title: Apolipoprotein A-I increases insulin secretion and production from pancreatic β-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism.
abstract: OBJECTIVE
  Therapeutic interventions that increase plasma levels of high-density lipoproteins and apolipoprotein A-I (apoA-I) A-I, the major high-density lipoprotein apolipoprotein, improve glycemic control in people with type 2 diabetes mellitus. High-density lipoproteins and apoA-I also enhance insulin synthesis and secretion in isolated pancreatic islets and clonal β-cell lines. This study identifies the signaling pathways that mediate these effects.
  
  
  RESULTS
  Incubation with apoA-I increased cAMP accumulation in Ins-1E cells in a concentration-dependent manner. The increase in cAMP levels was inhibited by preincubating the cells with the cell-permeable, transmembrane adenylate cyclase inhibitor, 2'5' dideoxyadenosine, but not with KH7, which inhibits soluble adenylyl cyclases. Incubation of Ins-1E cells with apoA-I resulted in colocalization of ATP-binding cassette transporter A1 with the Gαs subunit of a heterotrimeric G-protein and a Gαs subunit-dependent increase in insulin secretion. Incubation of Ins-1E cells with apoA-I also increased protein kinase A phosphorylation and reduced the nuclear localization of forkhead box protein O1 (FoxO1). Preincubation of Ins-1E cells with the protein kinase A-specific inhibitors, H89 and PKI amide, prevented apoA-I from increasing insulin secretion and mediating the nuclear exclusion of FoxO1. Transfection of Ins-1E cells with a mutated FoxO1 that is restricted to the nucleus confirmed the requirement for FoxO1 nuclear exclusion by blocking insulin secretion in apoA-I-treated Ins-1E cells. ApoA-I also increased Irs1, Irs2, Ins1, Ins2, and Pdx1 mRNA levels.
  
  
  CONCLUSIONS
  ApoA-I increases insulin synthesis and secretion via a heterotrimeric G-protein-cAMP-protein kinase A-FoxO1-dependent mechanism that involves transmembrane adenylyl cyclases and increased transcription of key insulin response and β-cell survival genes.
authors.affiliation: From the Lipid Research Group, Centre for Vascular Research (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.) and Redox Cell Signaling Group, School of Medical Sciences (E.N.G., S.R.T.), University of New South Wales, Sydney, Australia; Lipid Research Group, Heart Research Institute, Sydney, Australia (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.); Australian Centre for Nanomedicine, Sydney, Australia (J.R.); Immune Imaging, Centenary Institute, Sydney, Australia (R.J.B.); and Faculty of Medicine, University of Sydney, Sydney, Australia (P.J.B., K.-A.R.).
authors.forename: Blake J
authors.initials: BJ
authors.lastname: Cochran
authors.affiliation: From the Lipid Research Group, Centre for Vascular Research (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.) and Redox Cell Signaling Group, School of Medical Sciences (E.N.G., S.R.T.), University of New South Wales, Sydney, Australia; Lipid Research Group, Heart Research Institute, Sydney, Australia (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.); Australian Centre for Nanomedicine, Sydney, Australia (J.R.); Immune Imaging, Centenary Institute, Sydney, Australia (R.J.B.); and Faculty of Medicine, University of Sydney, Sydney, Australia (P.J.B., K.-A.R.).
authors.forename: Radjesh J
authors.initials: RJ
authors.lastname: Bisoendial
authors.affiliation: From the Lipid Research Group, Centre for Vascular Research (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.) and Redox Cell Signaling Group, School of Medical Sciences (E.N.G., S.R.T.), University of New South Wales, Sydney, Australia; Lipid Research Group, Heart Research Institute, Sydney, Australia (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.); Australian Centre for Nanomedicine, Sydney, Australia (J.R.); Immune Imaging, Centenary Institute, Sydney, Australia (R.J.B.); and Faculty of Medicine, University of Sydney, Sydney, Australia (P.J.B., K.-A.R.).
authors.forename: Liming
authors.initials: L
authors.lastname: Hou
authors.affiliation: From the Lipid Research Group, Centre for Vascular Research (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.) and Redox Cell Signaling Group, School of Medical Sciences (E.N.G., S.R.T.), University of New South Wales, Sydney, Australia; Lipid Research Group, Heart Research Institute, Sydney, Australia (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.); Australian Centre for Nanomedicine, Sydney, Australia (J.R.); Immune Imaging, Centenary Institute, Sydney, Australia (R.J.B.); and Faculty of Medicine, University of Sydney, Sydney, Australia (P.J.B., K.-A.R.).
authors.forename: Elias N
authors.initials: EN
authors.lastname: Glaros
authors.affiliation: From the Lipid Research Group, Centre for Vascular Research (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.) and Redox Cell Signaling Group, School of Medical Sciences (E.N.G., S.R.T.), University of New South Wales, Sydney, Australia; Lipid Research Group, Heart Research Institute, Sydney, Australia (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.); Australian Centre for Nanomedicine, Sydney, Australia (J.R.); Immune Imaging, Centenary Institute, Sydney, Australia (R.J.B.); and Faculty of Medicine, University of Sydney, Sydney, Australia (P.J.B., K.-A.R.).
authors.forename: Jérémie
authors.initials: J
authors.lastname: Rossy
authors.affiliation: From the Lipid Research Group, Centre for Vascular Research (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.) and Redox Cell Signaling Group, School of Medical Sciences (E.N.G., S.R.T.), University of New South Wales, Sydney, Australia; Lipid Research Group, Heart Research Institute, Sydney, Australia (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.); Australian Centre for Nanomedicine, Sydney, Australia (J.R.); Immune Imaging, Centenary Institute, Sydney, Australia (R.J.B.); and Faculty of Medicine, University of Sydney, Sydney, Australia (P.J.B., K.-A.R.).
authors.forename: Shane R
authors.initials: SR
authors.lastname: Thomas
authors.affiliation: From the Lipid Research Group, Centre for Vascular Research (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.) and Redox Cell Signaling Group, School of Medical Sciences (E.N.G., S.R.T.), University of New South Wales, Sydney, Australia; Lipid Research Group, Heart Research Institute, Sydney, Australia (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.); Australian Centre for Nanomedicine, Sydney, Australia (J.R.); Immune Imaging, Centenary Institute, Sydney, Australia (R.J.B.); and Faculty of Medicine, University of Sydney, Sydney, Australia (P.J.B., K.-A.R.).
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.affiliation: From the Lipid Research Group, Centre for Vascular Research (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.) and Redox Cell Signaling Group, School of Medical Sciences (E.N.G., S.R.T.), University of New South Wales, Sydney, Australia; Lipid Research Group, Heart Research Institute, Sydney, Australia (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.); Australian Centre for Nanomedicine, Sydney, Australia (J.R.); Immune Imaging, Centenary Institute, Sydney, Australia (R.J.B.); and Faculty of Medicine, University of Sydney, Sydney, Australia (P.J.B., K.-A.R.). k.rye@unsw.edu.au karye@ozemail.com.au.
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; C559724:Abcg1 protein, rat; D000067956:Adenylyl Cyclase Inhibitors; D016632:Apolipoprotein A-I; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D044385:GTP-Binding Protein alpha Subunits; D007328:Insulin; D009419:Nerve Tissue Proteins; C495125:Scarb1 protein, rat; D051122:Scavenger Receptors, Class B; C074639:Foxo1 protein, rat; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases
keywords: apolipoprotein A-I; diabetes mellitus, type 2