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

Kindler, Joseph M.; Pollock, Norman K.; Laing, Emma M.; Jenkins, Nathan T.; Oshri, Assaf; Isales, Carlos M.; Hamrick, Mark W.; Lewis, Richard D.

doi:10.1210/jc.2015-3451

Cited by 24 publications

(33 citation statements)

References 40 publications

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“…Even in nondiabetic subjects, muscle size and function are inversely associated with insulin resistance (31)(32)(33), so bone size deficits associated with insulin resistance could result from reduced strains. Furthermore, insulin resistance might modulate the muscle-bone relationship through downregulation of the anabolic effects of IGF-1 exposure in muscle tissue, as suggested in a cohort of prepubertal girls (34). In our study, adjustment for physical activity or muscle function, but not IGF-1, had a limited effect on the associations between insulin resistance and bone geometry.…”

Section: Discussionsupporting

confidence: 42%

Insulin Resistance Is Associated With Smaller Cortical Bone Size in Nondiabetic Men at the Age of Peak Bone Mass

Verroken

Zmierczak

Goemaere

et al. 2016

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context: In type 2 diabetes mellitus, fracture risk is increased despite preserved areal bone mineral density. Although this apparent paradox may in part be explained by insulin resistance affecting bone structure and/or material properties, few studies have investigated the association between insulin resistance and bone geometry.Objective: We aimed to explore this association in a cohort of nondiabetic men at the age of peak bone mass.Design, Setting, and Participants: Nine hundred ninety-six nondiabetic men aged 25 to 45 years were recruited in a cross-sectional, population-based sibling pair study at a university research center.Main Outcome Measures: Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR), with insulin and glucose measured from fasting serum samples. Bone geometry was assessed using peripheral quantitative computed tomography at the distal radius and the radial and tibial shafts.Results: In age-, height-, and weight-adjusted analyses, HOMA-IR was inversely associated with trabecular area at the distal radius and with cortical area, periosteal and endosteal circumference, and polar strength strain index at the radial and tibial shafts ( b # 20.13, P , 0.001). These associations remained essentially unchanged after additional adjustment for dual-energy X-ray absorptiometry-derived body composition, bone turnover markers, muscle size or function measurements, or adiponectin, leptin, insulin-like growth factor 1, or sex steroid levels. Conclusion:In this cohort of nondiabetic men at the age of peak bone mass, insulin resistance is inversely associated with trabecular and cortical bone size. These associations persist after adjustment for body composition, muscle size or function, or sex steroid levels, suggesting an independent effect of insulin resistance on bone geometry. (J Clin Endocrinol Metab 102: [1807][1808][1809][1810][1811][1812][1813][1814][1815] 2017) T he prevalence of type 2 diabetes mellitus (T2DM) has reached epidemic proportions. In addition to wellknown microvascular and macrovascular complications, skeletal fragility is being increasingly recognized as another important diabetes-associated condition. Indeed, despite having a comparable areal bone mineral density (aBMD) as measured by dual-energy X-ray absorptiometry (DXA), individuals with T2DM present with an Abbreviations: 25(OH)D, 25-hydroxyvitamin D; aBMD, areal bone mineral density; CSA, cross-sectional area; CTX, C-terminal telopeptide of type I collagen; CV, coefficient of variation; DXA, dual-energy X-ray absorptiometry; EC PC , endosteal circumference additionally adjusted for periosteal circumference; FE2, free estradiol; FT, free testosterone; HOMA-IR, homeostasis model assessment of insulin resistance; IGF-1, insulin-like growth factor 1; P1NP, procollagen type 1 N-terminal propeptide; pQCT, peripheral quantitative computed tomography; PTH, parathyroid hormone; SHBG, sex hormone-binding globulin; SSIp, polar strength strain index; T2DM, type 2 diabetes mellitus; v...

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Section: Discussionsupporting

confidence: 42%

Insulin Resistance Is Associated With Smaller Cortical Bone Size in Nondiabetic Men at the Age of Peak Bone Mass

Verroken

Zmierczak

Goemaere

et al. 2016

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…IGF-I signals upon target cells, specifically the bone-forming osteoblasts, through a similar downstream signaling pathway to that of insulin [39, 40]. Thus, children who are insulin resistant may be at risk of suboptimal IGF-I-dependent muscle and bone accrual [41, 42]. Although IGF-I is most known for its role in promoting cortical bone areal expansion [43, 44], Kirmani and colleagues found that boys with a greater IGF-I concentration had trabeculae that were less separated than those with lower IGF-I [45].…”

