Accumulation of endogenous methylglyoxal impaired insulin signaling in adipose tissue of fructose-fed rats

Mol Cell Biochem. 2007 Dec;306(1-2):133-9. doi: 10.1007/s11010-007-9563-x. Epub 2007 Jul 28.

Abstract

Increased accumulation of methylglyoxal (MG) has been linked to different insulin resistance states including diabetes and hypertension. In this study, the effects of MG on insulin signaling pathway were investigated. Following 9 weeks of fructose treatment, an insulin resistance state was developed in Sprague-Dawley (SD) rats, demonstrated as increased triglyceride and insulin levels, high blood pressure, and decreased insulin-stimulated glucose uptake by adipose tissue. More importantly, we observed a close correlation between the development of insulin resistance and elevated MG level in serum and adipose tissue. Both insulin resistance state and the elevated MG level were reversed by the MG scavenger, N-acetyl cysteine (NAC). When 3T3-L1 adipocytes were treated directly with MG, the impaired insulin signaling was also observed, indicated by decreased insulin-induced insulin-receptor substrate-1 (IRS-1) tyrosine phosphorylation and the decreased kinase activity of phosphatidylinositol (PI) 3-kinase (PI3K). The ability of NAC to block MG-impairment of PI3K activity and IRS-1 phosphorylation further confirmed the role of MG in the development of insulin resistance. In conclusion, the increase in endogenous MG accumulation impairs insulin-signaling pathway and decreases insulin-stimulated glucose uptake in adipose tissue, which may contribute to the development of insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells / drug effects
  • Acetylcysteine / pharmacology
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipose Tissue / metabolism*
  • Animals
  • Diet
  • Fluorescent Antibody Technique
  • Fructose / administration & dosage*
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Immunoblotting
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance*
  • Male
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Pyruvaldehyde / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*

Substances

  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Irs1 protein, rat
  • Phosphoproteins
  • Fructose
  • Pyruvaldehyde
  • Phosphatidylinositol 3-Kinases
  • Glucose
  • Acetylcysteine