A phenome-wide comparative analysis of genetic discordance between obesity and type 2 diabetes

Obesity and type 2 diabetes are causally related, yet there is considerable heterogeneity in the consequences of both conditions and the mechanisms of action are poorly defined. Here we show a genetic-driven approach defining two obesity profiles that convey highly concordant and discordant diabetogenic effects. We annotate and then compare association signals for these profiles across clinical and molecular phenotypic layers. Key differences are identified in a wide range of traits, including cardiovascular mortality, fat distribution, liver metabolism, blood pressure, specific lipid fractions and blood levels of proteins involved in extracellular matrix remodelling. We find marginal differences in abundance of Bacteroidetes and Firmicutes bacteria in the gut. Instrumental analyses reveal prominent causal roles for waist-to-hip ratio, blood pressure and cholesterol content of high-density lipoprotein particles in the development of diabetes in obesity. We prioritize 17 genes from the discordant signature that convey protection against type 2 diabetes in obesity, which may represent logical targets for precision medicine approaches.</p

Lifestyle precision medicine: the next generation in type 2 diabetes prevention?

The driving force behind the current global type 2 diabetes epidemic is insulin resistance in overweight and obese individuals. Dietary factors, physical inactivity, and sedentary behaviors are the major modifiable risk factors for obesity. Nevertheless, many overweight/obese people do not develop diabetes and lifestyle interventions focused on weight loss and diabetes prevention are often ineffective. Traditionally, chronically elevated blood glucose concentrations have been the hallmark of diabetes; however, many individuals will either remain ‘prediabetic’ or regress to normoglycemia. Thus, there is a growing need for innovative strategies to tackle diabetes at scale. The emergence of biomarker technologies has allowed more targeted therapeutic strategies for diabetes prevention (precision medicine), though largely confined to pharmacotherapy. Unlike most drugs, lifestyle interventions often have systemic health-enhancing effects. Thus, the pursuance of lifestyle precision medicine in diabetes seems rational. Herein, we review the literature on lifestyle interventions and diabetes prevention, describing the biological systems that can be characterized at scale in human populations, linking them to lifestyle in diabetes, and consider some of the challenges impeding the clinical translation of lifestyle precision medicine. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0938-x) contains supplementary material, which is available to authorized users

Components of a healthy diet and different types of physical activity and risk of atherothrombotic ischemic stroke : A prospective cohort study

Background: Diet and physical activity (PA) are modifiable risk factors thought to influence the risk of ischemic stroke (IS). However, few studies have examined their effect on different subtypes of IS. Aim: To examine components of overall diet quality and different types of PA in relation to the risk of atherothrombotic IS (aIS). Materials and methods: The study population included 23,797 participants (mean age 58 years; 63% women) from the Malmö Diet and Cancer Study cohort. Participants were enrolled between 1991 and 1996 and followed until end of 2016 (median follow-up 21.5 years). Incident aIS events were identified using national registries (total cases 1,937). Measures of PA (total, leisure-time, occupational, and domestic) were assessed using a baseline questionnaire and dietary intakes were estimated using a modified diet history method. Overall diet quality was assessed using a diet quality index. Intake of key food groups and beverages associated with overall diet quality were investigated separately. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression models adjusting for confounders. Results: A high diet quality with high intake of fruit and vegetables, fish and shellfish and low intake of sugar-sweetened beverages and red and processed meat compared to a low diet quality was associated with lower risk of aIS (HR = 0.82, 95% CI = 0.69–0.97; p = 0.015). Leisure-time PA was associated with reduced risk of aIS (HR = 0.95 per SD increase in MET-hours/week, 95% CI = 0.91–0.99; p = 0.028) with null associations observed for total, occupational and domestic PA level. We observed no significant interaction between diet and PA on the risk of aIS. The standardized 20-year risk of aIS among subjects with low leisure-time PA and low diet quality was 8.1% compared to 6.1% among those with high leisure-time PA and high diet quality. Conclusion: Several components of a healthy diet and being physically active may reduce the risk of aIS, however, the absolute risk reduction observed was modest. A high diet quality seemed to have a risk reducing effect regardless of level of PA suggesting that individuals with a sedentary lifestyle may still gain some positive health benefits through a healthy diet

Different domains of self-reported physical activity and risk of type 2 diabetes in a population-based Swedish cohort : the Malmö diet and Cancer study

