Molecular and Cellular Biochemistry

, Volume 328, Issue 1–2, pp 217–224 | Cite as

Molecular convergence of hexosamine biosynthetic pathway and ER stress leading to insulin resistance in L6 skeletal muscle cells

  • V. Srinivasan
  • U. Tatu
  • V. Mohan
  • M. Balasubramanyam
Article

Abstract

Augmentation of hexosamine biosynthetic pathway (HBP) and endoplasmic reticulum (ER) stress were independently related to be the underlying causes of insulin resistance. We hypothesized that there might be a molecular convergence of activated HBP and ER stress pathways leading to insulin resistance. Augmentation of HBP in L6 skeletal muscle cells either by pharmacological (glucosamine) or physiological (high-glucose) means, resulted in increased protein expression of ER chaperones (viz., Grp78, Calreticulin, and Calnexin), UDP-GlcNAc levels and impaired insulin-stimulated glucose uptake. Cells silenced for O-glycosyl transferase (OGT) showed improved insulin-stimulated glucose uptake (P < 0.05) but without any effect on ER chaperone upregulation. While cells treated with either glucosamine or high-glucose exhibited increased JNK activity, silencing of OGT resulted in inhibition of JNK and normalization of glucose uptake. Our study for the first time, demonstrates a molecular convergence of O-glycosylation processes and ER stress signals at the cross-road of insulin resistance in skeletal muscle.

Keywords

Insulin resistance Diabetes HBP ER stress UDP-GlcNAc OGT RNAi JNK Glucose uptake Skeletal muscle 

Supplementary material

11010_2009_92_MOESM1_ESM.pdf (33 kb)
(PDF 33 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • V. Srinivasan
    • 1
  • U. Tatu
    • 2
  • V. Mohan
    • 1
  • M. Balasubramanyam
    • 1
  1. 1.Department of Cell and Molecular BiologyMadras Diabetes Research Foundation, Dr. Mohan’s Diabetes Specialities CenterChennaiIndia
  2. 2.Department of BiochemistryIndian Institute of ScienceBangaloreIndia

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