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Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells

T Matsuoka1, Y Kajimoto, H Watada

  • 1First Department of Medicine, Osaka University School of Medicine, Tokyo, Japan.

The Journal of Clinical Investigation
|January 1, 1997
PubMed

Insights

Chronic hyperglycemia in diabetes impairs pancreatic beta cells. This study shows D-ribose-induced glycation reduces insulin gene transcription and PDX-1 activity, contributing to beta cell glucose toxicity.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Diabetes Research

Background:

  • Prolonged poor glycemic control in non-insulin-dependent diabetes mellitus (NIDDM) leads to pancreatic beta cell dysfunction.
  • This dysfunction includes reduced insulin secretion and content, a phenomenon termed glucose toxicity.
  • The precise mechanisms underlying glucose toxicity remain incompletely understood.

Purpose of the Study:

  • To investigate the effects of glycation on insulin gene transcription in pancreatic beta cells.
  • To elucidate the role of D-ribose-induced glycation in beta cell glucose toxicity.
  • To identify potential mediators involved in the suppression of insulin gene expression.

Main Methods:

  • Induction of glycation in HIT-T15 cells using D-ribose.
  • Reporter gene analyses to assess insulin gene promoter activity.
  • Measurement of insulin mRNA levels and insulin content.
  • Gel mobility shift assays to evaluate transcription factor DNA-binding activity.

Main Results:

  • D-ribose significantly reduced insulin gene promoter activity in a dose-dependent manner.
  • Glycation led to decreased insulin mRNA levels and cellular insulin content.
  • DNA-binding activity of the insulin gene transcription factor PDX-1/IPF1/STF-1 was diminished.
  • The observed effects were largely irreversible but could be prevented by aminoguanidine or N-acetylcysteine.

Conclusions:

  • Protein glycation, exacerbated by reactive oxygen species, suppresses insulin gene transcription in pancreatic beta cells.
  • This suppression of insulin gene transcription contributes to the beta cell glucose toxicity observed in chronic hyperglycemia.
  • The findings offer insights into the molecular mechanisms of diabetes-related beta cell failure.

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