Section: Discussionmentioning

confidence: 99%

Obese Versus Normal-Weight Late-Adolescent Females have Inferior Trabecular Bone Microarchitecture: A Pilot Case-Control Study

et al. 2017

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Though still a topic of debate, the position that skeletal health is compromised with obesity has received support in the pediatric and adult literature. The limited data relating specifically to trabecular bone microarchitecture, however, have been relatively inconsistent. The aim of this pilot cross-sectional case-control study was to compare trabecular bone microarchitecture between obese (OB) and normal-weight (NW) late-adolescent females. A secondary aim was to compare diaphyseal cortical bone outcomes between these two groups. Twenty-four non-Hispanic white females, ages 18–19 years, were recruited into OB (n = 12) or NW (n = 12) groups based on pre-specified criteria for percent body fat (≥32 vs. <30, respectively), body mass index (>90th vs. 20th–79th, respectively), and waist circumference (≥90th vs. 25th–75th, respectively). Participants were also individually matched on age, height, and oral contraceptive use. Using magnetic resonance imaging, trabecular bone microarchitecture was assessed at the distal radius and proximal tibia metaphysis, and cortical bone architecture was assessed at the mid-radius and mid-tibia diaphysis. OB versus NW had lower apparent trabecular thickness (radius and tibia), higher apparent trabecular separation (radius), and lower apparent bone volume to total volume (radius; all P < 0.050). Some differences in radius and tibia trabecular bone microarchitecture were retained after adjusting for insulin resistance or age at menarche. Mid-radius and mid-tibia cortical bone volume and estimated strength were lower in the OB compared to NW after adjusting for fat-free soft tissue mass (all P <0.050). These trabecular and cortical bone deficits might contribute to the increased fracture risk in obese youth.

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“…The short-term reliability of musculoskeletal and anthropometric measures in our laboratory has been reported, (29) based on repeat measures on 10 volunteers on the same day. One trained operator acquired and analyzed all scans and the manufacturer-supplied phantom was scanned daily to maintain quality assurance (Hologic Inc.).…”

Section: Muscular Assessmentmentioning

confidence: 99%

Sex-Specific Muscular Mediation of the Relationship Between Physical Activity and Cortical Bone in Young Adults

Higgins

Sokolowski

Vishwanathan

et al. 2019

Journal of Bone and Mineral Research

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Muscle mass is a commonly cited mediator of the relationship between physical activity (PA) and bone, representing the mechanical forces generated during PA. However, neuromuscular properties (eg, peak force) also account for unique portions of variance in skeletal outcomes. We used serial multiple mediation to explore the intermediary role of muscle mass and force in the relationships between cortical bone and moderate‐to‐vigorous intensity PA (MVPA). In a cross‐sectional sample of young adults (n = 147, 19.7 ± 0.7 years old, 52.4% female) cortical diaphyseal bone was assessed via peripheral quantitative computed tomography at the mid‐tibia. Peak isokinetic torque in knee extension was assessed via Biodex dynamometer. Thigh fat‐free soft tissue (FFST) mass, assessed via dual‐energy X‐ray absorptiometry, represented the muscular aspect of tibial mechanical forces. Habitual MVPA was assessed objectively over 7 days using Actigraph GT3X+ accelerometers. Participants exceeded MVPA guidelines (89.14 ± 27.29 min/day), with males performing 44.5% more vigorous‐intensity activity relative to females (p < 0.05). Males had greater knee extension torque and thigh FFST mass compared to females (55.3%, and 34.2%, respectively, all p < 0.05). In combined‐sex models, controlling for tibia length and age, MVPA was associated with strength strain index (pSSI) through two indirect pathways: (i) thigh FFST mass (b = 1.11 ± 0.37; 95% CI, 0.47 to 1.93), and (i) thigh FFST mass and knee extensor torque in sequence (b = 0.30 ± 0.16; 95% CI, 0.09 to 0.73). However, in sex‐specific models MVPA was associated with pSSI indirectly through its relationship with knee extensor torque in males (b = 0.78 ± 0.48; 95% CI, 0.04 to 2.02) and thigh FFST mass in females (b = 1.12 ± 0.50; 95% CI, 0.37 to 2.46). Bootstrapped CIs confirmed these mediation pathways. The relationship between MVPA and cortical structure appears to be mediated by muscle in young adults, with potential sex‐differences in the muscular pathway. If confirmed, these findings may highlight novel avenues for the promotion of bone strength in young adults. © 2019 American Society for Bone and Mineral Research.

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

Abstract: 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.

Cited by 24 publications

References 40 publications

Insulin Resistance Is Associated With Smaller Cortical Bone Size in Nondiabetic Men at the Age of Peak Bone Mass

Insulin Resistance Is Associated With Smaller Cortical Bone Size in Nondiabetic Men at the Age of Peak Bone Mass

Obese Versus Normal-Weight Late-Adolescent Females have Inferior Trabecular Bone Microarchitecture: A Pilot Case-Control Study

Sex-Specific Muscular Mediation of the Relationship Between Physical Activity and Cortical Bone in Young Adults

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