Emerging studies have investigated the association between puberty timing, particularly age at menarche (AAM), and type 2 diabetes. However, whether this association is independent of adiposity is ...unclear. We aimed to systematically review published evidence on the association between puberty timing and type 2 diabetes (T2D) or impaired glucose tolerance (IGT), with and without adjustment for adiposity, and to estimate the potential contribution of puberty timing to the burden of T2D in the United Kingdom (UK).
We searched PubMed, Medline, and Embase databases for publications until February 2019 on the timing of any secondary sexual characteristic in boys or girls in relation to T2D/IGT. Inverse-variance-weighted random-effects meta-analysis was used to pool reported estimates, and meta-regression was used to explore sources of heterogeneity. Twenty-eight observational studies were identified. All assessed AAM in women (combined N = 1,228,306); only 1 study additionally included men. In models without adjustment for adult adiposity, T2D/IGT risk was lower per year later AAM (relative risk RR = 0.91, 95% CI 0.89-0.93, p < 0.001, 11 estimates, n = 833,529, I2 = 85.4%) and higher for early versus later menarche (RR = 1.39, 95% CI 1.25-1.55, p < 0.001, 23 estimates, n = 1,185,444, I2 = 87.8%). Associations were weaker but still evident in models adjusted for adiposity (AAM: RR = 0.97 per year, 95% CI 0.95-0.98, p < 0.001, 12 estimates, n = 852,268, I2 = 51.8%; early menarche: RR = 1.19, 95% CI 1.11-1.28, p < 0.001, 21 estimates, n = 890,583, I2 = 68.1%). Associations were stronger among white than Asian women, and in populations with earlier average AAM. The estimated population attributable risk of T2D in white UK women due to early menarche unadjusted and adjusted for adiposity was 12.6% (95% CI 11.0-14.3) and 5.1% (95% CI 3.6-6.7), respectively. Findings in this study are limited by residual and unmeasured confounding, and self-reported AAM.
Earlier AAM is consistently associated with higher T2D/IGT risk, independent of adiposity. More importantly, this research has identified that a substantial proportion of T2D in women is related to early menarche, which would be expected to increase in light of global secular trends towards earlier puberty timing. These findings highlight the need to identify the underlying mechanisms linking early menarche to T2D/IGT risk.
We conducted a systematic review and meta-analysis to investigate the associations between menarcheal age and all-cause and cardiovascular death. Medline, Embase, Scopus, and Web of Knowledge were ...searched for articles published prior to March 2013 reporting on the associations between menarcheal age and death from all causes or from cardiovascular disease (total cardiovascular disease, ischemic heart disease (IHD), and stroke) in adult women. Nine articles were eligible for inclusion; these reported 5 estimates each for death from all causes and total cardiovascular death, 6 estimates for IHD, and 7 estimates for death from stroke. Our meta-analysis showed that each 1-year increase in age at menarche was associated with a 3% lower relative risk of death from all causes (pooled hazard ratio = 0.97, 95% confidence interval: 0.96, 0.98) with low heterogeneity (I(2) = 32.2%). Meta-analysis of 2 cohorts showed a higher risk of death from all causes for women who experienced early menarche (at <12 years of age) versus "not early" menarche (at ≥ 12 years of age) (pooled hazard ratio = 1.23, 95% confidence interval: 1.10, 1.38; I(2) = 0%). An inverse association between age at menarche and death from IHD was observed only among nonsmoking populations or populations with low prevalence of smoking. We found no evidence of association between age at menarche and death from all cardiovascular diseases or stroke. Early menarche was consistently associated with higher risk of death from all causes. Further studies are needed to clarify the role of menarcheal age on cardiovascular outcomes and to investigate the potential modifying role of smoking.
