Aims/hypothesis
Studies 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.
Methods
We 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.
Results
There 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/m
2
(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/m
2
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/interpretation
Among 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.
Graphical abstract
Plasma protein
-glycan profiling integrates information on enzymatic protein glycosylation, which is a highly controlled ubiquitous posttranslational modification. Here we investigate the ability of ...the plasma
-glycome to predict incidence of type 2 diabetes and cardiovascular diseases (CVDs; i.e., myocardial infarction and stroke).
Based on the prospective European Prospective Investigation of Cancer (EPIC)-Potsdam cohort (
= 27,548), we constructed case-cohorts including a random subsample of 2,500 participants and all physician-verified incident cases of type 2 diabetes (
= 820; median follow-up time 6.5 years) and CVD (
= 508; median follow-up time 8.2 years). Information on the relative abundance of 39
-glycan groups in baseline plasma samples was generated by chromatographic profiling. We selected predictive
-glycans for type 2 diabetes and CVD separately, based on cross-validated machine learning, nonlinear model building, and construction of weighted prediction scores. This workflow for CVD was applied separately in men and women.
The
-glycan-based type 2 diabetes score was strongly predictive for diabetes risk in an internal validation cohort (weighted C-index 0.83, 95% CI 0.78-0.88), and this finding was externally validated in the Finland Cardiovascular Risk Study (FINRISK) cohort.
-glycans were moderately predictive for CVD incidence (weighted C-indices 0.66, 95% CI 0.60-0.72, for men; 0.64, 95% CI 0.55-0.73, for women). Information on the selected
-glycans improved the accuracy of established and clinically applied risk prediction scores for type 2 diabetes and CVD.
Selected
-glycans improve type 2 diabetes and CVD prediction beyond established risk markers. Plasma protein
-glycan profiling may thus be useful for risk stratification in the context of precisely targeted primary prevention of cardiometabolic diseases.
Abstract Association analyses between longitudinal changes in diet quality scores (DQIs) and cardiometabolic risk remain scarce. Hence, we aimed to investigate how changes in two DQIs are associated ...with incident type 2 diabetes (T2D), myocardial infarction (MI) and stroke in the EPIC-Potsdam study. Changes in the Mediterranean Pyramid Score (MedPyr) and Healthy Diet Score (HDS) over 7 years from baseline (1994–1998) to follow-up 3 (2001–2005) were investigated in 23,548 middle-aged participants. Adjusted Cox Proportional Hazards Regression models were applied to investigate associations between changes in MedPyr and HDS and chronic disease incidence. More than 60% of the participants increased both DQIs more than 5%. Within a median follow-up time of 5 years 568 cases of T2D, 171 of MI, 189 of stroke were verified. An increased compared to stable MedPyr was associated with lower T2D risk (HR 0.74; 95% CI 0.59–0.92), while a decreased MedPyr was associated with higher stroke risk (HR 1.67; 95% CI 1.02–2.72). A decreased compared to stable HDS was associated with higher stroke risk (HR 1.80; 95% CI 1.02–3.20). The findings contribute further evidence on advantages of changing dietary intake towards a Mediterranean Diet. Although baseline HDS adherence was associated with T2D and stroke risk, longitudinal changes in HDS were only significantly associated with stroke risk.
Purpose
We aimed to examine the prospective association between manganese, iron, copper, zinc, iodine, selenium, selenoprotein P, free zinc, and their interplay, with incident type 2 diabetes (T2D), ...cardiovascular disease (CVD) and colorectal cancer (CRC).
Methods
Serum trace element (TE) concentrations were measured in a case-cohort study embedded within the EPIC-Potsdam cohort, consisting of a random sub-cohort (
n
= 2500) and incident cases of T2D (
n
= 705), CVD (
n
= 414), and CRC (
n
= 219). TE patterns were investigated using principal component analysis. Cox proportional hazard models were fitted to examine the association between TEs with T2D, CVD and CRC incidence.
