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Cardiovascular complications are commonly associated with obesity. However, a subgroup of obese individuals may not be at an increased risk for cardiovascular complications; these individuals are said to have metabolically healthy obesity (MHO). In contrast, metabolically unhealthy individuals are at high risk of cardiovascular disease (CVD), irrespective of BMI; thus, this group can include individuals within the normal weight category (BMI 18.5–24.9 kg/m2). This review provides a summary of prospective studies on MHO and metabolically unhealthy normal-weight (MUHNW) phenotypes. Notably, there is ongoing dispute surrounding the concept of MHO, including the lack of a uniform definition and the potentially transient nature of metabolic health status. This review highlights the relevance of alternative measures of body fatness, specifically measures of fat distribution, for determining MHO and MUHNW. It also highlights alternative approaches of risk stratification, which account for the continuum of risk in relation to CVD, which is observable for most risk factors. Moreover, studies evaluating the transition from metabolically healthy to unhealthy phenotypes and potential determinants for such conversions are discussed. Finally, the review proposes several strategies for the use of epidemiological research to further inform the current debate on metabolic health and its determination across different stages of body fatness.

Obesity and impaired metabolic health are established risk factors for the non-communicable diseases (NCDs) type 2 diabetes mellitus, cardiovascular disease, neurodegenerative diseases, cancer and nonalcoholic fatty liver disease, otherwise known as metabolic associated fatty liver disease (MAFLD). With the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), obesity and impaired metabolic health also emerged as important determinants of severe coronavirus disease 2019 (COVID-19). Furthermore, novel findings indicate that specifically visceral obesity and characteristics of impaired metabolic health such as hyperglycaemia, hypertension and subclinical inflammation are associated with a high risk of severe COVID-19. In this Review, we highlight how obesity and impaired metabolic health increase complications and mortality in COVID-19. We also summarize the consequences of SARS-CoV-2 infection for organ function and risk of NCDs. In addition, we discuss data indicating that the COVID-19 pandemic could have serious consequences for the obesity epidemic. As obesity and impaired metabolic health are both accelerators and consequences of severe COVID-19, and might adversely influence the efficacy of COVID-19 vaccines, we propose strategies for the prevention and treatment of obesity and impaired metabolic health on a clinical and population level, particularly while the COVID-19 pandemic is present.This Review highlights how obesity and impaired metabolic health increase complications and mortality in coronavirus disease 2019 (COVID-19) and summarizes the consequences of infection with severe acute respiratory syndrome coronavirus 2 for organ function. In addition, there is a discussion on the implications of the COVID-19 pandemic for the obesity pandemic.

Matthias B Schulze and colleagues discuss current knowledge on the associations between dietary patterns and cancer, coronary heart disease, stroke, and type 2 diabetes, focusing on areas of uncertainty and future research directions

Industry sponsors' financial interests might bias the conclusions of scientific research. We examined whether financial industry funding or the disclosure of potential conflicts of interest influenced the results of published systematic reviews (SRs) conducted in the field of sugar-sweetened beverages (SSBs) and weight gain or obesity. We conducted a search of the PubMed, Cochrane Library, and Scopus databases to identify published SRs from the inception of the databases to August 31, 2013, on the association between SSB consumption and weight gain or obesity. SR conclusions were independently classified by two researchers into two groups: those that found a positive association and those that did not. These two reviewers were blinded with respect to the stated source of funding and the disclosure of conflicts of interest. We identified 17 SRs (with 18 conclusions). In six of the SRs a financial conflict of interest with some food industry was disclosed. Among those reviews without any reported conflict of interest, 83.3% of the conclusions (10/12) were that SSB consumption could be a potential risk factor for weight gain. In contrast, the same percentage of conclusions, 83.3% (5/6), of those SRs disclosing some financial conflict of interest with the food industry were that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain or obesity. Those reviews with conflicts of interest were five times more likely to present a conclusion of no positive association than those without them (relative risk: 5.0, 95% CI: 1.3-19.3). An important limitation of this study is the impossibility of ruling out the existence of publication bias among those studies not declaring any conflict of interest. However, the best large randomized trials also support a direct association between SSB consumption and weight gain or obesity. Financial conflicts of interest may bias conclusions from SRs on SSB consumption and weight gain or obesity.