BACKGROUND: While a dose-response relationship between physical activity and risk of diabetes has been demonstrated, few studies have assessed the relative importance of different measures of physical activity on diabetes risk. The aim was to examine the association between different self-reported measures of physical activity and risk of type 2 diabetes in a prospective cohort study. METHODS: Out of 26,615 adults (45-74 years, 60% women) in the population-based Swedish Malmö Diet and Cancer Study cohort, 3791 type 2 diabetes cases were identified from registers during 17 years of follow-up. Leisure-time (17 activities), occupational and domestic physical activity were assessed through a questionnaire, and these and total physical activity were investigated in relation to type 2 diabetes risk. RESULTS: All physical activity measures showed weak to modest associations with type 2 diabetes risk. The strongest association was found in the lower end of leisure-time physical activity in dose-response analysis at levels approximately below 22 MET-hrs/week (300 min/week) representing around 40% of the population. Compared with the lowest quintile, the moderate leisure-time physical activity category had a 28% (95% CI: 0.71, 0.87) decreased risk of type 2 diabetes. Total physical activity showed a similar, but weaker, association with diabetes risk as to that of leisure-time physical activity. Domestic physical activity was positively and linearly related to diabetes risk, HR = 1.11 (95% CI: 0.99, 1.25) comparing highest to lowest quintile. There was no association between occupational physical activity and diabetes risk. CONCLUSION: A curvilinear association was observed between leisure-time physical activity and risk of diabetes. Beyond a threshold level of approximately 22 MET-hrs/week or 300 min/week, no additional risk reduction was observed with increase in physical activity

Investigating the causal relationships between excess adiposity and cardiometabolic health in men and women

AIMS/HYPOTHESIS: Excess adiposity is differentially associated with increased risk of cardiometabolic disease in men and women, according to observational studies. Causal inference studies largely assume a linear relationship between BMI and cardiometabolic outcomes, which may not be the case. In this study, we investigated the shapes of the causal relationships between BMI and cardiometabolic diseases and risk factors. We further investigated sex differences within the causal framework.METHODS: To assess causal relationships between BMI and the outcomes, we used two-stage least-squares Mendelian randomisation (MR), with a polygenic risk score for BMI as the instrumental variable. To elucidate the shapes of the causal relationships, we used a non-linear MR fractional polynomial method, and used piecewise MR to investigate threshold relationships and confirm the shapes.RESULTS: BMI was associated with type 2 diabetes (OR 3.10; 95% CI 2.73, 3.53), hypertension (OR 1.53; 95% CI 1.44, 1.62) and coronary artery disease (OR 1.20; 95% CI 1.08, 1.33), but not chronic kidney disease (OR 1.08; 95% CI 0.67, 1.72) or stroke (OR 1.08; 95% CI 0.92, 1.28). The data suggest that these relationships are non-linear. For cardiometabolic risk factors, BMI was positively associated with glucose, HbA1c, triacylglycerol levels and both systolic and diastolic BP. BMI had an inverse causal relationship with total cholesterol, LDL-cholesterol and HDL-cholesterol. The data suggest a non-linear causal relationship between BMI and BP and other biomarkers (p<0.001) except lipoprotein A. The piecewise MR results were consistent with the fractional polynomial results. The causal effect of BMI on coronary artery disease, total cholesterol and LDL-cholesterol was different in men and women, but this sex difference was only significant for LDL-cholesterol after controlling for multiple testing (p<0.001). Further, the causal effect of BMI on coronary artery disease varied by menopause status in women.CONCLUSIONS/INTERPRETATION: We describe the shapes of causal effects of BMI on cardiometabolic diseases and risk factors, and report sex differences in the causal effects of BMI on LDL-cholesterol. We found evidence of non-linearity in the causal effect of BMI on diseases and risk factor biomarkers. Reducing excess adiposity is highly beneficial for health, but there is greater need to consider biological sex in the management of adiposity

An investigation of causal relationships between prediabetes and vascular complications

Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35–50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes.Errata: Mutie, P.M., Pomares-Millan, H., Atabaki-Pasdar, N. et al. Author Correction: An investigation of causal relationships between prediabetes and vascular complications. Nat Commun 12, 202 (2021). DOI: 10.1038/s41467-020-20663-6</p