Microvascular endothelial dysfunction in skin is associated with higher risk of heart failure with preserved ejection fraction in women with type 2 diabetes: the Hoorn Diabetes Care System Cohort.

BACKGROUND: Microvascular dysfunction plays a crucial role in complications of type 2 diabetes and might contribute to heart failure with preserved ejection fraction (HFpEF), a disease that disproportionally affects women. We aimed to investigate if presence and degree of microvascular dysfunction (MVD) in skin relates to markers of left ventricular diastolic dysfunction (LVDD) and HFpEF risk in adults with type 2 diabetes, and whether sex modifies this association. METHODS: We recruited 154 participants (50% women) from the Hoorn Diabetes Care System Cohort, a prospective cohort study, for in vivo evaluation of skin MVD, echocardiography and blood sampling. MVD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin, acetylcholine and sodium nitroprusside (SNP). We performed a cross-sectional analysis of the association between perfusion responses and echocardiographic and clinical markers of LVDD and the H2FPEF score by multivariable linear regression analysis adjusted for confounders. Sex was evaluated as a potential effect modifier and the analysis was stratified. RESULTS: Mean age was 67 ± 6y, mean HbA1c 7.6 ± 1.3%. Women were more frequently obese (54.5 vs. 35.1%), had higher NT-proBNP plasma levels (80, IQR:34-165 vs. 46, 27-117 pg/ml) and E/E'(13.3 ± 4.3 vs. 11.4 ± 3.0) than men. Eleven women and three men were diagnosed with HFpEF, and showed lower perfusion response to insulin than those without HFpEF. A lower perfusion response to insulin and acetylcholine was associated with higher HFpEF risk in women, but not men (10% decreased perfusion response was associated with 5.8% [95%CI: 2.3;9.4%] and 5.9% [1.7;10.1%] increase of the H2FPEF score, respectively). A lower perfusion response to SNP was associated with higher pulmonary arterial systolic pressure in men while a lower perfusion response to acetylcholine associated with higher LV mass index in women and with worse LV longitudinal strain in the total population. No significant associations were found between perfusion responses and conventional LVDD markers. CONCLUSIONS: Impaired microvascular responses to insulin and acetylcholine in skin confers a higher risk of HFpEF in women with type 2 diabetes. In vivo measures of systemic MVD could represent novel risk markers for HFpEF, opening new avenues for the prevention of HFpEF in type 2 diabetes.

Alcohol-attributable burden of cancer in Argentina.

INTRODUCTION: Alcohol consumption is a risk factor for several types of cancer. Alcohol consumption levels in Argentina are among the highest in the world, and malignant neoplasms are the second cause of death in the country. Public health strategies aimed at reducing alcohol consumption could possibly lead to a decrease in cancer burden. Alcohol-attributable burden has been estimated before in neighboring countries Chile and Brazil. We now aimed to quantify the burden for Argentina. METHODS: We obtained data on alcohol consumption levels from a national representative health survey and etiologic effect sizes for the association between alcohol and cancer from the most recent comprehensive meta-analysis. We estimated the number of alcohol-attributable cancer-related deaths and disability-adjusted life years (DALYs), stratified by consumption level (light (0.1-12.5 g/day), moderate (12.6-50 g/day), or heavy (> 50 g/day) drinking). We additionally explored which hypothetical scenario would achieve the highest reduction in alcohol-attributable cancer burden: 1) heavy drinkers shifting to moderate drinking or 2) moderate drinkers shifting to light drinking. RESULTS: In 2018, 53% of the Argentinean population consumed alcohol. In men 3.7% of all cancer deaths and DALYs were attributable to alcohol consumption, in women this was 0.8% of all cancer deaths and DALYs. When moderate drinkers would shift to light drinking, 46% of alcohol-attributable cancer deaths and DALYs would be prevented, opposed to only 24% when heavy drinkers would shift to moderate drinking. CONCLUSION: Most cancer deaths and DALYs were attributable to moderate alcohol consumption (50%). This calls for implementation of population-wide strategies-instead of targeting heavy drinking only-to effectively reduce harmful use of alcohol and its impact on disease burden.

Cardiovascular risk factors and lifestyle behaviours in relation to longevity: a Mendelian randomization study.

