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

Steven Patterson*, Siobhan M.J. Scullion, Jane T. McCluskey, Peter R. Flatt, Neville H. McClenaghan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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 beta-cell genes and proteins. Cells were cultured for a further 18 h without homocysteine to determine any long-lasting effects.

Results: Homocysteine (250-1000 micromol/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, KCl, elevated Ca2+, forskolin and PMA, GLP-1, GIP and CCK-8 were reduced by 11-62% following culture with 100-250 micromol/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.
Original languageEnglish
Pages (from-to)324-334
Number of pages11
JournalDiabetes/Metabolism Research and Reviews
Volume23
Issue number4
Early online date6 Nov 2006
DOIs
Publication statusPublished - May 2007

Keywords

  • insulin secretion
  • homocysteine
  • pancreatic β-cells

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