Abstract
Excess flux through the hexosamine biosynthesis pathway results in enhanced protein modification by O‐linked‐β‐N‐acetylglucosamine (O‐GlcNAc), glucotoxicity and insulin resistance. Contributing factors are complex and may include environment as well as genetics. Aims were to examine differences in O‐GlcNAc in rats artificially selected for either low (LCR) or high (HCR) running capacity. Reduced fitness is known to impair mitochondrial function, perpetuate O‐GlcNAc modification and contribute to reduced insulin sensitivity. Insulin sensitivity was assessed by a hyperinsulinemic‐euglycemic clamp in conscious animals while 2‐[14C]deoxyglucose tracked glucose disposal. Immunoblots of heart tissue examined O‐GlcNAc levels and enzymes that control its regulation (OGT, OGA). Artificial selection of rats to generation 19 resulted in 6‐fold greater running capacity and 63% reduction in fat mass in HCR compared to LCR (p<0.05). LCR rats were insulin resistant disposing of 65% less glucose than HCR (p<0.05). Tissue analysis revealed enhanced O‐GlcNAcylation of Complex I, Complex IV, VDAC and SERCA in LCR compared to HCR (p<0.05). Levels of OGT and OGA were not different between groups. Thus, increased O‐GlcNAc in LCR animals may contribute to mitochondrial dysfunction and the pathogenesis of insulin resistance.
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