Makoto Kurano1, Masumi Hara2, Koichi Tsuneyama3, Hideyuki Sakoda4, Tomo Shimizu5, Kazuhisa Tsukamoto6, Hitoshi Ikeda7, Yutaka Yatomi8. 1. Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: kurano-tky@umin.ac.jp. 2. The Fourth Department of Internal Medicine, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan. Electronic address: masumihara-tky@umin.ac.jp. 3. Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. Electronic address: ktsune@med.u-toyama.ac.jp. 4. Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: hsakoda-tky@umin.ac.jp. 5. Tsukuba Research Institute, Research & Development Division, Sekisui Medical Co., Ltd., Ibaraki, Japan. Electronic address: shimizu154@sekisui.com. 6. Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Fukushima, Japan. Electronic address: kazut@fmu.ac.jp. 7. 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. 8. 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.
Abstract
BACKGROUNDS: 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. METHODS AND 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.
BACKGROUNDS: 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. METHODS AND 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. ApoMretarded 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.