Results
Higher manganese, zinc, iodine and selenium were associated with an increased risk of developing T2D (HR Q5 vs Q1: 1.56, 1.09–2.22; HR per SD, 95% CI 1.18, 1.05–1.33; 1.09, 1.01–1.17; 1.19, 1.06–1.34, respectively). Regarding CVD, manganese, copper and copper-to-zinc ratio were associated with an increased risk (HR per SD, 95% CI 1.13, 1.00–1.29; 1.22, 1.02–1.44; 1.18, 1.02–1.37, respectively). The opposite was observed for higher selenium-to-copper ratio (HR Q5 vs Q1, 95% CI 0.60, 0.39–0.93). Higher copper and zinc were associated with increasing risk of developing CRC (HR per SD, 95% CI 1.29, 1.05–1.59 and 1.14, 1.00–1.30, respectively). Selenium, selenoprotein P and selenium-to-copper-ratio were associated to decreased risk (HR per SD, 95% CI 0.82, 0.69–0.98; 0.81, 0.72–0.93; 0.77, 0.65–0.92, respectively). Two TE patterns were identified: manganese–iron–zinc and copper–iodine–selenium.
Conclusion
Different TEs were associated with the risk of developing T2D, CVD and CRC. The contrasting associations found for selenium with T2D and CRC point towards differential disease-related pathways.
Inclusion of clinical parameters limits the application of most cardiovascular disease (CVD) prediction models to clinical settings. We developed and externally validated a non-clinical CVD risk ...score with a clinical extension and compared the performance to established CVD risk scores. We derived the scores predicting CVD (non-fatal and fatal myocardial infarction and stroke) in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 25,992, cases = 683) using competing risk models and externally validated in EPIC-Heidelberg (n = 23,529, cases = 692). Performance was assessed by C-indices, calibration plots, and expected-to-observed ratios and compared to a non-clinical model, the Pooled Cohort Equation, Framingham CVD Risk Scores (FRS), PROCAM scores, and the Systematic Coronary Risk Evaluation (SCORE). Our non-clinical score included age, gender, waist circumference, smoking, hypertension, type 2 diabetes, CVD family history, and dietary parameters. C-indices consistently indicated good discrimination (EPIC-Potsdam 0.786, EPIC-Heidelberg 0.762) comparable to established clinical scores (thereof highest, FRS: EPIC-Potsdam 0.781, EPIC-Heidelberg 0.764). Additional clinical parameters slightly improved discrimination (EPIC-Potsdam 0.796, EPIC-Heidelberg 0.769). Calibration plots indicated very good calibration with minor overestimation in the highest decile of predicted risk. The developed non-clinical 10-year CVD risk score shows comparable discrimination to established clinical scores, allowing assessment of individual CVD risk in physician-independent settings.
Our knowledge about the connection between protein intake and diabetes-related complications comes largely from studies among those already diagnosed with type 2 diabetes (T2D). However, there is a ...lack of information on whether changing protein intake after diabetes diagnosis affects complications risk. We aimed to explore the association between protein intake (total, animal, and plant) and vascular complications in incident T2D patients considering pre-diagnosis intake and changes in intake after diagnosis. This prospective cohort study included 1064 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort who developed T2D during follow-up (physician-verified). Dietary protein intake was measured with a food frequency questionnaire at baseline and follow-up. We included physician-reported incident diabetes complications (myocardial infarction, stroke, nephropathy, and neuropathy). A total of 388 participants developed complications, 82 macrovascular complications, and 343 microvascular complications. Substituting carbohydrates with protein showed a trend towards lower complications risk, although this association was not statistically significant (hazard ratio (HR) for 5% energy (E) substitution: 0.83; 95% confidence intervals (CI): 0.60-1.14). Increasing protein intake at the expense of carbohydrates after diabetes diagnosis was not associated with total and microvascular complications (HR for 5% E change substitution: 0.98; 95% CI: 0.89-1.08 and HR for 5% E change substitution: 1.02; 95% CI: 0.92-1.14, respectively). Replacing carbohydrates with protein did not elevate the risk of diabetes complications in incident T2D cases.