Aims/hypothesisStudies suggest decreased mortality risk among people who are overweight or obese compared with individuals with normal weight in type 2 diabetes (obesity paradox). However, the relationship between body weight or weight change and microvascular vs macrovascular complications of type 2 diabetes remains unresolved. We investigated the association between BMI and BMI change with long-term risk of microvascular and macrovascular complications in type 2 diabetes in a prospective cohort study.MethodsWe studied participants with incident type 2 diabetes from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, who were free of cancer, cardiovascular disease and microvascular disease at diagnosis (n = 1083). Pre-diagnosis BMI and relative annual change between pre- and post-diagnosis BMI were evaluated in multivariable-adjusted Cox models.ResultsThere were 85 macrovascular (myocardial infarction and stroke) and 347 microvascular events (kidney disease, neuropathy and retinopathy) over a median follow-up of 10.8 years. Median pre-diagnosis BMI was 29.9 kg/m2 (IQR 27.4–33.2), and the median relative annual BMI change was −0.4% (IQR −2.1 to 0.9). Higher pre-diagnosis BMI was positively associated with total microvascular complications (multivariable-adjusted HR per 5 kg/m2 [95% CI]: 1.21 [1.07, 1.36], kidney disease 1.39 [1.21, 1.60] and neuropathy 1.12 [0.96, 1.31]) but not with macrovascular complications (HR 1.05 [95% CI 0.81, 1.36]). Analyses according to BMI categories corroborated these findings. Effect modification was not evident by sex, smoking status or age groups. In analyses according to BMI change categories, BMI loss of more than 1% indicated a decreased risk of total microvascular complications (HR 0.62 [95% CI 0.47, 0.80]), kidney disease (HR 0.57 [95% CI 0.40, 0.81]) and neuropathy (HR 0.73 [95% CI 0.52, 1.03]), compared with participants with a stable BMI; no clear association was observed for macrovascular complications (HR 1.04 [95% CI 0.62, 1.74]). The associations between BMI gain compared with stable BMI and diabetes-related vascular complications were less apparent. Associations were consistent across strata of sex, age, pre-diagnosis BMI or medication but appeared to be stronger among never-smokers compared with current or former smokers.Conclusions/interpretationAmong people with incident type 2 diabetes, pre-diagnosis BMI was positively associated with microvascular complications, while a reduced risk was observed with weight loss when compared with stable weight. The relationships with macrovascular disease were less clear.

An expert commission (The Lancet Diabetes & Endocrinology Commission on Clinical Obesity) proposed novel diagnostic criteria distinguishing between preclinical and clinical obesity and suggesting treatment indications for the latter. However, the proportional assignment to preclinical and clinical obesity in adults with BMI-defined obesity, the associated disease risks, as well as the response to lifestyle interventions are not well known. Here we show that among those with BMI-based obesity, 100% are confirmed to have obesity by at least one other anthropometric measure in NHANES 2017-2018 and the prospective EPIC-Potsdam cohort. More than 80% of adults with confirmed obesity meet the criteria for clinical obesity and have 2.8-fold increased risk of incident cardiovascular disease and 7.9-fold increased risk for type 2 diabetes compared to adults without obesity and not fulfilling clinical criteria. Adults with preclinical obesity have no elevated cardiovascular disease risk, but type 2 diabetes risk is markedly increased. A 9-months lifestyle intervention (Tübingen Lifestyle Intervention Programme) decreases the proportion of clinical obesity from 71% to 57%, and that of prediabetes from 52% to 29%. The Lancet Diabetes & Endocrinology Commission on Clinical Obesity proposed new diagnostic criteria distinguishing preclinical and clinical obesity. Here the authors report that according to these criteria 80% of individuals with BMI-defined obesity are classified with clinical obesity and have increased risk for cardiovascular diseases and type 2 diabetes. A lifestyle intervention can lower the prevalence of clinical obesity.

Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1 , FOXP1 , GABRA2 , GLR1A , RHOT1 , and TBC1D4 . We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1 -deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca 2+ , and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1 -deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1 methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets. Type 2 diabetes (T2D) is characterized by hyperglycemia caused by insufficient insulin release from pancreatic islets, often in combination with insulin resistance. Here the authors present an epigenetic case-control study in human pancreatic islets revealing changes that contribute to type 2 diabetes development, e.g., epigenetic downregulation of RHOT1.

