Abstract:
AIMS/HYPOTHESIS:Insulin-mediated glucose transport and utilisation are decreased in skeletal muscle from type 2 diabetic and glucose-intolerant individuals because of alterations in insulin receptor signalling, GLUT4 translocation to the plasma membrane and microvascular blood flow. Catalytic activity of the muscle-specific isoform of neuronal nitric oxide synthase (nNOS) also participates in the regulation of glucose transport and appears to be decreased in a relevant animal model of drastic insulin resistance, the obese Zucker fa/fa rat. Our objective was to determine the molecular mechanisms involved in this defect. METHODS:Isolated rat muscles and primary cultures of myocytes were used for western blot analysis of protein expression, immunohistochemistry, glucose uptake measurements and GLUT4 translocation assays. RESULTS:nNOS expression was reduced in skeletal muscle from fa/fa rats. This was caused by increased ubiquitination of the enzyme and subsequent degradation by the ubiquitin proteasome pathway. The degradation occurred through a greater interaction of nNOS with the chaperone heat-shock protein 70 and the co-chaperone, carboxyl terminus of Hsc70-interacting protein (CHIP). In addition, an alteration in nNOS sarcolemmal localisation was observed. We confirmed the implication of nNOS breakdown in defective insulin-induced glucose transport by demonstrating that blockade of proteasomal degradation or overexpression of nNOS improved basal and/or insulin-stimulated glucose uptake and GLUT4 translocation in primary cultures of insulin-resistant myocytes. CONCLUSIONS/INTERPRETATION:Recovery of nNOS in insulin-resistant muscles should be considered a potential new approach to address insulin resistance.
journal_name
Diabetologiajournal_title
Diabetologiaauthors
Mezghenna K,Leroy J,Azay-Milhau J,Tousch D,Castex F,Gervais S,Delgado-Betancourt V,Gross R,Lajoix ADdoi
10.1007/s00125-013-3084-9subject
Has Abstractpub_date
2014-01-01 00:00:00pages
177-86issue
1eissn
0012-186Xissn
1432-0428journal_volume
57pub_type
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