Cardiovascular disease risk among individuals across different categories of BMI might depend on their metabolic health. It remains unclear to what extent metabolic health status changes over time ...and whether this affects cardiovascular disease risk. In this study, we aimed to examine the association between metabolic health and its change over time and cardiovascular disease risk across BMI categories.
Between June and December, 1976, 121 701 female nurses were recruited to the Nurses' Health Study (NHS) of whom 103 298 returned a questionnaire in 1980 used as baseline in this study. After excluding women with a history of cardiovascular disease or cancer, with missing body weight and with underweight. 90 257 women were followed-up from 1980 to 2010 for incident cardiovascular disease. Participants were cross-classified by BMI categories, metabolic health (defined by absence of diabetes, hypertension and hypercholesterolaemia), and change in metabolic health status during follow-up. The cardiovascular component of the NHS is registered with ClinicalTrials.gov, number NCT00005152.
During 2 127 391 person-years of follow-up with a median follow-up of 24 years, we documented 6306 cases of cardiovascular disease including 3304 myocardial infarction cases and 3080 strokes. Cardiovascular disease risk of women with metabolically healthy obesity was increased compared with women with metabolically healthy normal weight (HR 1·39, 95% CI 1·15-1·68), but risk was considerably higher in women with metabolically unhealthy normal weight (2·43, 2·19-2·68), overweight (2·61, 2·36-2·89) and obesity (3·15, 2·83-3·50). The majority of metabolically healthy women converted to unhealthy phenotypes (2555 84% of 3027 women with obesity, 22 215 68% of 32 882 women with normal-weight after 20 years). Women who maintained metabolically healthy obesity during follow-up were still at a higher cardiovascular disease risk compared with women with stable healthy normal weight (HR 1·57, 1·03-2·38), yet this risk was lower than for initially metabolically healthy women who converted to an unhealthy phenotype (normal-weight 1·90, 1·66-2·17 vs obesity 2·74, 2·30-3·27). Particularly incident diabetes and hypertension increased the risk among women with initial metabolic health.
Even when metabolic health is maintained during long periods of time, obesity remains a risk factor for cardiovascular disease. However, risks are highest for metabolically unhealthy women across all BMI categories. A large proportion of metabolically healthy women converted to an unhealthy phenotype over time across all BMI categories, which is associated with an increased cardiovascular disease risk.
US National Institutes of Health, German Federal Ministry of Education and Research.
Aims/hypothesis
This study aimed to evaluate associations of height as well as components of height (sitting height and leg length) with risk of type 2 diabetes and to explore to what extent ...associations are explainable by liver fat and cardiometabolic risk markers.
Methods
A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising 26,437 participants who provided blood samples was designed. We randomly selected a subcohort of 2500 individuals (2029 diabetes-free at baseline and with anamnestic, anthropometrical and metabolic data for analysis). Of the 820 incident diabetes cases identified in the full cohort during 7 years of follow-up, 698 remained for analyses after similar exclusions.
Results
After adjustment for age, potential lifestyle confounders, education and waist circumference, greater height was related to lower diabetes risk (HR per 10 cm, men 0.59 95% CI 0.47, 0.75 and women 0.67 0.51, 0.88, respectively). Leg length was related to lower risk among men and women, but only among men if adjusted for total height. Adjustment for liver fat and triacylglycerols, adiponectin and C-reactive protein substantially attenuated associations between height and diabetes risk, particularly among women.
Conclusions/interpretation
We observed inverse associations between height and risk of type 2 diabetes, which was largely related to leg length among men. The inverse associations may be partly driven by lower liver fat content and a more favourable cardiometabolic profile.
Evidence on plasma n-6 polyunsaturated fatty acids (PUFAs) and type 2 diabetes risk is inconsistent. We examined the associations of lipid class-specific PUFA concentrations with type 2 diabetes ...risk.