BACKGROUND: The American Heart Association introduced the Life's Simple 7 initiative to improve cardiovascular health by modifying cardiovascular risk factors and lifestyle behaviours. It is unclear whether these risk factors are causally associated with longevity. OBJECTIVES: This study aimed to investigate causal associations of Life's Simple 7 modifiable risk factors, as well as sleep and education, with longevity using the two-sample Mendelian randomization design. METHODS: Instrumental variables for the modifiable risk factors were obtained from large-scale genome-wide association studies. Data on longevity beyond the 90th survival percentile were extracted from a genome-wide association meta-analysis with 11,262 cases and 25,483 controls whose age at death or last contact was ≤ the 60th survival percentile. RESULTS: Risk factors associated with a lower odds of longevity included the following: genetic liability to type 2 diabetes (OR 0.88; 95% CI: 0.84;0.92), genetically predicted systolic and diastolic blood pressure (per 1-mmHg increase: 0.96; 0.94;0.97 and 0.95; 0.93;0.97), body mass index (per 1-SD increase: 0.80; 0.74;0.86), low-density lipoprotein cholesterol (per 1-SD increase: 0.75; 0.65;0.86) and smoking initiation (0.75; 0.66;0.85). Genetically increased high-density lipoprotein cholesterol (per 1-SD increase: 1.23; 1.08;1.41) and educational level (per 1-SD increase: 1.64; 1.45;1.86) were associated with a higher odds of longevity. Fasting glucose and other lifestyle factors were not significantly associated with longevity. CONCLUSION: Most of the Life's Simple 7 modifiable risk factors are causally related to longevity. Prevention strategies should focus on modifying these risk factors and reducing education inequalities to improve cardiovascular health and longevity.

Characteristics associated with polypharmacy in people with type 2 diabetes: the Dutch Diabetes Pearl cohort.

AIM: To describe the prevalence and characteristics of polypharmacy in a Dutch cohort of individuals with type 2 diabetes. METHODS: We included people with type 2 diabetes from the Diabetes Pearl cohort, of whom 3886 were treated in primary care and 2873 in academic care (secondary/tertiary). With multivariable multinomial logistic regression analyses stratified for line of care, we assessed which sociodemographic, lifestyle and cardiometabolic characteristics were associated with moderate (5-9 medications) and severe polypharmacy (≥10 medications) compared with no polypharmacy (0-4 medications). RESULTS: Mean age was 63 ± 10 years, and 40% were women. The median number of daily medications was 5 (IQR 3-7) in primary care and 7 (IQR 5-10) in academic care. The prevalence of moderate and severe polypharmacy was 44% and 10% in primary care, and 53% and 29% in academic care respectively. Glucose-lowering and lipid-modifying medications were most prevalent. People with severe polypharmacy used a relatively large amount of other (i.e. non-cardiovascular and non-glucose-lowering) medication. Moderate and severe polypharmacy across all lines of care were associated with higher age, low educational level, more smoking, longer diabetes duration, higher BMI and more cardiovascular disease. CONCLUSIONS: Severe and moderate polypharmacy are prevalent in over half of people with type 2 diabetes in primary care, and even more in academic care. People with polypharmacy are characterized by poorer cardiometabolic status. These results highlight the significance of polypharmacy in type 2 diabetes.

Clinical profiles of post-load glucose subgroups and their association with glycaemic traits over time: An IMI-DIRECT study.

AIM: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. METHODS: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. RESULTS: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (ß = 0.36, 95% CI 0.13-0.58), Subgroup 3 (ß = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (ß = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. CONCLUSIONS: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.

The effect of on-shelf sugar labeling on beverage sales in the supermarket: a comparative interrupted time series analysis of a natural experiment.

