Proteasome inhibition in skeletal muscle cells unmasks metabolic derangements in type 2 diabetes.

Abstract

Two-dimensional difference gel electrophoresis (2-D DIGE)-based proteome analysis has revealed intrinsic insulin resistance in myotubes derived from type 2 diabetic patients. Using 2-D DIGE-based proteome analysis, we identified a subset of insulin-resistant proteins involved in protein turnover in skeletal muscle of type 2 diabetic patients, suggesting aberrant regulation of the protein homeostasis maintenance system underlying metabolic disease. We then validated the role of the ubiquitin-proteasome system (UPS) in myotubes to investigate whether impaired proteasome function may lead to metabolic arrest or insulin resistance. Myotubes derived from muscle biopsies obtained from people with normal glucose tolerance (NGT) or type 2 diabetes were exposed to the proteasome inhibitor bortezomib (BZ; Velcade) without or with insulin. BZ exposure increased protein carbonylation and lactate production yet impaired protein synthesis and UPS function in myotubes from type 2 diabetic patients, marking the existence of an insulin-resistant signature that was retained in cultured myotubes. In conclusion, BZ treatment further exacerbates insulin resistance and unmasks intrinsic features of metabolic disease in myotubes derived from type 2 diabetic patients. Our results highlight the existence of a confounding inherent abnormality in cellular protein dynamics in metabolic disease, which is uncovered through concurrent inhibition of the proteasome system.

• Authors: Lubna Al-Khalili, Thais de Castro Barbosa, Jörgen Ostling, Julie Massart, Pablo Garrido Cuesta, Megan E Osler, Mutsumi Katayama, Ann-Christin Nyström, Jan Oscarsson, Juleen R Zierath
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 307 Issue 9 Pg. C774-87 (Nov 01 2014) ISSN: 1522-1563 [Electronic] United States
• PMID: 25143351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• Boronic Acids
• Enzyme Inhibitors
• Insulin
• Proteasome Inhibitors
• Proteome
• Pyrazines
• Bortezomib
• Glycogen
• Proteasome Endopeptidase Complex
• Glucose

Topics

• Boronic Acids (pharmacology)
• Bortezomib
• Cells, Cultured
• Diabetes Mellitus, Type 2 (enzymology, metabolism)
• Enzyme Inhibitors (pharmacology)
• Glucose (metabolism)
• Glycogen (biosynthesis)
• Humans
• Insulin (pharmacology)
• Insulin Resistance
• Lipid Metabolism (drug effects)
• Male
• Muscle, Skeletal (drug effects, enzymology, metabolism)
• Oxidative Stress (drug effects)
• Proteasome Endopeptidase Complex (genetics, metabolism, physiology)
• Proteasome Inhibitors (pharmacology)
• Protein Carbonylation (drug effects)
• Proteome (metabolism)
• Pyrazines (pharmacology)
• RNA Interference
• Signal Transduction