electronic address: yatoyuta-tky@umin.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001053:Apolipoproteins / Q000235:genetics* / Q000378:metabolism; D000075243:Apolipoproteins M; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: C501623:ApoM protein, mouse; D001053:Apolipoproteins; D000075243:Apolipoproteins M; D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; D013110:Sphingosine
keywords: Apolipoprotein M; Insulin secretion; MIN6 cells; Sphingosine 1-phosphate