In the prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (nested case-cohort study: subcohort 1,084 participants, 536 participants with type 2 diabetes, median follow-up 6.5 years), we measured plasma 18:2, 20:3, and 20:4 concentrations in 12 lipid (sub)classes, likely reflecting the plasma concentrations of linoleic acid (18:2n-6), dihomo-γ-linolenic acid (20:3n-6), and arachidonic acid (20:4n-6). The Δ-5 desaturase (D5D) activity was estimated as the 20:4/20:3 ratio. Associations with diabetes were estimated with Cox proportional hazards models.
Higher concentrations of 18:2 were inversely associated with type 2 diabetes risk, particularly in lysophosphatidylcholines (hazard ratio HR per 1 SD 0.53; 95% CI 0.23-1.26) and monoacylglycerols (HR 0.59; 0.38-0.92). Higher concentrations of 20:3 in phospholipid classes phosphatidylcholines (HR 1.63; 1.23-2.14), phosphatidylethanolamines (HR 1.87; 1.32-2.65), and phosphatidylinositol (HR 1.40; 1.05-1.87); free fatty acids (HR 1.44; 1.10-1.90); and cholesteryl esters (HR 1.47; 1.09-1.98) were linked to higher type 2 diabetes incidence, and these associations remained statistically significant after correction for multiple testing. Higher 20:4 concentrations were not associated with risk. The estimated D5D activity in phospholipids and cholesteryl esters was associated with lower type 2 diabetes risk. Single nucleotide polymorphisms in the D5D-encoding FADS genes explained relatively high proportions of variation of estimated D5D activity in those lipid classes.
Plasma n-6 PUFAs were associated differently with type 2 diabetes, depending on fatty acid and the lipid class.
In blood and tissues, dietary and endogenously generated fatty acids (FAs) occur in free form or as part of complex lipid molecules that collectively represent the lipidome of the respective tissue. ...We assessed associations of plasma lipids derived from high-resolution lipidomics with incident cardiometabolic diseases and subsequently tested if the identified risk-associated lipids were sensitive to dietary fat modification.
The EPIC Potsdam cohort study (European Prospective Investigation into Cancer and Nutrition) comprises 27 548 participants recruited within an age range of 35 to 65 years from the general population around Potsdam, Germany. We generated 2 disease-specific case cohorts on the basis of a fixed random subsample (n=1262) and all respective cohort-wide identified incident primary cardiovascular disease (composite of fatal and nonfatal myocardial infarction and stroke; n=551) and type 2 diabetes (n=775) cases. We estimated the associations of baseline plasma concentrations of 282 class-specific FA abundances (calculated from 940 distinct molecular species across 15 lipid classes) with the outcomes in multivariable-adjusted Cox models. We tested the effect of an isoenergetic dietary fat modification on risk-associated lipids in the DIVAS randomized controlled trial (Dietary Intervention and Vascular Function; n=113). Participants consumed either a diet rich in saturated FAs (control), monounsaturated FAs, or a mixture of monounsaturated and n-6 polyunsaturated FAs for 16 weeks.
Sixty-nine lipids associated (false discovery rate<0.05) with at least 1 outcome (both, 8; only cardiovascular disease, 49; only type 2 diabetes, 12). In brief, several monoacylglycerols and FA16:0 and FA18:0 in diacylglycerols were associated with both outcomes; cholesteryl esters, free fatty acids, and sphingolipids were largely cardiovascular disease specific; and several (glycero)phospholipids were type 2 diabetes specific. In addition, 19 risk-associated lipids were affected (false discovery rate<0.05) by the diets rich in unsaturated dietary FAs compared with the saturated fat diet (17 in a direction consistent with a potential beneficial effect on long-term cardiometabolic risk). For example, the monounsaturated FA-rich diet decreased diacylglycerol(FA16:0) by 0.4 (95% CI, 0.5-0.3) SD units and increased triacylglycerol(FA22:1) by 0.5 (95% CI, 0.4-0.7) SD units.
We identified several lipids associated with cardiometabolic disease risk. A subset was beneficially altered by a dietary fat intervention that supports the substitution of dietary saturated FAs with unsaturated FAs as a potential tool for primary disease prevention.
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