Induction of insulin secretion by apolipoprotein M,a carrier for sphingosine 1-phosphate |
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Authors: | Makoto Kurano Masumi Hara Koichi Tsuneyama Hideyuki Sakoda Tomo Shimizu Kazuhisa Tsukamoto Hitoshi Ikeda Yutaka Yatomi |
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Institution: | 1. Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan;2. Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;3. The Fourth Department of Internal Medicine, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan;4. Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan;5. Tsukuba Research Institute, Research & Development Division, Sekisui Medical Co., Ltd., Ibaraki, Japan;6. Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Fukushima, Japan;g Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan |
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Abstract: | BackgroundsHigh-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.Methods and resultsWe 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.ConclusionsApoM augmented insulin secretion by maintaining the S1P concentration under both in vivo and in vitro conditions. |
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Keywords: | ApoA-I apolipoprotein A-I ApoM apolipoprotein M ApoM-Lps apoM-containing lipoproteins prepared from CM-apoM CM-null conditional media of HepG2 cells infected with blank adenovirus CM-apoM conditional media of HepG2 cells infected with adenovirus coding apoM ER endoreticulum HDL high-density lipoprotein Null-Lps control lipoproteins prepared from CM-null S1P sphingosine 1-phosphate VPC VPC 23019 |
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