Background Advanced glycation end-products are proteins that become glycated after contact with sugars and are implicated in endothelial dysfunction and arterial stiffening. We aimed to investigate the relationships between advanced glycation end-products, measured as skin autofluorescence, and vascular stiffness in various glycemic strata. Methods We performed a cross-sectional analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, comprising n = 3535 participants (median age 67 years, 60% women). Advanced glycation end-products were measured as skin autofluorescence with AGE-Reader™, vascular stiffness was measured as pulse wave velocity, augmentation index and ankle-brachial index with Vascular Explorer™. A subset of 1348 participants underwent an oral glucose tolerance test. Participants were sub-phenotyped into normoglycemic, prediabetes and diabetes groups. Associations between skin autofluorescence and various indices of vascular stiffness were assessed by multivariable regression analyses and were adjusted for age, sex, measures of adiposity and lifestyle, blood pressure, prevalent conditions, medication use and blood biomarkers. Results Skin autofluorescence associated with pulse wave velocity, augmentation index and ankle-brachial index, adjusted beta coefficients (95% CI) per unit skin autofluorescence increase: 0.38 (0.21; 0.55) for carotid-femoral pulse wave velocity, 0.25 (0.14; 0.37) for aortic pulse wave velocity, 1.00 (0.29; 1.70) for aortic augmentation index, 4.12 (2.24; 6.00) for brachial augmentation index and − 0.04 (− 0.05; − 0.02) for ankle-brachial index. The associations were strongest in men, younger individuals and were consistent across all glycemic strata: for carotid-femoral pulse wave velocity 0.36 (0.12; 0.60) in normoglycemic, 0.33 (− 0.01; 0.67) in prediabetes and 0.45 (0.09; 0.80) in diabetes groups; with similar estimates for aortic pulse wave velocity. Augmentation index was associated with skin autofluorescence only in normoglycemic and diabetes groups. Ankle-brachial index inversely associated with skin autofluorescence across all sex, age and glycemic strata. Conclusions Our findings indicate that advanced glycation end-products measured as skin autofluorescence might be involved in vascular stiffening independent of age and other cardiometabolic risk factors not only in individuals with diabetes but also in normoglycemic and prediabetic conditions. Skin autofluorescence might prove as a rapid and non-invasive method for assessment of macrovascular disease progression across all glycemic strata.

Purpose We aimed to evaluate age-dependent changes of six trace elements (TE) [manganese (Mn), iron (Fe), zinc (Zn), copper (Cu), iodine (I), and selenium (Se)] over a 20-year period. Methods TE concentrations were determined using repeated serum samples taken at baseline and after 20 years of follow-up from 219 healthy participants of the EPIC-Potsdam study, using inductively coupled plasma tandem mass spectrometry. For each TE, absolute and relative differences were calculated between the two time points, as well as the proportion of individuals within normal reference ranges. Interdependence between age-related TE differences was investigated using principal component analysis (PCA). Relationships between selected factors (lifestyle, sociodemographic, anthropometric factors, and hypertension) and corresponding TE longitudinal variability were examined using multivariable linear regression models. Results Median age of our study sample was 58.32 years (4.42) at baseline and 40% were females. Median Mn, Zn, Se concentrations and Se to Cu ratio significantly decreased during aging while median Fe, Cu, I concentrations and Cu to Zn ratio significantly increased. A substantial percentage of the participants, at both time points, had Zn concentrations below the reference range. The first PCA-extracted factor reflected the correlated decline in both Mn and Zn over time while the second factor reflected the observed (on average) increase in both Cu and I over time. Overall, none of the investigated factors were strong determinants of TE longitudinal variability, except possibly dietary supplement use, and alcohol use for Fe. Conclusions In conclusion, in this population-based study of healthy elderly, decrease in Mn, Zn, and Se concentrations and increase in Fe, Cu, and I concentrations were observed over 20 years of follow-up. Further research is required to investigate dietary determinants and markers of TE status as well as the relationships between TE profiles and the risk of age-related diseases.

Background The Mediterranean Diet (MedDiet) has been acknowledged as a healthy diet. However, its relation with risk of major chronic diseases in non-Mediterranean countries is inconclusive. The Nordic diet is proposed as an alternative across Northern Europe, although its associations with the risk of chronic diseases remain controversial. We aimed to investigate the association between the Nordic diet and the MedDiet with the risk of chronic disease (type 2 diabetes (T2D), myocardial infarction (MI), stroke, and cancer) in the EPIC-Potsdam cohort. Methods The EPIC-Potsdam cohort recruited 27,548 participants between 1994 and 1998. After exclusion of prevalent cases, we evaluated baseline adherence to a score reflecting the Nordic diet and two MedDiet scores (tMDS, reflecting the traditional MedDiet score, and the MedPyr score, reflecting the MedDiet Pyramid). Cox regression models were applied to examine the association between the diet scores and the incidence of major chronic diseases. Results During a follow-up of 10.6 years, 1376 cases of T2D, 312 of MI, 321 of stroke, and 1618 of cancer were identified. The Nordic diet showed a statistically non-significant inverse association with incidence of MI in the overall population and of stroke in men. Adherence to the MedDiet was associated with lower incidence of T2D (HR per 1 SD 0.93, 95% CI 0.88–0.98 for the tMDS score and 0.92, 0.87–0.97 for the MedPyr score). In women, the MedPyr score was also inversely associated with MI. No association was observed for any of the scores with cancer. Conclusions In the EPIC-Potsdam cohort, the Nordic diet showed a possible beneficial effect on MI in the overall population and for stroke in men, while both scores reflecting the MedDiet conferred lower risk of T2D in the overall population and of MI in women.