Circulating insulin-like growth factor-I and risk of 25 common conditions: outcome-wide analyses in the UK Biobank study

While there is strong epidemiological evidence that circulating insulin-like growth factor-I (IGF-I) is associated with a higher risk of several cancers, little is known about its association with non-cancer outcomes. We investigated associations of circulating IGF-I with risk of 25 common conditions, other than cancer, in a large British cohort. Study participants were 318,749 middle-aged adults enrolled in the UK Biobank Study. Serum IGF-I concentration was measured in samples collected at baseline (2006–2010), and re-measured in 12,334 participants after an average of 4.3 years. We followed-up participants over an average of 11.5 years by linking to hospital admissions and mortality registries. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating IGF-I and 25 common conditions, using the repeated IGF-I measurements to correct for regression dilution bias. After correction for multiple testing (P < 0.002), IGF-I was positively associated with carpal tunnel syndrome (HR per 5 nmol/l higher concentration = 1.12, 95% CI 1.08–1.16), and inversely associated with varicose veins (0.90, 0.85–0.95), cataracts (0.97, 0.95–0.99), diabetes (0.92, 0.90–0.95), and iron deficiency anaemia (0.90, 0.86–0.93). The associations for cataracts and diabetes attenuated when restricted to cases diagnosed after five or more years of follow-up, suggesting that these associations were likely affected by reverse causality. Higher IGF-I concentration might be associated with the risk for several conditions, but genetic studies are needed to clarify which associations may be causal.

Role of insulin and insulin-like growth factor I receptor expression in the pathogenesis of genital endometriosis

BACKGROUND: Growth factors play an important role in the pathogenesis of genital endometriosis. Insulin and insulin-like growth factors are involved in mitosis and differentiation in the endometrium during the menstrual cycle and early pregnancy, and are likely to indirectly affect the invasion of the endometrium during retrograde menstruation and the development of pain syndrome in endometriosis. However, the available literature data on insulin-like growth factors and insulin in the endometrium and endometrioid heterotopies in patients with genital endometriosis are scarse and contradictory. AIM: The aim of this study was to investigate the expression of insulin receptors and insulin-like growth factor I receptors in the eutopic endometrium and endometrioid heterotopies of patients with genital endometriosis. MATERIALS AND METHODS: This cross-sectional study included immunohistochemical analysis of surgical material obtained from two groups of women in the proliferative phase of the menstrual cycle: patients with endometriosis who received surgical treatment (endometrium and endometrioid heterotopies) and patients without endometriosis who were examined due to infertility (endometrium). The study also included investigation of carbohydrate metabolism (glucose tolerance test) and determination of blood serum insulin-like growth factor I, insulin and sex hormone levels. The material was stained to detect the expression of insulin receptors and insulin-like growth factor I receptors. Then, the relative area and optical density of the receptor expression were determined and the obtained data were analyzed statistically. RESULTS: We analyzed the examination results of 131 women matched in age and weight and height characteristics: 101 patients with genital endometriosis and 30 patients in the control group. Carbohydrate metabolism was characterized by a 2.1-fold increase in glucose-stimulated insulin secretion in patients with genital endometriosis compared with the control subjects. The blood level of insulin-like growth factor I did not differ in the study groups. Statistically significant differences in receptor expression were obtained between the groups. In the endometrium of patients with genital endometriosis, the optical density of insulin receptors was lower (p = 0.007) and the expression of insulin-like growth factor I receptors higher (p = 0.002) compared to the endometrium of the control subjects. The median values of insulin receptor expression in endometrioid heterotopies were decreased compared to the endometrium of the control group (p 0.001). The expression of insulin-like growth factor I receptors in endometrioid heterotopies was reduced compared to the endometrium of the same patients (p 0.001). CONCLUSIONS: The data obtained indicate significant features in the functioning of the insulin / insulin-like growth factor I system in patients with genital endometriosis: glucose-stimulated insulin secretion and relative endometrial insulin resistance due to the decreased expression of insulin receptors and the increased expression of insulin-like growth factor I receptors in the endometrium.

Circulating Insulin-Like Growth Factor-I and Risk of 25 Common Conditions: Outcome-Wide Analyses in The UK Biobank Study

While there is strong epidemiological evidence that circulating insulin-like growth factor-I (IGF-I) is associated with a higher risk of several cancers, little is known about its association with non-cancer outcomes. We investigated associations of circulating IGF-I with risk of 25 common conditions, other than cancer, in a large British cohort. Study participants were 318 749 middle-aged adults enrolled in the UK Biobank Study. Serum IGF-I concentration was measured in samples collected at baseline (2006–2010), and re-measured in 12 334 participants after an average of 4.3 years. We followed-up participants over an average of 11.5 years by linking to hospital admissions and mortality registries. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating IGF-I and 25 common conditions, using the repeated IGF-I measurements to correct for regression dilution bias. After correction for multiple testing (P < 0.002), IGF-I was positively associated with carpal tunnel syndrome (HR per 5 nmol/l higher concentration = 1.12, 95% CI, 1.08–1.16), and inversely associated with varicose veins (0.90, 0.85–0.95), cataracts (0.97, 0.95–0.99), diabetes (0.92, 0.90–0.95), and iron deficiency anaemia (0.90, 0.86–0.93). The associations for cataracts and diabetes attenuated when restricted to cases diagnosed after five or more years of follow-up, suggesting that these associations were likely affected by reverse causality. Higher IGF-I concentration might be associated with the risk for several conditions, but genetic studies are needed to clarify which associations may be causal.

Muscle insulin-like growth factor-I modulates murine craniofacial bone growth

Insulin-like growth factor I (IGF-I) is essential for muscle and bone development and a primary mediator of growth hormone (GH) actions. While studies have elucidated the importance of IGF-I specifically in muscle or bone development, few studies to date have evaluated the relationship between muscle and bone modulated by IGF-I in vivo, during post-natal growth. Mice with muscle-specific IGF-I overexpression (mIgf1+/+) were utilised to determine IGF-I- and muscle-mass-dependent effects on craniofacial skeleton development during post-natal growth. mIgf1+/+ mice displayed accelerated craniofacial bone growth when compared to wild-type animals. Virus-mediated expression of IGF-I targeting the masseter was performed to determine if post-natal modulation of IGF-I altered mandibular structures. Increased IGF-I in the masseter affected the mandibular base plane angle in a lateral manner, increasing the width of the mandible. At the cellular level, increased muscle IGF-I also accelerated cartilage thickness in the mandibular condyle. Importantly, mandibular length changes associated with increased IGF-I were not present in mice with genetic inhibition of muscle IGF-I receptor activity. These results demonstrated that muscle IGF-I could indirectly affect craniofacial growth through IGF-I-dependent increases in muscle hypertrophy. These findings have clinical implications when considering IGF-I as a therapeutic strategy for craniofacial disorders.