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The role of physical exercise in modulating peripheral inflammatory and neurotrophic biomarkers in older adults: A systematic review and meta-analysis.
Titus, J, Bray, NW, Kamkar, N, Camicioli, R, Nagamatsu, LS, Speechley, M, Montero-Odasso, M
Mechanisms of ageing and development. 2021;:111431
Abstract
BACKGROUND Physiological cascades of neurotrophic factors and inflammatory cytokines may mediate the exercise-induced amelioration of cognition in older adults. However, there is limited understanding on how different exercise modalities improving cognition alter biomarkers. Our aim was to evaluate the effects of different exercise modalities on blood biomarker concentrations in cognitive clinical trials of older adults. METHODS A systematic review (SR) and meta-analysis (MA) were performed using the databases PubMed, EMBASE, and SCOPUS. After exclusions, 17 trials with 18 distinct exercise interventions were included. RESULTS Aerobic training increased (n = 2) or did not significantly change BDNF (n = 5), and resistance training increased (n = 2) or did not significantly change (n = 2) IGF-1. Multimodal training significantly increased (n = 1) or did not change (n = 3) BDNF. Interventions that recruited sex-specific cohorts showed an advantage in males for blood marker concentrations and cognitive performance outcomes (n = 3) compared to females (n = 3). Only one of three interventions decreased concentrations of CRP. Eight studies examining BDNF changes were suited for MA and showed that higher BDNF concentrations were reached post intervention, although not reaching statistical significance (p = .26, I2 = 44 %). DISCUSSION Our results suggest that exercise has potential to ameliorate cognitive decline in older adults with divergent, modality-specific, neurotrophic mechanisms.
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Insulin/IGF-1 Signaling Is Downregulated in Barrett's Esophagus Patients Undergoing a Moderate Calorie and Protein Restriction Program: A Randomized 2-Year Trial.
Arcidiacono, D, Zaramella, A, Fabris, F, Sánchez-Rodríguez, R, Nucci, D, Fassan, M, Nardi, M, Benna, C, Cristofori, C, Morbin, T, et al
Nutrients. 2021;(10)
Abstract
Obesity and associated insulin resistance (Ins-R) have been identified as important risk factors for esophageal adenocarcinoma development. Elevated calories and protein consumption are also associated with Ins-R and glucose intolerance. We investigated the effect of a 24-month moderate calorie and protein restriction program on overweight or obese patients affected by Barrett's esophagus (BE), as no similar dietary approach has been attempted to date in this disease context. Anthropometric parameters, levels of serum analytes related to obesity and Ins-R, and the esophageal insulin/IGF-1 signaling pathway were analyzed. This study is registered with ClinicalTrials.gov, number NCT03813381. Insulin, C-peptide, IGF-1, IGF-binding protein 3 (IGFBP3), adipokines, and esophageal expression of the main proteins involved in insulin/IGF-1 signal transduction were quantified using Luminex-XMAP® technology in 46 patients who followed the restriction program (IA) and in 54 controls (CA). Body mass index and waist circumference significantly decreased in 76.1% of IA and 35.2% of CA. IGF-1 levels were reduced in 71.7% of IA and 51.8% of CA. The simultaneous reduction of glycaemia, IGF-1, the IGF-1/IGFBP3 ratio, and the improvement in weight loss-dependent insulin sensitivity, were associated with the downregulation of the insulin/IGF-1 signal on BE tissue. The proposed intervention program was an effective approach to counteract obesity-associated cancer risk factors. The improvement in metabolic condition resulted in a downregulation of the ERK-mediated mitogenic signal in 43.5% of patients, probably affecting the molecular mechanism driving adenocarcinoma development in BE lesions.
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Short stature with low insulin-like growth factor 1 availability due to pregnancy-associated plasma protein A2 deficiency in a Saudi family.
Babiker, A, Al Noaim, K, Al Swaid, A, Alfadhel, M, Deeb, A, Martín-Rivada, Á, Barrios, V, Pérez-Jurado, LA, Alfares, A, Al Alwan, I, et al
Clinical genetics. 2021;(5):601-606
Abstract
In 2016 a new syndrome with postnatal short stature and low IGF1 bioavailability caused by biallelic loss-of-function mutations in the gene encoding the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) was described in two families. Here we report two siblings of a third family from Saudi Arabia with postnatal growth retardation and decreased IGF1 availability due to a new homozygous nonsense mutation (p.Glu886* in exon 7) in PAPPA2. The two affected males showed progressively severe short stature starting around 8 years of age, moderate microcephaly, decreased bone mineral density, and high circulating levels of total IGF1, IGFBP3, and the IGF acid-labile subunit (IGFALS), with decreased free IGF1 concentrations. Interestingly, circulating IGF2 and IGFBP5 were not increased. An increase in growth velocity and height was seen in the prepuberal patient in response to rhIGF1. These patients contribute to the confirmation of the clinical picture associated with PAPP-A2 deficiency and that the PAPPA2 gene should be studied in all patients with short stature with this characteristic phenotype. Hence, pediatric endocrinologists should measure circulating PAPP-A2 levels in the study of short stature as very low or undetectable levels of this protein can help to focus the diagnosis and treatment.
