Femke Rutters

Role of Vitamin D in the Development of Insulin Resistance and Type 2 Diabetes

Vitamin D deficiency is mainly a consequence of insufficient sunlight induced vitamin D production in the skin and has been associated with various chronic diseases including type 2 diabetes. Experimental data have shown that vitamin D is important for glucose induced insulin secretion, improves insulin resistance, and exerts anti-inflammatory actions. Epidemiological studies have largely documented that a poor vitamin D status is associated with higher risk of insulin resistance and type 2 diabetes. The majority of randomized controlled trials (RCTs) in healthy or prediabetic individuals have, however, failed to demonstrate relevant vitamin D effects on insulin resistance or diabetes incidence. In patients with type 2 diabetes, a few RCTs reported some moderate effects of vitamin D on glycemic control and insulin resistance. While these findings warrant further in-depth studies, the current evidence is insufficient to recommend vitamin D supplementation for the prevention or treatment of type 2 diabetes.

Is social jetlag associated with an adverse endocrine, behavioral, and cardiovascular risk profile?

Social jetlag represents the discrepancy between circadian and social clocks, which is measured as the difference in hours in midpoint of sleep between work days and free days. Previous studies have shown social jetlag to be associated with body mass index (BMI), glycated hemoglobin levels, heart rate, depressive symptoms, smoking, mental distress and alcohol use. The objective of our current study was to investigate, in a group of 145 apparently healthy participants (67 men and 78 women, aged 18-55 years, BMI 18-35 kg/m2), the prevalence of social jetlag and its association with adverse endocrine, behavioral and cardiovascular risk profiles as measured in vivo. participants with ≥2 h social jetlag had higher 5-h cortisol levels, slept less during the week, were more often physically inactive and had an increased resting heart rate, compared with participants who had ≤1 h social jetlag. We therefore concluded that social jetlag is associated with an adverse endocrine, behavioral and cardiovascular risk profile in apparently healthy participants. These adverse profiles put healthy participants at risk for development of metabolic diseases and mental disorders, including diabetes and depression, in the near future.

Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium

Background Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. Methods In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. Findings We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00–1.29), 1.33 (1.16–1.51), and 1.67 (1.44–1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. Interpretation In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.

Disease Prevention: Vitamin D Trials

Although there is a debate on cut-offs for appropriate vitamin D supplementation (“Uncertain verdict as vitamin D goes on trial,” K. Kupferschmidt, News, special section on Disease Prevention, 21 September, p. [1476][1]), clinicians universally agree that vitamin D deficiency is detrimental for

Homoarginine and mortality in an older population: the Hoorn study

Homoarginine is an amino acid that may be involved in nitric oxide and energy metabolism. Previous studies in patient populations showed that low homoarginine levels indicate an increased risk of mortality and cardiovascular disease. We evaluated whether low plasma levels of homoarginine are associated with elevated, overall and cause‐specific mortality.

Top down modulation of attention to food cues via working memory

Attentional biases towards food cues may be linked to the development of obesity. The present study investigated the mechanisms underlying attentional biases to food cues by assessing the role of top down influences, such as working memory (WM). We assessed whether attention in normal-weight, sated participants was drawn to food items specifically when that food item was held in WM. Twenty-three participants (15 f/8 m, age 23.4±5 year, BMI 23.5±4 kg/m(2)) took part in a laboratory based study assessing reaction times to food and non-food stimuli. Participants were presented with an initial cue stimulus to either hold in WM or to merely attend to, and then searched for the target (a circle) in a two-item display. On valid trials the target was flanked by a picture matching the cue, on neutral trials the display did not contain a picture matching the cue, and on invalid trials the distractor (a square) was flanked by a picture matching the cue. Cues were food, cars or stationery items. We observed that, relative to the effects with non-food stimuli, food items in WM strongly affected attention when the memorised cue re-appeared in the search display. In particular there was an enhanced response on valid trials, when the re-appearance of the memorised cue coincided with the search target. There were no effects of cue category on attentional guidance when the cues were merely attended to but not held in WM. These data point towards food having a strong effect on top-down guidance of search from working memory, and suggest a mechanism whereby individuals who are preoccupied with thoughts of food, for example obese individuals, show facilitated detection of food cues in the environment.

Insulin Sensitivity and Albuminuria: The RISC Study

OBJECTIVE Accumulating evidence suggests an association between insulin sensitivity and albuminuria, which, even in the normal range, is a risk factor for cardiovascular diseases. We evaluated whether insulin sensitivity is associated with albuminuria in healthy subjects. RESEARCH DESIGN AND METHODS We investigated 1,415 healthy, nondiabetic participants (mean age 43.9 ± 8.3 years; 54.3% women) from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study, of whom 852 participated in a follow-up examination after 3 years. At baseline, insulin sensitivity was assessed by hyperinsulinemic–euglycemic clamps, expressed as the M/I value. Oral glucose tolerance test–based insulin sensitivity (OGIS), homeostasis model assessment of insulin resistance (HOMA-IR), and urinary albumin-to-creatinine ratio (UACR) were determined at baseline and follow-up. RESULTS Microalbuminuria (UACR ≥30 mg/g) was present in fewer than 2% at either study visit. After multivariate adjustments, there was no cross-sectional association between UACR and any measure of insulin sensitivity. Neither OGIS nor HOMA-IR was significantly associated with follow-up UACR, but in a multivariate regression analysis, baseline M/I emerged as an independent predictor of UACR at follow-up (β-coefficient −0.14; P = 0.001). CONCLUSIONS In healthy middle-aged adults, reduced insulin sensitivity, assessed by hyperinsulinemic–euglycemic clamp, is continuously associated with a greater risk of increasing albuminuria. This finding suggests that reduced insulin sensitivity either is simply related to or might causally contribute to the initial pathogenesis of albuminuria.

Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: rationale and design of the epidemiological studies within the IMI DIRECT Consortium.

Aims/hypothesisThe DIRECT (Diabetes Research on Patient Stratification) Study is part of a European Union Framework 7 Innovative Medicines Initiative project, a joint undertaking between four industry and 21 academic partners throughout Europe. The Consortium aims to discover and validate biomarkers that: (1) predict the rate of glycaemic deterioration before and after type 2 diabetes onset; (2) predict the response to diabetes therapies; and (3) help stratify type 2 diabetes into clearly definable disease subclasses that can be treated more effectively than without stratification. This paper describes two new prospective cohort studies conducted as part of DIRECT.MethodsPrediabetic participants (target sample size 2,200–2,700) and patients with newly diagnosed type 2 diabetes (target sample size ~1,000) are undergoing detailed metabolic phenotyping at baseline and 18xa0months and 36xa0months later. Abdominal, pancreatic and liver fat is assessed using MRI. Insulin secretion and action are assessed using frequently sampled OGTTs in non-diabetic participants, and frequently sampled mixed-meal tolerance tests in patients with type 2 diabetes. Biosamples include venous blood, faeces, urine and nail clippings, which, among other biochemical analyses, will be characterised at genetic, transcriptomic, metabolomic, proteomic and metagenomic levels. Lifestyle is assessed using high-resolution triaxial accelerometry, 24xa0h diet record, and food habit questionnaires.Conclusions/interpretationDIRECT will yield an unprecedented array of biomaterials and data. This resource, available through managed access to scientists within and outside the Consortium, will facilitate the development of new treatments and therapeutic strategies for the prevention and management of type 2 diabetes.

Relationship between short sleep duration and cardiovascular risk factors in a multi-ethnic cohort - the helius study.

BACKGROUND AND AIMnThe aim of this study was to investigate the association between short sleep duration and cardiovascular disease (CVD) risk factors including hypertension, diabetes, obesity and lipid profile among various ethnic groups (South Asian Surinamese, African Surinamese, Ghanaians, Turks, Moroccans and the Dutch) living in the Netherlands. The contribution of social economic status (SES) and lifestyle factors were also examined to this association.nnnMETHODnA total of 12,805 participants (aged 18-70 years) from the multi-ethnic Healthy Life in an Urban Setting (HELIUS) cohort. Short sleep duration was defined as <7u2009h/night. The association between short sleep and CVD risk factors, along with the contribution of SES and lifestyle factors, was assessed using prevalence ratios (PRs).nnnRESULTSnShort sleep was significantly associated with obesity in four out of six ethnic groups, with the socio-demographic-adjusted PR of 1.45 (95% CI, 1.07-1.95) in the Dutch, 1.21 (1.01-1.44) in South Asian Surinamese, 1.25 (1.09-1.43) in African Surinamese and 1.16 (1.04-1.29) in Turks. Short sleep was significantly associated with diabetes in African Surinamese (1.45, 1.14-1.84), Turks (1.59, 1.26-2.02) and Moroccans (1.29, 1.02-1.63). By contrast, the associations between other cardiovascular risk factors and short sleep were not significant in most ethnic groups, with the exception of the association with hypertension in the Dutch and Turks, and dyslipidaemia in South Asian Surinamese (reduced high-density lipoprotein cholesterol and triglyceride) and Moroccans (raised total cholesterol). SES and lifestyle factors contributed little to the observed associations.nnnCONCLUSIONnThe findings indicate that short sleep is associated with obesity and diabetes in most ethnic groups. The associations for other risk factors vary between ethnic groups. Further studies are warranted to establish the potential factors that might lead to the observed differences across populations.

The Association between Social Jetlag, the Metabolic Syndrome, and Type 2 Diabetes Mellitus in the General Population: The New Hoorn Study:

Only a few studies have investigated the metabolic consequences of social jetlag. Therefore, we examined the association of social jetlag with the metabolic syndrome and type 2 diabetes mellitus in a population-based cohort. We used cross-sectional data from the New Hoorn Study cohort (n = 1585, 47% men, age 60.8 ± 6 years). Social jetlag was calculated as the difference in midpoint sleep (in hours) between weekdays and weekend days. Poisson and linear regression models were used to study the associations, and age was regarded as a possible effect modifier. We adjusted for sex, employment status, education, smoking, physical activity, sleep duration, and body mass index. In the total population, we only observed an association between social jetlag and the metabolic syndrome, with prevalence ratios adjusted for sex, employment status, and educational levels of 1.64 (95% CI 1.1-2.4), for participants with >2 h social jetlag, compared with participants with <1 h social jetlag. However, we observed an interaction effect of median age (<61 years). In older participants (≥61 years), no significant associations were observed between social jetlag status, the metabolic syndrome, and diabetes or prediabetes. In the younger group (<61 years), the adjusted prevalence ratios were 1.29 (95% CI 0.9-1.9) and 2.13 (95% CI 1.3-3.4) for the metabolic syndrome and 1.39 (95% CI 1.1-1.9) and 1.75 (95% CI 1.2-2.5) for diabetes/prediabetes, for participants with 1-2 h and >2 h social jetlag, compared with participants with <1 h social jetlag. In conclusion, in our population-based cohort, social jetlag was associated with a 2-fold increased risk of the metabolic syndrome and diabetes/prediabetes, especially in younger (<61 years) participants.