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

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.

Induction of endoplasmic reticulum stress impairs insulin-stimulated vasomotor relaxation in rat aortic rings: role of endothelin-1.

Sustained endoplasmic reticulum (ER) stress and thus activation of the unfolded protein response is now thought to be the foundation of various chronic disorders including whole-body insulin resistance and cardiovascular disease. The purpose of the present study was to test the hypothesis that ER stress impairs insulin-stimulated vasomotor reactivity. We report that experimental induction of ER stress in isolated aortic rings with tunicamycin (20 µg/mL), a well-established inducer of ER stress, resulted in insulin-stimulated vascular contraction (-78±21% at 1000 µIU/mL; -100±27% at 10,000 µIU/mL; all p<0.05) rather than relaxation (+23±7% at 1000 µIU/mL; +43±8% at 10,000 µIU/mL; all p<0.05). Importantly, we found that insulin-stimulated vascular contraction as a result of ER stress was largely eliminated in the presence of tezosentan (3 µM), a nonselective endothelin-1 (ET-1) receptor blocker (+1±14% at 1000 µIU/mL; +8±17% at 10,000 µIU/mL). Similarly, inhibition of ET-1 receptors fully restored the impairment of acetylcholine-mediated relaxation induced by ER stress (maximal relaxation: control = 94±2%, tunicamycin = 76±5%, tunicamycin + tezosentan = 90±3). Furthermore, we demonstrate that ER stress caused a ≈20-fold greater release of ET-1 from aortic endothelial cells under basal conditions as well as a ≈15-fold increase under insulin-stimulated conditions (p<0.05). This ER stress-mediated up-regulation in ET-1 release from endothelial cells was accompanied by a ≈3-fold increase in phosphorylation of p44/22 MAPK (p<0.05), a known pathway by which insulin signaling activates ET-1. Together, these findings support the hypothesis that vascular ER stress-mediated activation of ET-1 may be an underlying cause of impaired vasomotor responsiveness to insulin and endothelial dysfunction.

The effects of aerobic training and age on plasma sICAM-1.

Chronic low-grade systemic inflammation plays a role in the development of cardiovascular (CV) disease. Habitual endurance exercise training reduces the risk of CV disease in part through anti-inflammatory mechanisms. The purpose of this study was to investigate the effects of age, endurance training status, and their interaction on pro-inflammatory plasma cytokines involved in the pathogenesis of CV disease. Subjects were BMI-matched young (25±3 years; endurance trained: n=9, sedentary: n=11) and older (62±5 years; endurance-trained: n=12, sedentary: n=11) men. Plasma cytokine concentrations were determined by multiplex cytometric bead assay. Soluble intercellular adhesion molecule-1 (sICAM-1) levels were 40% higher in sedentary older men compared to young sedentary subjects (P=0.048), but they were not different between the young and older trained men. Furthermore, sICAM-1 levels were negatively correlated with maximal oxygen uptake (V˙O2max; r= - 0.38, P=0.01) across all subjects. There were no significant differences among the groups in plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), soluble tumor necrosis-α receptor (sTNFR), soluble CD40 ligand (sCD40L), or resistin. We conclude that habitual endurance training is associated with an attenuated age-related increase in plasma sICAM-1.

Exercise training, genetics and type 2 diabetes-related phenotypes.

Type 2 diabetes mellitus (T2DM) is at virtually pandemic levels world-wide. Diabetes has been referred to as 'a geneticist's nightmare'. However, dramatic advances in our understanding of the genetics of T2DM have occurred in the past 5 years. While endurance exercise training and increased habitual physical activity levels have consistently been shown to improve or be associated with improved T2DM-related phenotypes, there is substantial interindividual variation in these responses. There is some evidence that T2DM-related phenotype responses to exercise training are heritable, indicating that they might have a genetic basis. Genome-wide linkage studies have not identified specific chromosomal loci that could account for these differences, and no genome-wide association studies have been performed relative to T2DM-related phenotype responses to exercise training. From candidate gene studies, there are relatively strong and replicated data supporting a role for the PPARγ Pro12Ala variant in the interindividual differences in T2DM-related phenotype responses to training. This is a potentially important candidate locus because it affects T2DM susceptibility, has high biological plausibility and is the target for the primary pharmaceutical method for treating T2DM. Is it time to conduct a hypothesis-driven large-scale exercise training intervention trial based on PPARγ Pro12Ala genotype with T2DM-related phenotypes as the primary outcome measures, while also assessing potential mechanistic changes in skeletal muscle and adipose tissue? Or would it be more appropriate to propose a smaller trial to address the specific skeletal muscle and adipose tissue mechanisms affected by the interaction between the PPARγ Pro12Ala genotype and exercise training?

Nitro-oxidative stress biomarkers in active and inactive men.

Oxidative stress markers are novel factors shown to be related to cardiovascular (CVD) risk. We examined the effects of long-term exercise, age, and their interaction on plasma oxidized LDL (ox-LDL), nitrotyrosine, and myeloperoxidase (MPO) levels, all biomarkers of oxidative stress, and determined their association with plasma nitric oxide (NOx) levels as an index of NO bioavailability. Older (62±2 yr) active men (n=12) who had exercised for >30 years and young (25±4 yr) active men (n=7) who had exercised for >3 years were age- and BMI-matched to older (n=11) and young (n=8) inactive men. Young subjects had lower plasma nitrotyrosine levels than older subjects (P=0.047). Young inactive subjects had higher ox-LDL levels than either the young active (P=0.042) or the older active (P=0.041) subjects. In addition, plasma oxidative stress levels, particularly ox-LDL, were correlated with various conventional plasma lipoprotein-lipid levels, and in older subjects were associated with Framingham risk score (r=0.49, P=0.015). We found no relationships between plasma oxidative stress markers and NOx levels. The findings suggest that a sedentary lifestyle may be associated with higher ox-LDL levels and that the levels of oxidative stress markers are related to levels of other conventional CVD risk factors and overall CVD risk.