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Effect of Transdermal Estradiol and Insulin-like Growth Factor-1 on Bone Endpoints of Young Women With Anorexia Nervosa.
Singhal, V, Bose, A, Slattery, M, Haines, MS, Goldstein, MA, Gupta, N, Brigham, KS, Ebrahimi, S, Javaras, KN, Bouxsein, ML, et al
The Journal of clinical endocrinology and metabolism. 2021;(7):2021-2035
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Abstract
CONTEXT Anorexia nervosa (AN) is prevalent in adolescent girls and is associated with bone impairment driven by hormonal alterations in nutritional deficiency. OBJECTIVE To assess the impact of estrogen replacement with and without recombinant human insulin-like growth factor-1 (rhIGF-1) administration on bone outcomes. DESIGN Double-blind, randomized, placebo-controlled 12-month longitudinal study. PARTICIPANTS Seventy-five adolescent and young adult women with AN age 14 to 22 years. Thirty-three participants completed the study. INTERVENTION Transdermal 17-beta estradiol 0.1 mg/day with (i) 30 mcg/kg/dose of rhIGF-1 administered subcutaneously twice daily (AN-IGF-1+) or (ii) placebo (AN-IGF-1-). The dose of rhIGF-1 was adjusted to maintain levels in the upper half of the normal pubertal range. MAIN OUTCOME MEASURES Bone turnover markers and bone density, geometry, microarchitecture, and strength estimates. RESULTS Over 12 months, lumbar areal bone mineral density increased in AN-IGF-1- compared to AN-IGF-1+ (P = 0.004). AN-IGF-1+ demonstrated no improvement in areal BMD in the setting of variable compliance to estrogen treatment. Groups did not differ for 12-month changes in bone geometry, microarchitecture, volumetric bone mineral density (vBMD), or strength (and results did not change after controlling for weight changes over 12 months). Both groups had increases in radial cortical area and vBMD, and tibia cortical vBMD over 12 months. Levels of a bone resorption marker decreased in AN-IGF-1- (P = 0.042), while parathyroid hormone increased in AN-IGF-1+ (P = 0.019). AN-IGF-1- experienced irregular menses more frequently than did AN-IGF-1+, but incidence of all other adverse events did not differ between groups. CONCLUSIONS We found no additive benefit of rhIGF-1 administration for 12 months over transdermal estrogen replacement alone in this cohort of young women with AN.
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Testosterone, sex hormone-binding globulin, insulin-like growth factor-1 and endometrial cancer risk: observational and Mendelian randomization analyses.
Mullee, A, Dimou, N, Allen, N, O'Mara, T, Gunter, MJ, Murphy, N
British journal of cancer. 2021;(9):1308-1317
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BACKGROUND Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR. RESULTS In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22-1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66-2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67-0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk. CONCLUSIONS Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.
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Quercetin Modulates IGF-I and IGF-II Levels After Eccentric Exercise-Induced Muscle-Damage: A Placebo-Controlled Study.