BACKGROUND: Nutrition labels show potential in increasing healthy food and beverage purchases, but their effectiveness seems to depend on the type of label, the targeted food category and the setting, and evidence on their impact in real-world settings is limited. The aim of this study was to evaluate the effectiveness of an industry-designed on-shelf sugar label on the sales of beverages with no, low, medium and high sugar content implemented within a real-world supermarket. METHODS: In week 17 of 2019, on-shelf sugar labels were implemented by a Dutch supermarket chain. Non-alcoholic beverages were classified using a traffic-light labeling system and included the beverage categories "green" for sugar free (< 1.25 g/250 ml), "blue" for low sugar (1.25-6.24 g/250 ml), "yellow" for medium sugar (6.25-13.5 g/250 ml) and "amber" for high sugar (> 13.5 g/250 ml). Store-level data on beverage sales and revenue from 41 randomly selected supermarkets for 13 weeks pre-implementation and 21 weeks post-implementation were used for analysis. In total, 30 stores implemented the on-shelf sugar labels by week 17, and the 11 stores that had not were used as comparisons. Outcome measures were differences in the number of beverages sold in the four label categories and the total revenue from beverage sales in implementation stores relative to comparison stores. Analyses were conducted using a multiple-group Interrupted Time Series Approach. Results of individual store data were combined using random effect meta-analyses. RESULTS: At the end of the intervention period, the changes in sales of beverages with green (B 3.4, 95%CI -0.3; 7.0), blue (B 0.0, 95%CI -0.6; 0.7), yellow (B 1.3, 95%CI -0.9; 3.5), and amber (B 0.9, 95%CI -5.5; 7.3) labels were not significantly different between intervention and comparison stores. The changes in total revenues for beverages at the end of the intervention period were also not significantly different between intervention and comparison stores. CONCLUSION: The implementation of an on-shelf sugar labeling system did not significantly decrease unhealthy beverage sales or significantly increase healthier beverage sales. Nutrition labeling initiatives combined with complementary strategies, such as pricing strategies or other healthy food nudging approaches, should be considered to promote healthier beverage purchases.

Local fast-food environment, diet and blood pressure: the moderating role of mastery.

PURPOSE: To examine the moderating role of mastery in the association of local fast-food restaurants (FFR) with diet quality and systolic blood pressure (SBP). METHODS: We used cross-sectional data from 1543 adults participating in wave six of the Netherlands Study of Depression and Anxiety (NESDA). Data were collected between 2013 and 2016. Diet quality was defined by adherence with the dietary approaches to stop hypertension (DASH) diet. Individuals reported on their food consumption through a food frequency questionnaire and SBP was measured. Density of FFR in 1600 m, 800 m and 400 m circular buffers around the home postal code was calculated using Geographic Information Systems. We assessed the association between density of FFR, diet and SBP using linear regression analyses, testing for moderation by mastery. RESULTS: Mean age was 52 years and 32.2% of the sample were men. Exposure to FFR ranged from 0 to 35 FFR per km2. Density of FFR was not significantly associated with DASH adherence or SBP. Only one out of the six interaction terms was significant, suggesting that for individuals with lower levels of mastery, higher density of FFR in an 800-m buffer was negatively associated with DASH adherence, while for individuals with higher levels of mastery, this association was positive. CONCLUSIONS: Exposure to FFR was not associated with diet quality and SBP, and we observed little evidence for moderation by level of mastery. This research question should be further explored in a large sample of healthy adults.

Built environmental characteristics and diabetes: a systematic review and meta-analysis.

BACKGROUND: The built environment influences behaviour, like physical activity, diet and sleep, which affects the risk of type 2 diabetes mellitus (T2DM). This study systematically reviewed and meta-analysed evidence on the association between built environmental characteristics related to lifestyle behaviour and T2DM risk/prevalence, worldwide. METHODS: We systematically searched PubMed, EMBASE.com and Web of Science from their inception to 6 June 2017. Studies were included with adult populations (>18 years), T2DM or glycaemic markers as outcomes, and physical activity and/or food environment and/or residential noise as independent variables. We excluded studies of specific subsamples of the population, that focused on built environmental characteristics that directly affect the cardiovascular system, that performed prediction analyses and that do not report original research. Data appraisal and extraction were based on published reports (PROSPERO-ID: CRD42016035663). RESULTS: From 11,279 studies, 109 were eligible and 40 were meta-analysed. Living in an urban residence was associated with higher T2DM risk/prevalence (n = 19, odds ratio (OR) = 1.40; 95% CI, 1.2-1.6; I2 = 83%) compared to living in a rural residence. Higher neighbourhood walkability was associated with lower T2DM risk/prevalence (n = 8, OR = 0.79; 95% CI, 0.7-0.9; I2 = 92%) and more green space tended to be associated with lower T2DM risk/prevalence (n = 6, OR = 0.90; 95% CI, 0.8-1.0; I2 = 95%). No convincing evidence was found of an association between food environment with T2DM risk/prevalence. CONCLUSIONS: An important strength of the study was the comprehensive overview of the literature, but our study was limited by the conclusion of mainly cross-sectional studies. In addition to other positive consequences of walkability and access to green space, these environmental characteristics may also contribute to T2DM prevention. These results may be relevant for infrastructure planning.