Summary
Pharmacological options for management of obesity and type 2 diabetes mellitus (T2DM) in children are limited. We aimed to synthesize published randomized controlled trial (RCT) evidence on ...the efficacy of glucagon‐like peptide‐1 (GLP‐1) agonists in T2DM, pre‐diabetes, and obesity in children aged <18 years. Inclusion criteria were RCTs of any GLP‐1 agonist, solely or in conjunction with other drugs, for the treatment of obesity, pre‐diabetes, and/or T2DM in children aged <18 years old. Nine studies met the inclusion criteria (two for T2DM, one for pre‐diabetes, and six for obesity without diabetes). In total, 286 children were allocated to GLP‐1 agonist therapy. Compared with controls, GLP‐1 agonist therapy reduced HbA1c by −0.30% (95% confidence interval CI −0.57, −0.04) with a larger effect in children with (pre‐)diabetes (−0.72%; 95% CI −1.17, −0.28; three studies) than in children with obesity (−0.08%; 95% CI −0.13, −0.02; four studies). Conversely, GLP‐1 agonist therapy reduced body weight more in children with obesity (−2.74 kg; 95% CI −3.77, −1.70; six studies) than in children with T2DM (−0.97 kg; 95% CI −2.01, 0.08; two studies). Adverse effects included gastrointestinal symptoms and minor hypoglycemic episodes, but not severe hypoglycemia. GLP‐1 agonists are efficacious in treating children with obesity and/or T2DM. Effect sizes are comparable with those reported in adults.
Individuals with obesity do not represent a homogeneous group in terms of cardiometabolic risk. Using 3 nationally representative British birth cohorts, we investigated whether the duration of ...obesity was related to heterogeneity in cardiometabolic risk.
We used harmonised body mass index (BMI) and cardiometabolic disease risk factor data from 20,746 participants (49.1% male and 97.2% white British) enrolled in 3 British birth cohort studies: the 1946 National Survey of Health and Development (NSHD), the 1958 National Child Development Study (NCDS), and the 1970 British Cohort Study (BCS70). Within each cohort, individual life course BMI trajectories were created between 10 and 40 years of age, and from these, age of obesity onset, duration spent obese (range 0 to 30 years), and cumulative obesity severity were derived. Obesity duration was examined in relation to a number of cardiometabolic disease risk factors collected in mid-adulthood: systolic (SBP) and diastolic blood pressure (DBP), high-density-lipoprotein cholesterol (HDL-C), and glycated haemoglobin (HbA1c). A greater obesity duration was associated with worse values for all cardiometabolic disease risk factors. The strongest association with obesity duration was for HbA1c: HbA1c levels in those with obesity for <5 years were relatively higher by 5% (95% CI: 4, 6), compared with never obese, increasing to 20% (95% CI: 17, 23) higher in those with obesity for 20 to 30 years. When adjustment was made for obesity severity, the association with obesity duration was largely attenuated for SBP, DBP, and HDL-C. For HbA1c, however, the association with obesity duration persisted, independent of obesity severity. Due to pooling of 3 cohorts and thus the availability of only a limited number harmonised variables across cohorts, our models included adjustment for only a small number of potential confounding variables, meaning there is a possibility of residual confounding.
Given that the obesity epidemic is characterised by a much earlier onset of obesity and consequently a greater lifetime exposure, our findings suggest that health policy recommendations aimed at preventing early obesity onset, and therefore reducing lifetime exposure, may help reduce the risk of diabetes, independently of obesity severity. However, to test the robustness of our observed associations, triangulation of evidence from different epidemiological approaches (e.g., mendelian randomization and negative control studies) should be obtained.
In a systematic review, we identified 21 separate studies with data on the association between rapid infancy weight gain, up to age 2 y, and subsequent obesity risk. Uniformly all studies reported ...significant positive associations. We transformed the reported effect sizes to a standard infancy weight gain exposure, and found that further differences in study design accounted for much of the variation in risk. An accompanying paper by Melinda Yeung reminds us that there are benefits of postnatal catch‐up growth in certain populations, and suggests that genetic and nutritional factors could moderate the unhealthy translation of rapid infancy weight gain to visceral fat and insulin resistance. Further evidence is needed, and we will need to rigorously test the benefits and risks of any interventions. However, the concept of “healthy” rapid catch‐up infancy growth is an attractive prospect.
Conclusion: Rapid infancy weight gain is consistently associated with increased subsequent obesity risk, but the predictive ability of different weight gain cut‐offs needs to be tested.
