Relationship between serum circulating insulin-like growth factor-1 and liver fat in the United States.

BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD), circulating insulin-like growth factor-1 (IGF-1), and IGF-1/IGF-binding protein-3 (IGFBP-3) concentrations are associated with adiposity and insulin resistance. We aimed to determine whether serum IGF-1, IGFBP-3, and IGF-1/IGFBP-3 are associated with presence or severity of NAFLD independent of potential confounding. METHODS: We performed a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey, 1988­1994, a representative sample of the United States adult population. Among participants who had a fasting blood draw and ultrasound examination, we excluded those with missing data, viral hepatitis, iron overload, excessive alcohol intake, pregnancy, or taking glucose-lowering therapy, yielding 4172 adults for this analysis. RESULTS: In logistic regression analyses adjusted for age, gender, and race/ethnicity, higher IGF-1 and IGF-1/IGFBP-3 quartiles were associated with lower likelihood of NAFLD and lower grade steatosis. These associations became non-significant when further adjusted for adiposity (body mass index, waist circumference) with the exception of the association between IGF-1/IGFBP-3 and severity of NAFLD which remained significant after adjustment for homeostasis model assessment for insulin resistance (HOMA-IR) (odds ratio [95% CI]: Q3: 0.71 [0.53­0.96], Q4: 0.62 [0.43­0.89]) and adiposity (Q4: 0.67 [0.47­0.96]). Full adjustment (age, gender, race/ethnicity, adiposity, HOMA-IR, A1C%) further attenuated associations between IGF-1 or IGF-1/IGFBP-3 and liver fat such that they were no longer significant. CONCLUSIONS: Adiposity explains much of the observed association between IGF-1 or IGF-1/IGFBP-3 and liver fat. These findings do not support a direct role for the growth hormone-IGF-1/IGFBP-3 axis in the pathophysiology of NAFLD.

Acute estradiol treatment reduces skeletal muscle protein breakdown markers in early- but not late-postmenopausal women.

OBJECTIVES: Menopause and decline in estradiol (E2) may contribute to sarcopenia (i.e., age-related decline in muscle mass and strength) in women. E2 may directly impact skeletal muscle protein breakdown via estrogen receptor (ER) signaling, primarily ERα. It is not yet known whether: 1) E2 regulates pathways of skeletal muscle protein breakdown; 2) E2-mediated changes in protein breakdown markers are associated with ERα activation and insulin sensitivity; and 3) the effects of E2 on protein breakdown markers differ by increasing time since menopause. STUDY DESIGN: We studied 27 women who were ≤6 years past menopause (early postmenopausal, EPM; n = 13) or ≥10 years past menopause (late postmenopausal, LPM; n = 14). Fasted skeletal muscle samples were collected following 1 week of transdermal E2 or placebo treatment in a randomized cross-over design. MAIN OUTCOME MEASURES: We analyzed for cytosolic protein content of the: 1) structural proteins myosin heavy chain (MHC) and tropomyosin; and 2) protein regulatory markers: protein kinase B (Akt), muscle-specific ring finger protein1 (MuRF1), atrogin1, and forkhead box O3 (FOXO3) using Western blot. RESULTS: In response to acute E2, FOXO3 activation (dephosphorylation) and MuRF1 protein expression decreased in EPM but increased in LPM women (p < 0.05). ERα activation was not associated with these protein breakdown markers, but FOXO3 activation tended to be inversely correlated (r = -0.318, p = 0.065) to insulin sensitivity. CONCLUSIONS: These preliminary studies suggest the effects of E2 on skeletal muscle protein breakdown markers were dependent on time since menopause, which is consistent with our previous study on insulin sensitivity.

Effect of low- and high-glycemic load on circulating incretins in a randomized clinical trial.

OBJECTIVE: Low-glycemic load diets lower post-prandial glucose and insulin responses; however, the effect of glycemic load on circulating incretin concentrations is unclear. We aimed to assess effects of dietary glycemic load on fasting and post-prandial glucose, insulin and incretin (i.e., glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)) concentrations and to examine for effect modification by adiposity. MATERIALS AND METHODS: We conducted a single-center, randomized controlled crossover feeding trial in which a subset of participants had post-prandial testing. Participants were recruited from the local Seattle area. We enrolled 89 overweight-obese (BMI 28.0-39.9 kg/m(2)) and lean (BMI 18.5-25.0 kg/m(2)) healthy adults. Participants consumed two 28-day, weight-maintaining high- and low-glycemic load controlled diets in random order. Primary outcome measures were post-prandial circulating concentrations of glucose, insulin, GIP and GLP-1, following a test breakfast. RESULTS: Of the 80 participants completing both diet interventions, 16 had incretin testing and comprise the group for analyses. Following each 28-day high- and low-glycemic load diet, mean fasting concentrations of insulin, glucose, GIP and GLP-1 were not significantly different. Mean integrated post-prandial concentrations of glucose, insulin and GIP were higher (1504±476 mg/dL/min, p<0.01; 2012±644 µU/mL/min, p<0.01 and 15517±4062 pg/mL/min, p<0.01, respectively) and GLP-1 was lower (-81.6±38.5 pmol/L/min, p<0.03) following the high-glycemic load breakfast as compared to the low-glycemic load breakfast. Body fat did not significantly modify the effect of glycemic load on metabolic outcomes. CONCLUSIONS: High-glycemic load diets in weight-maintained healthy individuals lead to higher post-prandial GIP and lower post-prandial GLP-1 concentrations. Future studies evaluating dietary glycemic load manipulation of incretin effects would be helpful for establishing diabetes nutrition guidelines.

Anticardiolipin antibodies as a risk factor for venous thromboembolism in a population-based prospective study.

Anticardiolipin antibodies, one of the family of 'antiphospholipid' antibodies, increase the risk of venous thromboembolism in the presence of autoimmune disease. Our objective was to determine prospectively whether there is a positive association between anticardiolipin antibodies and venous thromboembolism in ostensibly healthy adults. We conducted a nested case-control study (n = 317 patients and n = 655 control subjects) in a longitudinal study of over 20 000 participants. Baseline (prediagnosis) anticardiolipin IgG and IgM antibodies were assessed by enzyme-linked immunoassays. Venous thromboembolism was validated using standardized criteria for venous thrombosis and pulmonary embolism. There was no association between anticardiolipin antibodies and subsequent venous thromboembolism occurrence, overall or in any subgroup. For example, the multivariate-adjusted relative risk was 0.88 (95% confidence interval, 0.43, 1.78) for greater than versus less than the 95th percentile of anticardiolipin IgG. In conclusion, in this general population sample, an elevated anticardiolipin antibody level was not a risk factor for venous thromboembolism.