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Prolonged exposure to homocysteine results in diminished but reversible pancreatic beta-cell responsiveness to insulinotropic agents

Biomedical Sciences Research Institute Computer Science Research Institute Environmental Sciences Research Institute Nanotechnology & Advanced Materials Research Institute

Patterson, Steven, Scullion, Siobhan M. J., McCluskey, Janie, Flatt, Peter and McClenaghan, Neville (2007) Prolonged exposure to homocysteine results in diminished but reversible pancreatic beta-cell responsiveness to insulinotropic agents. DIABETES-METABOLISM RESEARCH AND REVIEWS, 23 (4). pp. 324-334. [Journal article]

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DOI: 10.1002/dmrr.699

Abstract

Background Plasma homocysteine levels may be elevated in poorly controlled diabetes with pre-existing vascular complications and/or nephropathy. Since homocysteine has detrimental effects on a wide diversity of cell types, the present study examined the effects of long-term homocysteine exposure on the secretory function of clonal BRIN-BD11 beta-cells. Methods Acute insulin secretory function, cellular insulin content and viability of BRIN-BD11 cells were assessed following long-term (18 h) exposure to homocysteine in culture. RT-PCR and Western blot analysis were used to determine the expression of key P-cell genes and proteins. Cells were cultured for a further 18 h without homocysteine to determine any long-lasting effects. Results Homocysteine (250-1000 mu mol/L) exposure reduced insulin secretion at both moderate (5.6 mmol/L) and stimulatory (16.7 mmol/L) glucose by 48-63%. Similarly, insulin secretory responsiveness to stimulatory concentrations of alanine, arginine, 2-ketoisocaproate, tolbutamide, KCI, elevated Ca2+, forskolin and PMA, GLP-1, GIP and CCK-8 were reduced by 11-62% following culture with 100-250 mu mol/L homocysteine. These inhibitory effects could not simply be attributed to changes in cellular insulin content, cell viability, H2O2 generation or any obvious alterations of gene/protein expression for insulin, glucokinase, GLUT2, VDCC, or Kir6.2 and SUR1. Additional culture for 18 h in standard culture media after homocysteine exposure restored secretory responsiveness to all agents tested. Conclusion These findings suggest that long-term exposure to high homocysteine levels causes a reversible impairment of pancreatic beta-cell insulinotropic pathways. The in vivo actions of hyperhomocysteinaemia on islet cell function merit investigation. Copyright (C) 2006 John Wiley & Sons, Ltd.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:2942
Deposited By:Professor Peter Flatt
Deposited On:17 Dec 2009 11:52
Last Modified:22 Jun 2011 15:31

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