The negative impacts of social isolation and loneliness on health are well documented. However, little is known about their possible biological determinants. In up to 452,302 UK Biobank study ...participants, we perform genome-wide association study analyses for loneliness and regular participation in social activities. We identify 15 genomic loci (P < 5 × 10
) for loneliness, and demonstrate a likely causal association between adiposity and increased susceptibility to loneliness and depressive symptoms. Further loci were identified for regular attendance at a sports club or gym (N = 6 loci), pub or social club (N = 13) or religious group (N = 18). Across these traits there was strong enrichment for genes expressed in brain regions that control emotional expression and behaviour. We demonstrate aetiological mechanisms specific to each trait, in addition to identifying loci that are pleiotropic across multiple complex traits. Further study of these traits may identify novel modifiable risk factors associated with social withdrawal and isolation.
It was previously observed that maternal iron supplementation in pregnancy was associated with increased offspring size and adiposity at birth, possibly mediated through increased risk of gestational ...diabetes. In this study we investigated potential long-term associations of maternal iron supplementation in pregnancy with offspring growth in infancy, and growth and cardiometabolic risk factors in mid-childhood to seek evidence of nutritional programming. Using a nested case-control format, markers of growth and adiposity were measured at 3, 12 and 24 months of age in 341 infants from the Cambridge Baby Growth Study whose mothers supplemented with iron in pregnancy and 222 infants whose mothers did not. Measures of growth, glucose tolerance (using a 30 minute 1.75 g glucose/kg body weight oral glucose tolerance test), insulin sensitivity (HOMA IR) and blood pressure were collected in 122 and 79 of these children, respectively, at around 9.5 years of age. In infancy adiposity-promoting associations with maternal iron supplementation in pregnancy were evident at 3 months of age (e.g. mean difference in skinfold thickness: β = +0.15 mm, p = 0.02, in n = 341 whose mothers supplemented versus 222 that did not; waist circumference: β = +0.7 cm, p = 0.04, in n = 159 and 78, respectively) but differences lessened after this time (e.g. 3-12 month change in mean difference in skinfold thickness: β = -0.2 mm, p = 0.03, in n = 272 and 178, respectively). At ~9.5 years of age children whose mothers supplemented with iron in pregnancy had lower mean arterial blood pressures (β = -1.0 mmHg, p = 0.03, in n = 119 and 78, respectively). There were no apparent differences in markers of growth or other cardiometabolic factors. These results suggest that most of the associations of maternal iron supplementation in pregnancy on growth and adiposity evident at birth disappear during infancy, but there may be some evidence of long-term nutritional programming of blood pressure in mid-childhood.
Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we ...identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.
"Collider bias" (also referred to as the "reversal paradox")1 describes the artificial association created between two exposures (A and B) when a shared outcome (X) is included in the model as a ...covariate (Figure 1). A recent paper by Aschard et al. described the potential for collider bias when adjusting for heritable covariates in genetic association studies.2 However, in their examples, the authors acknowledged that they could not exclude the possibility of a true biological explanation for the genetic association seen only in the adjusted model.
Aim
To systematically appraise and summarise published evidence on the association between childhood physical activity (PA) and subsequent age at menarche (AAM).
Methods
We searched PubMed ...(1990–2018) for studies that reported the relationship between childhood PA and AAM. We performed tabular synthesis of population‐based studies and a random‐effects meta‐analysis of results of athlete/nonathlete studies.
Results
One randomised controlled trial was identified, in which an intervention to prevent obesity reduced the likelihood of menarche during the two‐year study period (relative risk: 0.75, 95% CI: 0.66–0.87; n = 422 girls). One of five prospective cohort studies (total n = 4492) reported a significant association between self‐reported PA duration and subsequent menarche timing. Four of five historical cohort studies (total n = 89 470) reported significant associations between recalled premenarcheal PA and later AAM. Meta‐analysis across 12 athlete/nonathlete studies showed that menarche occurred 1.13 years later (95% CI: 0.80–1.47) in athletes compared to nonathletes.
Conclusion
These findings suggest that AAM is a behaviourally modifiable trait. However, the quality of reported population‐based study evidence is low and estimation of the true relationship between childhood PA and AAM is likely confounded by concomitant changes in diet and lifestyle behaviours.
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