| Objective: Musclin is a novel skeletal muscle-derived secretory factor discovered in 2004 and has been considered to associated with insulin resistance(IR) of skeletal muscle. However, the alterations of endogenous musclin in type 2 diabetes mellitus(T2DM) have not been adequately investigated. In current study, we examined the changes of musclin levels in plasma and investigate the association between musclin levels and T2 DM. We also investigate the endogenous changes of musclin in insulin resistance(IR) of rats.Measurements:In this hospital-based case-control study, 38 newly diagnosed T2 DM subjects who never received anti-diabetic therapy, 41 T2 DM subjects under insulin treatment and 41 normal subjects were enrolled. High fat diet(HFD) induced obese rats were used as the IR model. Plasma musclin levels were measured by radioimmunoassay. Radioimmunoassay and western blot were used to determine musclin levels in skeletal muscle. Association between musclin levels and T2 DM was assessed using univariate and multivariate analyses. Value of musclin levels for the detection of T2 DM was evaluated using receiver operating characteristic(ROC) curve.Results: We found that plasma musclin level were significantly higher in the newly diagnosed T2 DM group than in the normal group and were significantly decreased in T2 DM with insulin therpay group. Plasma musclin concentration in newly diagnosed T2 DM patients displayed positive correlation with fasting plasma glucose(FPG)(r=0.467,p<0.01), hemoglobin A1c(Hb A1c)(r=0.383, P<0.05), triglyceride(TG)(r=0.452,p<0.01) and homeostasis model assessment of insulin resistance index(HOMA-IRI)(r=0.388, p<0.05). High-density lipoprotein(HDL) displayed a negative correlation with musclin level in plasma(r=-0.0.339, P<0.05). Odds ratios(95% confidence intervals) of T2 DM across increasing quartiles of plasma musclin level were 1.17(0.31 to 4.43), 3.25(0.87 to 12.13), and 4.02(1.06 to 15.27). The test for trend was significant(p =0.0087). Spline regression analyses indicated a linear relation between plasma musclin level and T2 DM risk. The sensitivity of musclin was 46.43% and the specificity was 82.93% whereas the musclin cutoff value was 99.45 pg/m L. The area under the ROC curve was 0.71. Compared with controls, HFD rats showed increased levels of(FPG) and serum insulin, by 37.6% and 76.68%, respectively(both p<0.01), and insulin-stimulated [3H]-2-deoxy-D-glucose(3H-2-DG) uptake of the soleus muscles decreased by 26.3%(p<0.05). HFD rats showed increased musclin immunoreactivity(musclin-ir) in plasma(p<0.01) and in skeletal muscle(p<0.05), increased musclin m RNA levels in skeletal muscle(p<0.01). Preincubation with musclin(1.5×10-7mol/L) induced insulin resistance in skeletal muscle.Insulin induced glucose uptake of the soleus muscle decreased by 48.3%(P<0.01). As compared with normal diet(ND) rat, HFD rat markedly decreased the protein level of GLUT-4 by 83.1%(P<0.05). Compared with normal diet rat, Musclin treatment reduced the protein level of glucose transporter 4(GLUT4) by 30%(P<0.05). After HFD for 20 weeks, glucose regulated protein(GRP)78 and GRP94 protein levels in skeletal muscle were significantly increased by 136.1% and 48.6%(both P<0.05) respectively compared with normal diet rats. On western blot analysismusclin treatment increased protein levels of GRP78 and GRP94 by 146.8% and 54%(both P<0.05) respectively, compared with ND group.Conclusion:The present work indicates that plasma musclin level was associated with increased risk of T2 DM and a potential link between musclin and the pathogenesis of T2 DM. Upregulation of endogenous musclin during HFD induced IR and musclin could induced the skeletal muscle IR,at least in part,through activating skeletal muscle endoplasmic reticulum stress. |
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