OR26-03 Lower Serum Myostatin Levels Are Associated with Higher Insulin Sensitivity in Adults with Overweight/Obesity

In preclinical models, inhibition of the myokine myostatin prevents or improves insulin resistance (IR). However, studies investigating the association between serum myostatin levels and IR in humans are discrepant, perhaps in part because myostatin immunoassays lack specificity and sensitivity. New sensitive and specific myostatin LC-MS/MS assays make it possible to determine if higher serum myostatin levels are independently associated with greater IR in adults with overweight/obesity. If true, therapeutic manipulation of myostatin pathways may be a potential therapeutic target to prevent or treat type 2 diabetes (T2DM) in this high-risk population, in which current strategies, e.g. weight loss, are difficult to implement and maintain. We studied 75 adults (53% women), 20–65 yo, BMI ≥25 kg/m(2) and generally healthy without T2DM. Serum myostatin levels (1° independent variable) were measured by LC-MS/MS (Brigham Research Assay Core, Boston, MA), with no cross-reactivity with growth differentiation factor 11 (GDF11), activins or transforming growth factor beta (TGF-β), sensitivity of 0.5 ng/mL and intra- and inter-assay coefficient of variation of 10 and 12%. Insulin sensitivity (IS) (1° dependent variable) was estimated by QUICKI, appendicular lean mass (ALM) by DXA, visceral adipose tissue (VAT) by CT and intrahepatic (IHL) and intramyocellular lipids (IMCL) by MR spectroscopy. Models were run sex- combined and stratified given sex differences in muscle mass. Mean age was 47.9±12.2 years and BMI was 33.2±5.7 kg/m(2) (mean±SD). Compared to men, women had lower mean ALM (20.9±3.3 vs 29.2±3.3 kg, p<0.0001) and serum myostatin levels (7.28±1.87 vs 8.28±1.89 ng/mL, p=0.02) and similar mean IS (0.16±0.02 vs 0.15±0.02, p=0.13). Lower serum myostatin levels were associated with higher IS in the whole group (R=-0.32, p=0.008) and in women (R=-0.41, p=0.02)—both remained significant after controlling for ALM—but not in men (R=-0.16, p=0.36). In a multivariate model including VAT, IHL, IMCL and ALM, lower serum myostatin levels were associated with higher IS in the whole group (B(1)= -0.37, p=0.003), in women (B(1)= -0.43, p=0.02) and in men (B(1)= -0.37, p=0.05). In a stepwise regression model including VAT, IHL, IMCL and ALM, VAT explained 18%, IHL explained 10% and myostatin explained 8% of the variability in IS in the whole group; in women, myostatin explained 18% and IHL explained 12% of the variability; in men, VAT explained 26% of the variability and myostatin was not a significant determinant. In conclusion, lower serum myostatin levels were associated with greater IS in adults with overweight/obesity, independent of muscle and adipose depots known to be associated with T2DM risk. Future studies should investigate potential sex differences in the association between myostatin and IS. Therapeutic manipulation of myostatin pathways may be a potential therapeutic target to prevent or treat T2DM.