Insulin Resistance Negatively Influences the Muscle‐Dependent Relationship between IGF‐I and Bone Mass in Pre‐Menarcheal Girls

Abstract

Insulin-like growth factor I (IGF-I) is an important hormone involved in musculoskeletal development, promoting bone growth via direct and muscle-dependent processes. Insulin and IGF-I share a converging downstream cellular signaling process; thus, insulin resistance may influence the IGF-I-muscle-bone relationship. The aim of this study was to determine the effect of insulin resistance on the muscle-dependent relationship between IGF-I and bone mass in pre-menarcheal girls. Participants included 147 otherwise healthy black and white pre-menarcheal girls. Glucose, insulin and IGF-I were measured from fasting blood samples. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin. Fat-free soft tissue (FFST) mass and bone mineral content (BMC) were measured by dual-energy X-ray absorptiometry (Delphi A, Hologic Inc.). Our primary outcome was BMC/height. To test the moderating effect of HOMA-IR on the FFST mass-mediated relationship between IGF-I and BMC/height, we performed a moderated mediation analysis controlling for sexual maturation rating stage. The interaction between HOMA-IR and IGF-I was tested at a cut-point of HOMA-IR = 4.0. In our path model (Figure 1), IGF-I predicted FFST mass, which in turn, predicted BMC/height (both P < .001). IGF-I predicted BMC/height (P < .010), but not after accounting for the mediator, FFST mass. The HOMA-IR by IGF-I interaction was a negative predictor of FFST mass (P < .050). HOMA-IR had a significant and negative effect on the FFST mass-dependent relationship between IGF-I and BMC/height (b = −0.151; P = .047). Lean body mass is an important intermediary factor in the IGF-I-bone relationship. For this reason, bone development may be compromised indirectly via suboptimal IGF-I-dependent muscle development in insulin resistant children. Support or Funding Information National Institutes of Health (HD54630), National Institute of Food and Agriculture (GEO00645) Figure 1Open in figure viewerPowerPoint Insulin resistance has a negative effect on the FFST mass-dependent relationship between IGF-I and bone mass. Unstandardized regression coefficients are presented as b (SE). Sexual maturation was included as a covariate in this model. a Indicates the relationship between IGF-I and BMC/height after adjusting for sexual maturation. HOMA-IR, homeostasis model assessment of insulin resistance; IGF-I, insulin-like growth factor I; FFST, fat-free soft tissue; BMC, bone mineral content.