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The Maastricht Study is an extensive phenotyping study that focuses on the etiology of type 2 diabetes (T2DM), its classic complications, and its emerging comorbidities. The study uses state-of-the-art imaging techniques and extensive biobanking to determine health status in a population-based cohort of 10,000 individuals that is enriched with T2DM individuals. Enrollment started in November 2010 and is anticipated to last 5-7 years. The Maastricht Study is expected to become one of the most extensive phenotyping studies in both the general population and T2DM participants worldwide. The Maastricht study will specifically focus on possible mechanisms that may explain why T2DM accelerates the development and progression of classic complications, such as cardiovascular disease, retinopathy, neuropathy and nephropathy and of emerging comorbidities, such as cognitive decline, depression, and gastrointestinal, musculoskeletal and respiratory diseases. In addition, it will also examine the association of these variables with quality of life and use of health care resources. This paper describes the rationale, overall study design, recruitment strategy and methods of basic measurements, and gives an overview of all measurements that are performed within The Maastricht Study.

Background The gut microbiota evolves from birth and is in early life influenced by events such as birth mode, type of infant feeding, and maternal and infant antibiotics use. However, we still have a gap in our understanding of gut microbiota development in older children, and to what extent early events and pre-school lifestyle modulate the composition of the gut microbiota, and how this impinges on whole body metabolic regulation in school-age children. Results Taking advantage of the KOALA Birth Cohort Study, a long-term prospective birth cohort in the Netherlands with extensive collection of high-quality host metadata, we applied shotgun metagenomics sequencing and systematically investigated the gut microbiota of children at 6–9 years of age. We demonstrated an overall adult-like gut microbiota in the 281 Dutch school-age children and identified 3 enterotypes dominated by the genera Bacteroides , Prevotella , and Bifidobacterium , respectively. Importantly, we found that breastfeeding duration in early life and pre-school dietary lifestyle correlated with the composition and functional competences of the gut microbiota in the children at school age. The correlations between pre-school dietary lifestyle and metabolic phenotypes exhibited a striking enterotype dependency. Thus, an inverse correlation between high dietary fiber consumption and low plasma insulin levels was only observed in individuals with the Bacteroides and Prevotella enterotypes, but not in Bifidobacterium enterotype individuals in whom the gut microbiota displayed overall lower microbial gene richness, alpha-diversity, functional potential for complex carbohydrate fermentation, and butyrate and succinate production. High total fat consumption and elevated plasma free fatty acid levels in the Bifidobacterium enterotype are associated with the co-occurrence of Streptococcus . Conclusions Our work highlights the persistent effects of breastfeeding duration and pre-school dietary lifestyle in affecting the gut microbiota in school-age children and reveals distinct compositional and functional potential in children according to enterotypes. The findings underscore enterotype-specific links between the host metabolic phenotypes and dietary patterns, emphasizing the importance of microbiome-based stratification when investigating metabolic responses to diets. Future diet intervention studies are clearly warranted to examine gut microbe-diet-host relationships to promote knowledge-based recommendations in relation to improving metabolic health in children.

Aims/hypothesis In diabetes, advanced glycation end-products (AGEs) and the AGE precursor methylglyoxal (MGO) are associated with endothelial dysfunction and the development of microvascular complications. In this study we used a rat model of diabetes, in which rats transgenically overexpressed the MGO-detoxifying enzyme glyoxalase-I (GLO-I), to determine the impact of intracellular glycation on vascular function and the development of early renal changes in diabetes. Methods Wild-type and Glo1 -overexpressing rats were rendered diabetic for a period of 24 weeks by intravenous injection of streptozotocin. Mesenteric arteries were isolated to study ex vivo vascular reactivity with a wire myograph and kidneys were processed for histological examination. Glycation was determined by mass spectrometry and immunohistochemistry. Markers for inflammation, endothelium dysfunction and renal dysfunction were measured with ELISA-based techniques. Results Diabetes-induced formation of AGEs in mesenteric arteries and endothelial dysfunction were reduced by Glo1 overexpression. Despite the absence of advanced nephrotic lesions, early markers of renal dysfunction (i.e. increased glomerular volume, decreased podocyte number and diabetes-induced elevation of urinary markers albumin, osteopontin, kidney-inflammation-molecule-1 and nephrin) were attenuated by Glo1 overexpression. In line with this, downregulation of Glo1 in cultured endothelial cells resulted in increased expression of inflammation and endothelium dysfunction markers. In fully differentiated cultured podocytes incubation with MGO resulted in apoptosis. Conclusions/interpretation This study shows that effective regulation of the GLO-I enzyme is important in the prevention of vascular intracellular glycation, endothelial dysfunction and early renal impairment in experimental diabetes. Modulating the GLO-I pathway therefore may provide a novel approach to prevent vascular complications in diabetes.