Sgrò, P, Ceci, R, Lista, M, Patrizio, F, Sabatini, S, Felici, F, Sacchetti, M, Bazzucchi, I, Duranti, G, Di Luigi, L
Frontiers in endocrinology. 2021;:745959
Abstract
BACKGROUND Prolonged or unaccustomed eccentric exercise may cause muscle damage and depending from its extent, this event negatively affects physical performance. OBJECTIVES The aim of the present investigation was to evaluate, in humans, the effect of the flavonoid quercetin on circulating levels of the anabolic insulin-like growth factor 1 (IGF-I) and insulin-like growth factor 2 (IGF-II), produced during the recovery period after an eccentric-induced muscle damage (EIMD). METHODS A randomized, double-blind, crossover study has been performed; twelve young men ingested quercetin (1 g/day) or placebo for 14 days and then underwent an eccentric-induced muscle damaging protocol. Blood samples were collected, and cell damage markers [creatine kinase (CK), lactate dehydrogenase (LDH) and myoglobin (Mb)], the inflammatory responsive interleukin 6 (IL-6), IGF-I and IGF-II levels were evaluated before the exercise and at different recovery times from 24 hours to 7 days after EIMD. RESULTS We found that, in placebo treatment the increase in IGF-I (72 h) preceded IGF-II increase (7 d). After Q supplementation there was a more marked increase in IGF-I levels and notably, the IGF-II peak was found earlier, compared to placebo, at the same time of IGF-I (72 h). Quercetin significantly reduced plasma markers of cell damage [CK (p<0.005), LDH (p<0.001) and Mb (p<0.05)] and the interleukin 6 level [IL-6 (p<0.05)] during recovery period following EIMD compared to placebo. CONCLUSIONS Our data are encouraging about the use of quercetin as dietary supplementation strategy to adopt in order to mitigate and promote a faster recovery after eccentric exercise as suggested by the increase in plasma levels of the anabolic factors IGF-I and IGF-II.
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Investigation of the Interplay between Circulating Lipids and IGF-I and Relevance to Breast Cancer Risk: An Observational and Mendelian Randomization Study.
Tan, VY, Bull, CJ, Biernacka, KM, Teumer, A, Richardson, TG, Sanderson, E, Corbin, LJ, Dudding, T, Qi, Q, Kaplan, RC, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2021;(12):2207-2216
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BACKGROUND Circulating lipids and insulin-like growth factor 1 (IGF-I) have been reliably associated with breast cancer. Observational studies suggest an interplay between lipids and IGF-I, however, whether these relationships are causal and if pathways from these phenotypes to breast cancer overlap is unclear. METHODS Mendelian randomization (MR) was conducted to estimate the relationship between lipids or IGF-I and breast cancer risk using genetic summary statistics for lipids (low-density lipoprotein cholesterol, LDL-C; high-density lipoprotein cholesterol, HDL-C; triglycerides, TGs), IGF-I and breast cancer from GLGC/UKBB (N = 239,119), CHARGE/UKBB (N = 252,547), and Breast Cancer Association Consortium (N = 247,173), respectively. Cross-sectional observational and MR analyses were conducted to assess the bi-directional relationship between lipids and IGF-I in SHIP (N = 3,812) and UKBB (N = 422,389), and using genetic summary statistics from GLGC (N = 188,577) and CHARGE/UKBB (N = 469,872). RESULTS In multivariable MR (MVMR) analyses, the OR for breast cancer per 1-SD increase in HDL-C and TG was 1.08 [95% confidence interval (CI), 1.04-1.13] and 0.94 (95% CI, 0.89-0.98), respectively. The OR for breast cancer per 1-SD increase in IGF-I was 1.09 (95% CI, 1.04-1.15). MR analyses suggested a bi-directional TG-IGF-I relationship (TG-IGF-I β per 1-SD: -0.13; 95% CI, -0.23 to -0.04; and IGF-I-TG β per 1-SD: -0.11; 95% CI, -0.18 to -0.05). There was little evidence for a causal relationship between HDL-C and LDL-C with IGF-I. In MVMR analyses, associations of TG or IGF-I with breast cancer were robust to adjustment for IGF-I or TG, respectively. CONCLUSIONS Our findings suggest a causal role of HDL-C, TG, and IGF-I in breast cancer. Observational and MR analyses support an interplay between IGF-I and TG; however, MVMR estimates suggest that TG and IGF-I may act independently to influence breast cancer. IMPACT Our findings should be considered in the development of prevention strategies for breast cancer, where interventions are known to modify circulating lipids and IGF-I.
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[Acromegaly and it's cardiovascular implications].
Cadena-Obando, DA, Remba-Shapiro, I, Abreu-Rosario, CG, Mercado, M
Revista medica del Instituto Mexicano del Seguro Social. 2021;(1):73-80
Abstract
Acromegaly is a chronic and slowly progressive disease that results from the hypersecretion of growth hormone (GH) and consequently insulin-like growth factor type 1 (IGF-1), due to a GH-secreting pituitary adenoma in 95-98% of cases. There are several complications or co-morbidities associated with acromegaly, the most frequent being cardiovascular, metabolic and neoplastic. The cardiovascular complications of acromegaly go from arterial hypertension to a peculiar form of cardiomyopathy and are the result of the long-standing exposure to high GH and IGF-1 levels. The pathophysiology of these complications is complex and includes an increased tubular reabsorption of sodium and the direct effects of GH and IGF-1 on the endothelium and the cardiac tissue itself. Frequently, the cardiovascular comorbidities of acromegaly occur concomitantly with metabolic complications such as diabetes and respiratory abnormalities such as the sleep apnea syndrome. In this brief review we analyze the pathophysiology, the clinical manifestations and the management of the cardiovascular complications of acromegaly.