Characteristics of high- and low-risk individuals in the PRIORITY study: urinary proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in Type 2 diabetes.

AIM: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. RESULTS: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01). CONCLUSIONS: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).

Exploring the relationship between perceived barriers to healthy eating and dietary behaviours in European adults.

PURPOSE: Dietary behaviours may be influenced by perceptions of barriers to healthy eating. Using data from a large cross-European study (N = 5900), we explored associations between various perceived barriers to healthy eating and dietary behaviours among adults from urban regions in five European countries and examined whether associations differed across regions and socio-demographic backgrounds. METHODS: Frequency of consumption of fruit, vegetables, fish, fast food, sugar-sweetened beverages, sweets, breakfast and home-cooked meals were split by the median into higher and lower consumption. We tested associations between barriers (irregular working hours; giving up preferred foods; busy lifestyle; lack of willpower; price of healthy food; taste preferences of family and friends; lack of healthy options and unappealing foods) and dietary variables using multilevel logistic regression models. We explored whether associations differed by age, sex, education, urban region, weight status, household composition or employment. RESULTS: Respondents who perceived any barrier were less likely to report higher consumption of healthier foods and more likely to report higher consumption of fast food. 'Lack of willpower', 'time constraints' and 'taste preferences' were most consistently associated with consumption. For example, those perceiving lack of willpower ate less fruit [odds ratio (OR) 0.57; 95% confidence interval (CI) 0.50-0.64], and those with a busy lifestyle ate less vegetables (OR 0.54; 95% CI 0.47-0.62). Many associations differed in size, but not in direction, by region, sex, age and household composition. CONCLUSION: Perceived 'lack of willpower', 'time constraints' and 'taste preferences' were barriers most strongly related to dietary behaviours, but the association between various barriers and lower intake of fruit and vegetables was somewhat more pronounced among younger participants and women.

Individual and partner's level of occupation and the association with HbA1c levels in people with Type 2 diabetes mellitus: the Dutch Diabetes Pearl cohort.

AIMS: Individual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA1c levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA1c levels in people with Type 2 diabetes in the Netherlands. METHODS: We included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication. RESULTS: In total, 3257 participants (59.8% men, mean 62.2±9.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA1c levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or -0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA1c levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level. CONCLUSIONS: Partner's occupational status provided additional information on the association between socio-economic status and HbA1c levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.

Dietary intake of carotenoids and risk of type 2 diabetes.

BACKGROUND AND AIMS: Carotenoids may reduce diabetes risk, due to their antioxidant properties. However, the association between dietary carotenoids intake and type 2 diabetes risk is still unclear. Therefore, the objective of this study was to examine whether higher dietary carotenoid intakes associate with reduced type 2 diabetes risk. METHODS AND RESULTS: Data from 37,846 participants of the European Prospective Investigation into Cancer and Nutrition- Netherlands study were analyzed. Dietary intakes of ß-carotene, α-carotene, ß-cryptoxanthin, lycopene, lutein & zeaxanthin and the sum of these carotenoids were assessed using a validated food frequency questionnaire. Incident type 2 diabetes was mainly self-reported, and verified against general practitioner information. Mean ±SD total carotenoid intake was 10 ± 4 mg/day. During a mean ±SD follow-up of 10 ± 2 years, 915 incident cases of type 2 diabetes were ascertained. After adjustment for age, sex, diabetes risk factors, dietary intake, waist circumference and BMI, higher ß-carotene intakes associated inversely with diabetes risk [Hazard Ratio quartile 4 versus quartile 1 (HR(Q4)): 0.78 (95%CI:0.64,0.95), P-linear trend 0.01]. For α-carotene, a borderline significant reduced risk was observed, with a HR(Q4) of 0.85 (95%CI:0.70,1.03), and P-linear trend 0.05. ß-cryptoxanthin, lycopene, lutein & zeaxanthin, and the sum of all carotenoids did not associate with diabetes risk. CONCLUSIONS: This study shows that diets high in ß-carotene and α-carotene are associated with reduced type 2 diabetes in generally healthy men and women.

Effectiveness and cost-effectiveness of 3-monthly versus 6-monthly monitoring of well-controlled type 2 diabetes patients: a pragmatic randomised controlled patient-preference equivalence trial in primary care (EFFIMODI study).

