Daily Endocrinology Research Analysis

OBJECTIVE: To examine the association between adolescent cardiorespiratory fitness and risk of type 2 diabetes in late adulthood, including the potential influence of unobserved familial confounding on the association. DESIGN: Nationwide sibling controlled cohort study. SETTING: Swedish Military Service Conscription Register, Sweden, 1972-95, with Multi-Generation Register for identifying full siblings. National Patient Register and Prescribed Drug Register for data on diagnoses of type 2 diabetes, deaths from National Cause of Death Register, and Statistics Sweden for emigration and socioeconomic data. PARTICIPANTS: 1 124 049 Swedish men who participated in mandatory military conscription examinations with completed standardised cardiorespiratory fitness testing. Participants were followed up until 31 December 2023. MAIN OUTCOME MEASURES: Type 2 diabetes, defined as a composite endpoint of diagnosis in inpatient or specialist outpatient care and dispensation of antidiabetic drug treatment, until 31 December 2023. RESULTS: 1 124 049 men, including 477 453 full siblings, with a mean age of 18.3 (standard deviation 0.7) years at baseline were included. During follow-up, 115 958 men (10.3%) and 48 089 full siblings (10.1%) had a first type 2 diabetes event at a median age of 53.4 (interquartile range 47.6-59.3) years. Cardiorespiratory fitness was categorised into deciles (referred to as groups, with group 1 being the lowest fitness level and group 10 the highest). In a cohort analysis, the adjusted hazard ratio in fitness group 2 versus fitness group 1 was 0.83 (95% confidence interval (CI) 0.81 to 0.85), with a difference in the standardised cumulative incidence at age 65 years of 4.3 (95% CI 3.8 to 4.8) percentage points, decreasing to a hazard ratio of 0.38 (0.36 to 0.39; incidence difference 17.8 (17.3 to 18.3) percentage points) in fitness group 10. When comparing full siblings, and thus controlling for all unobserved shared behavioural, environmental, and genetic confounders, the association was replicated, but with a reduction in magnitude. The hazard ratio in fitness group 2 was 0.89 (95% CI 0.85 to 0.94; incidence difference 2.3 (1.3 to 3.3) percentage points) and 0.53 (0.50 to 0.57; incidence difference 10.9 (9.7 to 12.1) percentage points) in fitness group 10. Hypothetically moving all participants in fitness group 1 to fitness group 2 was estimated to prevent 7.2% (95% CI 6.4% to 8.0%) of events at age 65 years in the cohort analysis versus 4.6% (2.6% to 6.5%) in the full sibling analysis, whereas hypothetically moving all participants to fitness group 10 was estimated to prevent 35.6% (34.1% to 37.0%) versus 24.3% (20.5 to 28.0) of events. Indications of effect modification by overweight status were found, where the association was smaller in those with overweight than in those without overweight, particularly in the full sibling analysis. CONCLUSIONS: The findings indicate that adolescent cardiorespiratory fitness could be important in the development of type 2 diabetes in late adulthood, but conventional observational analysis might give biased estimates of the magnitude of the effect.

The aim of this international meta-analysis was to quantify the predictive value of BMI for incident fracture and relationship of this risk with age, sex, follow-up time, and BMD. A total of 1 667 922 men and women from 32 countries (63 cohorts), followed for a total of 16.0 million person-years were studied. 293 325 had FN BMD measured (2.2 million person-years follow-up). An extended Poisson model in each cohort was used to investigate relationships between WHO-defined BMI categories (Underweight: <18.5 kg/m2; Normal: 18.5-24.9 kg/m2; Overweight: 25.0-29.9 kg/m2; Obese I: 30.0-34.9 kg/m2; Obese II: ≥35.0 kg/m2) and risk of incident osteoporotic, major osteoporotic and hip fracture (HF). Inverse-variance weighted β-coefficients were used to merge the cohort-specific results. For the subset with BMD available, in models adjusted for age and follow-up time, the hazard ratio (95% CI) for HF comparing underweight with normal weight was 2.35 (2.10-2.60) in women and for men was 2.45 (1.90-3.17). Hip fracture risk was lower in overweight and obese categories compared to normal weight [obese II vs normal: women 0.66 (0.55-0.80); men 0.91 (0.66-1.26)]. Further adjustment for FN BMD T-score attenuated the increased risk associated with underweight [underweight vs normal: women 1.69 (1.47-1.96); men 1.46 (1.00-2.13)]. In these models, the protective effects of overweight and obesity were attenuated, and in both sexes, the direction of association reversed to higher fracture risk in Obese II category [Obese II vs Normal: women 1.24 (0.97-1.58); men 1.70 (1.06-2.75)]. Results were similar for other fracture outcomes. Underweight is a risk factor for fracture in both men and women regardless of adjustment for BMD. However, while overweight/obesity appeared protective in base models, they became risk factors after additional adjustment for FN BMD, particularly in the Obese II category. This effect in the highest BMI categories was of greater magnitude in men than women. These results will inform the second iteration of FRAX®.

In this study, we generated and integrated plasma proteomics and metabolomics with the genotype datasets of over 2300 European (EUR) and 400 African (AFR) ancestries to identify ancestry-specific multi-omics quantitative trait loci (QTLs). In total, we mapped 954 AFR pQTLs, 2848 EUR pQTLs, 65 AFR mQTLs, and 490 EUR mQTLs. We further applied these QTLs to ancestry-stratified type-2 diabetes (T2D) risk to pinpoint key proteins and metabolites underlying the disease-associated genetic loci. Using INTACT that combined trait-imputation and colocalization results, we nominated 270 proteins and 72 metabolites from the EUR set; seven proteins and one metabolite from the AFR set as molecular effectors of T2D risk in an ancestry-stratified manner. Here, we show that the integration of genetic and omic studies of different ancestries can be used to identify distinct effector molecular traits underlying the same disease across diverse ancestral groups.