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Associations of circulating insulin-like growth factor-I with intake of dietary proteins and other macronutrients.
Watling, CZ, Kelly, RK, Tong, TYN, Piernas, C, Watts, EL, Tin Tin, S, Knuppel, A, Schmidt, JA, Travis, RC, Key, TJ, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(7):4685-4693
Abstract
BACKGROUND & AIMS Circulating insulin-like growth factor-I (IGF-I) is associated with the risk of several cancers. Dietary protein intake, particularly dairy protein, may increase circulating IGF-I; however, associations with different protein sources, other macronutrients, and fibre are inconclusive. To investigate the associations between intake of protein, macronutrients and their sources, fibre, and alcohol with serum IGF-I concentrations. METHODS A total of 11,815 participants from UK Biobank who completed ≥4 24-h dietary assessments and had serum IGF-I concentrations measured at baseline were included. Multivariable linear regression was used to assess the cross-sectional associations of macronutrient and fibre intake with circulating IGF-I concentrations. RESULTS Circulating IGF-I concentrations were positively associated with intake of total protein (per 2.5% higher energy intake: 0.56 nmol/L (95% confidence interval: 0.47, 0.66)), milk protein: 1.20 nmol/L (0.90, 1.51), and yogurt protein: 1.33 nmol/L (0.79, 1.86), but not with cheese protein: -0.07 nmol/L (-0.40, 0.25). IGF-I concentrations were also positively associated with intake of fibre (per 5 g/day higher intake: 0.46 nmol/L (0.35, 0.57)) and starch from wholegrains (Q5 vs. Q1: 1.08 nmol/L (0.77, 1.39)), and inversely associated with alcohol consumption (>40 g/day vs <1 g/day: -1.36 nmol/L (-1.00, -1.71)). CONCLUSIONS These results show differing associations with IGF-I concentrations depending on the source of dairy protein, with positive associations with milk and yogurt protein intake but no association with cheese protein. The positive association of fibre and starch from wholegrains with IGF-I warrants further investigation.
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Effects of Behavioral Weight Loss and Metformin on IGFs in Cancer Survivors: A Randomized Trial.
Yeh, HC, Maruthur, NM, Wang, NY, Jerome, GJ, Dalcin, AT, Tseng, E, White, K, Miller, ER, Juraschek, SP, Mueller, NT, et al
The Journal of clinical endocrinology and metabolism. 2021;(10):e4179-e4191
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CONTEXT Higher levels of insulin-like growth factor-1 (IGF-1) are associated with increased risk of cancers and higher mortality. Therapies that reduce IGF-1 have considerable appeal as means to prevent recurrence. DESIGN Randomized, 3-parallel-arm controlled clinical trial. INTERVENTIONS AND OUTCOMES Cancer survivors with overweight or obesity were randomized to (1) self-directed weight loss (comparison), (2) coach-directed weight loss, or (3) metformin treatment. Main outcomes were changes in IGF-1 and IGF-1:IGFBP3 molar ratio at 6 months. The trial duration was 12 months. RESULTS Of the 121 randomized participants, 79% were women, 46% were African Americans, and the mean age was 60 years. At baseline, the average body mass index was 35 kg/m2; mean IGF-1 was 72.9 (SD, 21.7) ng/mL; and mean IGF1:IGFBP3 molar ratio was 0.17 (SD, 0.05). At 6 months, weight changes were -1.0% (P = 0.07), -4.2% (P < 0.0001), and -2.8% (P < 0.0001) in self-directed, coach-directed, and metformin groups, respectively. Compared with the self-directed group, participants in metformin had significant decreases on IGF-1 (mean difference in change: -5.50 ng/mL, P = 0.02) and IGF1:IGFBP3 molar ratio (mean difference in change: -0.0119, P = 0.011) at 3 months. The significant decrease of IGF-1 remained in participants with obesity at 6 months (mean difference in change: -7.2 ng/mL; 95% CI: -13.3 to -1.1), but not in participants with overweight (P for interaction = 0.045). There were no significant differences in changes between the coach-directed and self-directed groups. There were no differences in outcomes at 12 months. CONCLUSIONS In cancer survivors with obesity, metformin may have a short-term effect on IGF-1 reduction that wanes over time.