Insulin Resistance Negatively Influences the Muscle-Dependent IGF-1-Bone Mass Relationship in Premenarcheal Girls

Abstract

Context: IGF-1 promotes bone growth directly and indirectly through its effects on skeletal muscle. Insulin and IGF-1 share a common cellular signaling process; thus, insulin resistance may influence the IGF-1-muscle-bone relationship.

Objective: We sought to determine the effect of insulin resistance on the muscle-dependent relationship between IGF-1 and bone mass in premenarcheal girls.

Design, setting, and participants: This was a cross-sectional study conducted at a university research center involving 147 girls ages 9 to 11 years.

Main outcome measures: Glucose, insulin, and IGF-1 were measured from fasting blood samples. 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. Our primary outcome was BMC/height.

Results: In our path model, IGF-1 predicted FFST mass (b = 0.018; P = .001), which in turn predicted BMC/height (b = 0.960; P < .001). IGF-1 predicted BMC/height (b = 0.001; P = .002), but not after accounting for the mediator of this relationship, FFST mass. The HOMA-IR by IGF-1 interaction negatively predicted FFST mass (b = -0.044; P = .034). HOMA-IR had a significant and negative effect on the muscle-dependent relationship between IGF-1 and BMC/height (b = -0.151; P = .047).

Conclusions: Lean body mass is an important intermediary factor in the IGF-1-bone relationship. For this reason, bone development may be compromised indirectly via suboptimal IGF-1-dependent muscle development in insulin-resistant children.

Trial registration: ClinicalTrials.gov NCT01892098.

Figures

Figure 1.

Hypothesized effect of insulin resistance (ie, HOMA-IR) on the FFST mass-dependent relationship between IGF-1 and BMC/height. HOMA-IR, homeostasis model assessment of insulin resistance; FFST, fat-free soft tissue mass.

Figure 2.

Insulin resistance has a negative effect on the FFST mass-dependent relationship between IGF-1 and bone mass. The interaction between HOMA-IR and IGF-1 was tested at a cut-point of HOMA-IR = 4.0. Unstandardized regression coefficients are presented as b (standard error). Sexual maturation and HOMA-IR were included as covariates in this model but are not displayed. a Relationship between IGF-1 and BMC/height after adjusting for sexual maturation. Broken lines represent nonsignificant relationships. RMSEA, root mean square error of approximation; CFI, comparative fit index; TLI, Tucker-Lewis index; SRMR, standardized root mean square residual. HOMA-IR*IGF-I represents interaction between HOMA-IR and IGF-I.