Fat-free mass and glucose homeostasis: is greater fat-free mass an independent predictor of insulin resistance?

Background: A greater fat-free mass (FFM) is purported to be associated with protective effects on insulin resistance (IR). However, recent studies suggested negative associations between FFM and IR.
Objectives: (1) To explore the direction of the association between FFM and IR in a large heterogeneous sample after controlling for confounding factors. (2) To determine cut off values of FFM associated with an increased risk of IR.
Methods: Outcome variables were measured in 7044 individuals (48.6% women, 20-79 years; NHANES, 1999-2006): body composition [fat mass (FM), FFM and appendicular FFM (aFFM); DXA], FFM index [FFMI: FFM/height (kg/m ² )], appendicular FFMI [aFFM/height (kg/m ² )] and insulin resistance (HOMA-IR). Multivariate regression analyses were performed to determine the independent predictors of HOMA-IR in younger (20-49 years) and older (50-79 years) men and women. ROC analyses were used to determine FFM cut-offs to identify a higher risk of insulin resistance (HOMA-IR > 75th percentile).
Results: aFFMI was an independent predictor of IR in younger (men: β = 0.21; women: β = 0.31; all p ≤ 0.001) and older (men: β = 0.11; women: β = 0.37; all p ≤ 0.001) individuals. Thresholds for aFFMI at which the risk of IR was significantly increased were 8.96 and 8.39 kg/m ² in younger and older men, and 7.22 and 6.64 kg/m ² in younger and older women, respectively.
Conclusion: Independently of age, a greater aFFMI was an independent predictor of IR. These results suggest revisiting how we envision the link between FFM and IR and explore potential mechanisms.