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Apolipoprotein A-I increases insulin secretion and production from pancreatic β-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism

Apolipoprotein A-I increases insulin secretion and production from pancreatic β-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism

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COCHRAN, Blake J., Radjesh J. BISOENDIAL, Liming HOU, Elias N. GLAROS, Jérémie ROSSY, Shane R. THOMAS, Philip J. BARTER, Kerry-Anne RYE, 2014. Apolipoprotein A-I increases insulin secretion and production from pancreatic β-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 34(10), pp. 2261-2267. ISSN 1079-5642. eISSN 1524-4636. Available under: doi: 10.1161/ATVBAHA.114.304131

@article{Cochran2014-10Apoli-43444, title={Apolipoprotein A-I increases insulin secretion and production from pancreatic β-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism}, year={2014}, doi={10.1161/ATVBAHA.114.304131}, number={10}, volume={34}, issn={1079-5642}, journal={Arteriosclerosis, Thrombosis, and Vascular Biology}, pages={2261--2267}, author={Cochran, Blake J. and Bisoendial, Radjesh J. and Hou, Liming and Glaros, Elias N. and Rossy, Jérémie and Thomas, Shane R. and Barter, Philip J. and Rye, Kerry-Anne} }

Glaros, Elias N. Bisoendial, Radjesh J. Bisoendial, Radjesh J. Rossy, Jérémie Apolipoprotein A-I increases insulin secretion and production from pancreatic β-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism Thomas, Shane R. 2014-10 Rye, Kerry-Anne OBJECTIVE:<br />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.<br /><br />APPROACH AND RESULTS:<br />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.<br /><br />CONCLUSIONS:<br />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. eng Cochran, Blake J. Cochran, Blake J. 2018-10-08T09:39:40Z 2018-10-08T09:39:40Z Thomas, Shane R. Barter, Philip J. Rossy, Jérémie Hou, Liming Hou, Liming Glaros, Elias N. Barter, Philip J. Rye, Kerry-Anne

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