AIM: To investigate effectiveness and cost-effectiveness of 6-monthly monitoring compared with 3-monthly monitoring of well-controlled type 2 diabetes patients in primary care. METHODS: A pragmatic randomised controlled patient-preference equivalence trial was performed. From April 2009 to August 2010, 2215 patients from 233 general practitioners across the Netherlands were included. Patients were eligible if between 40- and 80-years-old, diagnosed with type 2 diabetes for more than a year, treated by their general practitioner, not on insulin treatment and well-controlled during the last year (HbA1c ≤ 58 mmol/mol, systolic blood pressure ≤ 145 mmHg and total cholesterol ≤ 5.2 mmol/l). Patients without a strong preference for their monitoring frequency were randomised to 3-monthly or 6-monthly monitoring. Follow-up was 18 months. The primary outcome is the percentage of patients remaining under: HbA1c ≤ 58 mmol/mol, systolic blood pressure ≤ 145 mmHg and total cholesterol ≤ 5.2 mmol/l. Equivalence was assumed if the two-sided 95% confidence interval (CI) was between -5 and 5%. Cost-effectiveness was determined using a cost-minimisation analysis. RESULTS: In the 3-monthly group 69.5% remained under good cardiometabolic control, versus 69.8% in the 6-monthly group (difference: 0.3%; 95%CI: -6.2-6.7%). All secondary outcomes were equivalent for 3-monthly and 6-monthly monitoring, except the systolic blood pressure target, physical activity and antihypertensive drug use. Six-monthly monitoring was €387 (£333) cheaper per patient compared to 3-monthly monitoring during the study period. CONCLUSIONS: Patients with good cardiometabolic control and without preference for their monitoring frequency can visit the primary care physician less often. The cost-savings can be considerable.

Intensification of medication and glycaemic control among patients with type 2 diabetes - the ADVANCE trial.

AIMS: The aim of this study was to assess associations between patient characteristics, intensification of blood glucose-lowering treatment through oral glucose-lowering therapy and/or insulin and effective glycaemic control in type 2 diabetes. METHODS: 11 140 patients from the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) trial who were randomized to intensive glucose control or standard glucose control and followed up for a median of 5 years were categorized into two groups: effective glycaemic control [haemoglobin A1c (HbA1c) ≤ 7.0% or a proportionate reduction in HbA1c over 10%] or ineffective glycaemic control (HbA1c > 7.0% and a proportionate reduction in HbA1c less than or equal to 10%). Therapeutic intensification was defined as addition of an oral glucose-lowering agent or commencement of insulin. Pooled logistic regression models examined the associations between patient factors, intensification and effective glycaemic control. RESULTS: A total of 7768 patients (69.7%), including 3198 in the standard treatment group achieved effective glycaemic control. Compared to patients with ineffective control, patients with effective glycaemic control had shorter duration of diabetes and lower HbA1c at baseline and at the time of treatment intensification. Treatment intensification with addition of an oral agent or commencement of insulin was associated with a 107% [odds ratio, OR: 2.07 (95% confidence interval, CI: 1.95-2.20)] and 152% [OR: 2.52 (95% CI: 2.30-2.77)] greater chance of achieving effective glycaemic control, respectively. These associations were robust after adjustment for several baseline characteristics and not modified by the number of oral medications taken at the time of treatment intensification. CONCLUSIONS: Effective glycaemic control was associated with treatment intensification at lower HbA1c levels at all stages of the disease course and in both arms of the ADVANCE trial.

Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease.

INTRODUCTION: Micro- and macrovascular complications are common among persons with type 2 diabetes. Recently there has been growing interest to investigate the potential of circulating small non-coding RNAs (sncRNAs) as contributors to the development of diabetic complications. In this study we investigate to what extent circulating sncRNAs levels associate with prevalent diabetic kidney disease (DKD) in persons with type 2 diabetes. METHODS: Plasma sncRNAs levels were determined using small RNA-seq, allowing detection of miRNAs, snoRNAs, piRNAs, tRNA fragments, and various other sncRNA classes. We tested for differentially expressed sncRNAs in persons with type 2 diabetes, with DKD (n = 69) or without DKD (n = 405). In secondary analyses, we also tested the association with eGFR, albuminuria (UACR), and the plasma proteome. RESULTS: In total seven sncRNAs were negatively associated with prevalent DKD (all PFDR ≤ 0.05). Including one microRNA (miR-143-5p), five snoRNAs (U8, SNORD118, SNORD24, SNORD107, SNORD87) and a piRNA (piR-019825 | DQ597218). Proteomic analyses showed that the seven sncRNAs, and especially the piRNA piR-019825, were associated with plasma levels of 24 proteins of which several have known associations with kidney function including TNF sR-I (TNFRFS1A), DAN (NBL1) and cystatin C (CST3). CONCLUSION: We have identified novel small non-coding RNAs, primarily from classes other than microRNAs, that are associated with diabetic kidney disease. Our results show that the involvement of small non-coding RNAs in DKD goes beyond the already known microRNAs and also involves other classes of sncRNA, in particular snoRNAs and the piRNA piR-019825, that have never been studied before in relation to kidney function.

Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct.

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.

The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the EPIC-InterAct study.

AIMS/HYPOTHESIS: Although a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association. METHODS: A total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created. RESULTS: A family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50 years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history. CONCLUSIONS/INTERPRETATION: Prominent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.

Dietary patterns derived from principal component- and k-means cluster analysis: long-term association with coronary heart disease and stroke.

BACKGROUND AND AIMS: Studies comparing dietary patterns derived from different a posteriori methods in view of predicting disease risk are scarce. We aimed to explore differences between dietary patterns derived from principal component- (PCA) and k-means cluster analysis (KCA) in relation to their food group composition and ability to predict CHD and stroke risk. METHODS AND RESULTS: The study was conducted in the EPIC-NL cohort that consists of 40,011 men and women. Baseline dietary intake was measured using a validated food-frequency questionnaire. Food items were consolidated into 31 food groups. Occurrence of CHD and stroke was assessed through linkage with registries. After 13 years of follow-up, 1,843 CHD and 588 stroke cases were documented. Both PCA and KCA extracted a prudent pattern (high intakes of fish, high-fiber products, raw vegetables, wine) and a western pattern (high consumption of French fries, fast food, low-fiber products, other alcoholic drinks, soft drinks with sugar) with small variation between components and clusters. The prudent component was associated with a reduced risk of CHD (HR for extreme quartiles: 0.87; 95%-CI: 0.75-1.00) and stroke (0.68; 0.53-0.88). The western component was not related to any outcome. The prudent cluster was related with a lower risk of CHD (0.91; 0.82-1.00) and stroke (0.79; 0.67-0.94) compared to the western cluster. CONCLUSION: PCA and KCA found similar underlying patterns with comparable associations with CHD and stroke risk. A prudent pattern reduced the risk of CHD and stroke.

The effect of six-month oral vitamin K supplementation on calcification propensity time in individuals with type 2 diabetes mellitus: A post hoc analysis of a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: Experimental studies suggested that vitamin K supplementation may retard arterial calcification. Recently, serum calcification propensity time (T50) has been suggested as a functional biomarker for arterial wall calcification propensity. In this post-hoc analysis of a clinical trial, we evaluated the effect of six-month oral vitamin K supplementation on T50 and assessed the correlation between T50 and imaging arterial calcification parameters in people with type 2 diabetes (T2DM). METHODS: This double-blind, randomized, placebo-controlled trial included 68 participants (age = 69 ± 8 years, 76% male) with T2DM. Participants were assigned to menaquinone-7 (360 µg/day; n = 35) or placebo (n = 33). T50 was measured via nephelometry in serum collected at baseline, three and six months. Arterial calcification was measured at baseline and six months via 18F-Na PET-CT and conventional CT using Target-to-Background ratio (TBR) and Agatston score. Longitudinal analysis of covariance adjusted for baseline T50 was used to study the treatment effect. Spearman's correlation was used to assess the correlation between T50 and imaging calcification parameters. RESULTS: Median baseline T50 was similar in the vitamin K (350 [321-394] minutes) and placebo groups (363 [320-398]). There was no significant difference in T50 between treatment arms over time (ẞ = 1.00, 95%C.I. = 0.94-1.07, p = 0.982). The correlation coefficient of T50 with TBR and Agatston score at baseline were -0.185 (p = 0.156) and -0.121 (p = 0.358), respectively. CONCLUSIONS: No effect of vitamin K supplementation on T50 was observed in T2DM. Moreover, T50 did not correlate with TBR and Agatston score. Further research on vitamin K in arterial calcification and on the validity of T50 as arterial calcification marker is warranted.