Schistosomiasis is a parasitic disease affecting over 200 million people in multiple organs, including the lungs. Despite this, there is little understanding of pulmonary immune responses during ...schistosomiasis. Here, we show type-2 dominated lung immune responses in both patent (egg producing) and pre-patent (larval lung migration) murine Schistosoma mansoni (S. mansoni) infection. Human pre-patent S. mansoni infection pulmonary (sputum) samples revealed a mixed type-1/type-2 inflammatory cytokine profile, whilst a case-control study showed no significant pulmonary cytokine changes in endemic patent infection. However, schistosomiasis induced expansion of pulmonary type-2 conventional dendritic cells (cDC2s) in human and murine hosts, at both infection stages. Further, cDC2s were required for type-2 pulmonary inflammation in murine pre-patent or patent infection. These data elevate our fundamental understanding of pulmonary immune responses during schistosomiasis, which may be important for future vaccine design, as well as for understanding links between schistosomiasis and other lung diseases.
The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development
. The central melanocortin system ...acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure
. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.
Aims/hypothesis
Consumption of sugar-sweetened beverages has been shown, largely in American populations, to increase type 2 diabetes incidence. We aimed to evaluate the association of consumption of ...sweet beverages (juices and nectars, sugar-sweetened soft drinks and artificially sweetened soft drinks) with type 2 diabetes incidence in European adults.
Methods
We established a case–cohort study including 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 participants selected from eight European cohorts participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. After exclusions, the final sample size included 11,684 incident cases and a subcohort of 15,374 participants. Cox proportional hazards regression models (modified for the case–cohort design) and random-effects meta-analyses were used to estimate the association between sweet beverage consumption (obtained from validated dietary questionnaires) and type 2 diabetes incidence.
Results
In adjusted models, one 336 g (12 oz) daily increment in sugar-sweetened and artificially sweetened soft drink consumption was associated with HRs for type 2 diabetes of 1.22 (95% CI 1.09, 1.38) and 1.52 (95% CI 1.26, 1.83), respectively. After further adjustment for energy intake and BMI, the association of sugar-sweetened soft drinks with type 2 diabetes persisted (HR 1.18, 95% CI 1.06, 1.32), but the association of artificially sweetened soft drinks became statistically not significant (HR 1.11, 95% CI 0.95, 1.31). Juice and nectar consumption was not associated with type 2 diabetes incidence.
Conclusions/interpretation
This study corroborates the association between increased incidence of type 2 diabetes and high consumption of sugar-sweetened soft drinks in European adults.
Aims/hypothesis
Studying gene–lifestyle interaction may help to identify lifestyle factors that modify genetic susceptibility and uncover genetic loci exerting important subgroup effects. Adequately ...powered studies with prospective, unbiased, standardised assessment of key behavioural factors for gene–lifestyle studies are lacking. This case–cohort study aims to investigate how genetic and potentially modifiable lifestyle and behavioural factors, particularly diet and physical activity, interact in their influence on the risk of developing type 2 diabetes.
Methods
Incident cases of type 2 diabetes occurring in European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts between 1991 and 2007 from eight of the ten EPIC countries were ascertained and verified. Prentice-weighted Cox regression and random-effects meta-analyses were used to investigate differences in diabetes incidence by age and sex.
Results
A total of 12,403 verified incident cases of type 2 diabetes occurred during 3.99 million person-years of follow-up of 340,234 EPIC participants eligible for InterAct. We defined a centre-stratified subcohort of 16,154 individuals for comparative analyses. Individuals with incident diabetes who were randomly selected into the subcohort (
n
= 778) were included as cases in the analyses. All prevalent diabetes cases were excluded from the study. InterAct cases were followed-up for an average of 6.9 years; 49.7% were men. Mean baseline age and age at diagnosis were 55.6 and 62.5 years, mean BMI and waist circumference values were 29.4 kg/m
2
and 102.7 cm in men, and 30.1 kg/m
2
and 92.8 cm in women, respectively. Risk of type 2 diabetes increased linearly with age, with an overall HR of 1.56 (95% CI 1.48–1.64) for a 10 year age difference, adjusted for sex. A male excess in the risk of incident diabetes was consistently observed across all countries, with a pooled HR of 1.51 (95% CI 1.39–1.64), adjusted for age.
Conclusions/interpretation
InterAct is a large, well-powered, prospective study that will inform our understanding of the interplay between genes and lifestyle factors on the risk of type 2 diabetes development.
The association of glycemic index (GI) and glycemic load (GL) with the risk of type 2 diabetes remains unclear. We investigated associations of dietary GI, GL, and digestible carbohydrate with ...incident type 2 diabetes. We performed a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition Study, including a random subcohort (n = 16,835) and incident type 2 diabetes cases (n = 12,403). The median follow-up time was 12 y. Baseline dietary intakes were assessed using country-specific dietary questionnaires. Country-specific HR were calculated and pooled using random effects meta-analysis. Dietary GI, GL, and digestible carbohydrate in the subcohort were (mean ± SD) 56 ± 4, 127 ± 23, and 226 ± 36 g/d, respectively. After adjustment for confounders, GI and GL were not associated with incident diabetes HR highest vs. lowest quartile (HRQ4) for GI: 1.05 (95% CI = 0.96, 1.16); HRQ4 for GL: 1.07 (95% CI = 0.95, 1.20). Digestible carbohydrate intake was not associated with incident diabetes HRQ4: 0.98 (95% CI = 0.86, 1.10). In additional analyses, we found that discrepancies in the GI value assignment to foods possibly explain differences in GI associations with diabetes within the same study population. In conclusion, an expansion of the GI tables and systematic GI value assignment to foods may be needed to improve the validity of GI values derived in such studies, after which GI associations may need reevaluation. Our study shows that digestible carbohydrate intake is not associated with diabetes risk and suggests that diabetes risk with high-GI and -GL diets may be more modest than initial studies suggested.
