Abstract from upcoming EAS conference in June This is not from RVX, but from an Austrailian group. Effects of apoAI on insulin secretion and beta cell survival. This has applications to the effect of RVX-208 on treatment of diabetes.
https://www2.kenes.com/eas2013/sci/Pages/ScientificProgramme.aspx
| APOA-I INCREASES INSULIN SECRETION FROM PANCREATIC BETA CELLS VIA A CAMP-PKA-FOXO1 DEPENDANT MECHANISM |    |
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| Blake J. Cochran, R.J. Bisoendial, K.-A. Rye |
| Centre for Vascular Research, University of New South Wales, Sydney, NSW, Australia |
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Introduction: The progression to hyperglycaemia in type 2 diabetes is marked by β-cell insulin secretory dysfunction and cell loss. We have previously demonstrated that apolipoprotein (apo) A-I, the major apolipoprotein constituent of high density lipoproteins (HDL), increases insulin expression and secretion from β-cells. Pharmacological elevation of HDL levels is also associated with improved glycemic control in patients with type 2 diabetes. With the current interest in HDL raising therapeutics, defining the mechanism by which apoA-I acts on insulin secretion is important.
Objective: The objective of this study was to elucidate the cell signalling events responsible for increasing insulin secretion from pancreatic β-cells treated with lipid-free apoA-I.
Results: Incubation with apoA-I (1 mg/ml final concentration) increased cAMP accumulation in Ins1-E cells in a dose dependant manner. This increase was totally inhibited when the cells were pre-incubated with the cell-permeable transmembrane adenylate cyclase inhibitor, 2'5' dideoxyadenosine, but not with KH7, which inhibits soluble adenylyl cyclases. Incubation with apoA-I also increased phosphorylation of PKA and increased insulin secretion from Ins1-E cells and isolated rat islets, 3-fold and 2-fold, respectively. The increased insulin secretion was reduced to control levels by pre-treatment with the PKA-specific inhibitor H89. Confocal microscopy was used to establish that apoA-I mediates nuclear exclusion of FoxO1, and that this was blocked by pre-incubation with H89. Transfection of Ins-1E cells with constitutive nuclear FoxO1 (FoxO1-ADA) confirmed the requirement of FoxO1 nuclear exclusion for mediating increased long-term insulin secretion in cells treated with apoA-I. ApoA-I also increased the transcription of the IRS1, IRS2, Ins1, Ins2, Pdx1 and Pax6 genes.
Conclusion: ApoA-I increases insulin secretion from pancreatic β-cells via a cAMP-PKA-FoxO1-dependent mechanism that involves transmembrane adenyl cyclases. ApoA-I also upregulates transcription of key insulin response and b-cell survival genes. |
Assigned speakers:
Dr. Blake Cochran, University of New South Wales , Sydney , Australia |
Assigned in sessions:
05.06.2013, 10:50-12:40, Workshop, Metabolic regulation of apoliprotein A-I-containing lipoproteins, Michel Macheboeuf |
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