Lower circulating irisin is associated with type 2 diabetes mellitus

Abstract

Aims

Irisin is a novel myokine secreted in response to PPAR-γ co-activator-1α (PGC-1α) activation. Earlier studies suggested that PGC-1α expression and activity were lower in myocytes in type 2 diabetes mellitus (T2DM). Therefore, we hypothesize that circulating irisin levels are lower in T2DM patients.

Methods

In this observational study, we recruited 96 T2DM subjects and 60 non-diabetic control subjects. Among T2DM subjects, 38% were on insulin treatment, 78% were taking statins and 72% were taking renin-angiotensin system antagonists. Circulating irisin was quantified by ELISA and its association with markers of metabolic phenotype was analyzed by Pearson bivariate correlation and multiple linear regression.

Results

Circulating irisin was significantly lower in individuals with T2DM compared with non-diabetic controls (T2DM 204 ± 72 ng/ml vs. non-diabetic control 257 ± 24 ng/ml, p < 0.0001). In non-diabetic subjects, circulating irisin was correlated with age (r = 0.398, p < 0.01), BMI (r = 0.387, p < 0.01), total cholesterol (r = 0.341, p < 0.01), total triglycerides (r = 0.299, p < 0.05), fasting blood glucose (r = 0.430, p < 0.01) and diastolic blood pressure (r = 0.306, p < 0.05). Multiple linear regression model revealed that BMI (β = 0.407, p = 0.012) and FBG (β = 0.315, p = 0.034) were associated with irisin in non-diabetic subjects after adjusting for multiple co-variates. However, similar analysis in T2DM subjects didn’t reveal significant association between circulating irisin and major markers of metabolic phenotype.

Conclusions

Circulating irisin is lower in T2DM compared with non-diabetic controls. Plasma irisin levels appear to be associated with important metabolic factors in non-diabetic subjects but not in individuals with type 2 diabetes.

Introduction

Muscle has been thought to be an important secretory organ since many years. Cytokines and other peptides produced and secreted by myocytes are classified as “myokines” (Pedersen et al., 2003). Bioinformatics modeling and proteomics studies suggest that myocytes may secrete up to hundreds of putative myokines (Bortoluzzi et al., 2006, Henningsen et al., 2010). These myokines work as endocrine hormones and regulate functions of distant organs.

Sedentary lifestyle is a major risk factor for type 2 diabetes mellitus (T2DM). Randomized controlled trials have demonstrated that physical activity interventions improve glucose tolerance and reduce the risk of T2DM in those with a high risk of the disease, even without obvious body weight change (Gillies et al., 2007, Laaksonen et al., 2005). Therefore, it has been speculated for a long time that physical exercise may exert its beneficial effects on energy metabolism through secreted factors from myocytes (Pedersen & Febbraio, 2012).

Peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) is a versatile transcription cofactor which can be induced by various nutritional and physiological cues and involves in glucose/fatty acid metabolism, mitochondrial function and mitochondria biogenesis (Charos et al., 2012). Exercise, especially chronic exercise, increases PGC-1α expression in muscles while sedentary life style and T2DM are associated with reduced expression of PGC-1α (Handschin & Spiegelman, 2008). Prompted by the finding that transgenic mice expressing PGC-1α selectively in muscle showed remarkable resistance to age-related obesity and metabolic disorders, Bostrom et al. recently reported that membrane protein fibronectin type III domain containing 5 (FNDC5) is stimulated by PGC-1α expression in myocytes (Bostrom et al., 2012, Wenz et al., 2009). FNDC5 expressed on plasma membrane of myocytes can be cleaved and secreted as a novel myokine termed as irisin. Further studies revealed that irisin induced browning of subcutaneous adipocytes in vitro and in vivo and protected diet-induced obesity and diabetes in mouse models (Bostrom et al., 2012). Whether or not these findings can be translated into humans has important implications in prevention and treatment of metabolic disorders including T2DM (Cunha, 2012, Kelly, 2012, Sanchis-Gomar et al., 2012, Timmons et al., 2012, Villarroya, 2012).

PGC-1α is strongly expressed in human skeletal muscles and can be induced by endurance training. Weighted evidences support that dysregulation of PGC-1α involves in pathogenesis of type 2 diabetes (Russell et al., 2003, Soyal et al., 2006). Earlier studies found that expression of PGC-1α and its activities were reduced in skeletal muscles in T2DM (Mootha et al., 2003, Patti et al., 2003, Petersen et al., 2004). These findings prompt us to hypothesize that circulating irisin may be lower in T2DM patients, presumably due to lower PGC-1α activity in skeletal muscles.