Aims/hypothesis Obesity is a major risk factor for type 2 diabetes. Recent genome-wide association (GWA) studies have identified multiple loci robustly associated with BMI and risk of obesity. ...However, information on their associations with type 2 diabetes is limited. Such information could help increase our understanding of the link between obesity and type 2 diabetes. We examined the associations of 12 obesity susceptibility loci, individually and in combination, with risk of type 2 diabetes in the population-based European Prospective Investigation of Cancer (EPIC) Norfolk cohort. Methods We genotyped 12 SNPs, identified by GWA studies of BMI, in 20,428 individuals (aged 39-79 years at baseline) with an average follow-up of 12.9 years, during which 729 individuals developed type 2 diabetes. A genetic predisposition score was calculated by adding the BMI-increasing alleles across the 12 SNPs. Associations with incidence of type 2 diabetes were examined by logistic regression models. Results Of the 12 SNPs, eight showed a trend with increased risk of type 2 diabetes, consistent with their BMI-increasing effects. Each additional BMI-increasing allele in the genetic predisposition score was associated with a 4% increased odds of developing type 2 diabetes (OR 1.041, 95% CI 1.005-1.078; p = 0.02). Adjustment for BMI completely abolished the association with incident type 2 diabetes (OR 1.003, 95% CI 0.967-1.039; p = 0.89). Conclusions/interpretation The genetic predisposition to obesity leads to increased risk of developing type 2 diabetes, which is completely mediated by its obesity-predisposing effect.
Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide. In high-income countries, low socioeconomic status seems to be related to a high incidence of T2DM, but very ...little is known about the intermediate factors of this relationship. Method We performed a case-cohort study in eight Western European countries nested in the EPIC study (n = 340, 234, 3.99 million person-years of follow-up). A random sub-cohort of 16,835 individuals and a total of 12,403 incident cases of T2DM were identified. Crude and multivariate-adjusted hazard ratios (HR) were estimated for each country and pooled across countries using meta-analytical methods. Age-, gender- and country-specific relative indices of inequality (RII) were used as the measure of educational level and RII tertiles were analysed.
Compared with participants with a high educational level (RII tertile 1), participants with a low educational level (RII tertile 3) had a higher risk of T2DM HR: 1.77, 95% confidence interval (CI): 1.69-1.85; P-trend < 0.01. The HRs adjusted for physical activity, smoking status and propensity score according to macronutrient intake were very similar to the crude HR (adjusted HR: 1.67, 95% CI: 1.52-1.83 in men; HR: 1.88, 95% CI: 1.73-2.05 in women). The HRs were attenuated only when they were further adjusted for BMI (BMI-adjusted HR: 1.36, 95% CI: 1.23-1.51 in men; HR: 1.32, 95% CI: 1.20-1.45 in women).
This study demonstrates the inequalities in the risk of T2DM in Western European countries, with an inverse relationship between educational level and risk of T2DM that is only partially explained by variations in BMI.
Abstract
Aims
The hypothesis of ‘metabolically healthy obesity’ implies that, in the absence of metabolic dysfunction, individuals with excess adiposity are not at greater cardiovascular risk. We ...tested this hypothesis in a large pan-European prospective study.
Methods and results
We conducted a case-cohort analysis in the 520 000-person European Prospective Investigation into Cancer and Nutrition study (‘EPIC-CVD’). During a median follow-up of 12.2 years, we recorded 7637 incident coronary heart disease (CHD) cases. Using cut-offs recommended by guidelines, we defined obesity and overweight using body mass index (BMI), and metabolic dysfunction (‘unhealthy’) as ≥ 3 of elevated blood pressure, hypertriglyceridaemia, low HDL-cholesterol, hyperglycaemia, and elevated waist circumference. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CI) within each country using Prentice-weighted Cox proportional hazard regressions, accounting for age, sex, centre, education, smoking, diet, and physical activity. Compared with metabolically healthy normal weight people (reference), HRs were 2.15 (95% CI: 1.79; 2.57) for unhealthy normal weight, 2.33 (1.97; 2.76) for unhealthy overweight, and 2.54 (2.21; 2.92) for unhealthy obese people. Compared with the reference group, HRs were 1.26 (1.14; 1.40) and 1.28 (1.03; 1.58) for metabolically healthy overweight and obese people, respectively. These results were robust to various sensitivity analyses.
Conclusion
Irrespective of BMI, metabolically unhealthy individuals had higher CHD risk than their healthy counterparts. Conversely, irrespective of metabolic health, overweight and obese people had higher CHD risk than lean people. These findings challenge the concept of ‘metabolically healthy obesity’, encouraging population-wide strategies to tackle obesity.
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