Background Type 2 diabetes mellitus (T2DM) is a common chronic disease that disproportionally affects disadvantaged groups. People with a low socioeconomic position (SEP) have increased risk of T2DM and people with a low SEP and T2DM have higher HbA 1c -levels compared to people with T2DM and high SEP. The aim of this study is to analyze longitudinal socioeconomic differences in health-related functioning in people with T2DM. Methods Longitudinal data from 1,537 participants of The Maastricht Study with T2DM were used (32.6% female, mean (SD) age 62.9 (7.7) years). SEP was determined by baseline measures of education, occupation and income. Health-related functioning (physical, mental and social) was measured with the Short-Form Health Survey and the Impact on Participation and Autonomy survey (all scored from 0 to 100). Associations of SEP and health-related functioning were studied annually over a 10-year period (median (IQR) 7.0 (5.0) years, baseline 2010–2018) using linear mixed methods adjusting for demographics, HbA 1c -levels and lifestyle factors. Results Participants with a low SEP had significantly worse health-related functioning compared to those with a high SEP. For example, participants with low income had lower scores for physical (-4.49[CI -5.77;-3.21]), mental (-2.61[-3.78,-1.44]) and social functioning (-9.76[-12.30;-7.23]) compared to participants with high income on a scale from 0 to 100. In addition, participants with a low education significantly declined more over time in mental (score for interaction education with time − 0.23[-0.37;-0.09]) and social functioning (-0.44[-0.77;-0.11]) compared to participants with high education. Participants with low and intermediate incomes significantly declined more over time in physical functioning (-0.17 [-0.34, -0.01 and − 0.18 [-0.36, 0.00]) compared to participants with high income. Conclusions Among people with T2DM, those with a lower SEP had worse health-related functioning in general than people with a higher SEP. Additionally, people with T2DM and low education developed poorer mental and social functioning over time compared to people with T2DM and high education. People with T2DM and low or intermediate income declined more in physical functioning over time than those with high incomes. In addition to HbA 1c -levels and lifestyle patterns, more attention is needed for socioeconomic differences in health-related functioning for people living with T2DM.

Patients with chronic kidney disease (CKD) have an increased risk for cardiovascular morbidity and mortality. Capillary rarefaction may be both one of the causes as well as a consequence of CKD and cardiovascular disease. We reviewed the published literature on human biopsy studies and conclude that renal capillary rarefaction occurs independently of the cause of renal function decline. Moreover, glomerular hypertrophy may be an early sign of generalized endothelial dysfunction, while peritubular capillary loss occurs in advanced renal disease. Recent studies with non-invasive measurements show that capillary rarefaction is detected systemically (e.g., in the skin) in individuals with albuminuria, as sign of early CKD and/or generalized endothelial dysfunction. Decreased capillary density is found in omental fat, muscle and heart biopsies of patients with advanced CKD as well as in skin, fat, muscle, brain and heart biopsies of individuals with cardiovascular risk factors. No biopsy studies have yet been performed on capillary rarefaction in individuals with early CKD. At present it is unknown whether individuals with CKD and cardiovascular disease merely share the same risk factors for capillary rarefaction, or whether there is a causal relationship between rarefaction in renal and systemic capillaries. Further studies on renal and systemic capillary rarefaction, including their temporal relationship and underlying mechanisms are needed. This review stresses the importance of preserving and maintaining capillary integrity and homeostasis in the prevention and management of renal and cardiovascular disease.

Background Numerous studies have investigated the potential association of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) with an increased risk of lower limb amputations (LLAs), but have produced conflicting results. Particularly studies comparing SGLT2-Is to glucagon-like peptide-1 receptor agonists (GLP1-RAs) seem to find a higher LLA risk with SGLT2-I use. This raises the question whether the results are driven by a protective GLP1-RA-effect rather than a harmful SGLT2-I-effect. GLP1-RAs could promote wound healing and therefore reduce the risk of LLAs, but the associations between both drug classes and LLA remain uncertain. Therefore, the aim of the current study was to investigate the risk of LLA and diabetic foot ulcer (DFU) with SGLT2-I use and GLP1-RA use versus sulfonylurea use. Methods A retrospective population-based cohort study was conducted using data from the Danish National Health Service (2013–2018). The study population (N = 74,475) consisted of type 2 diabetes patients aged 18 + who received a first ever prescription of an SGLT2-I, GLP1-RA or sulfonylurea. The date of the first prescription defined the start of follow-up. Time-varying Cox proportional hazards models estimated the hazard ratios (HRs) of LLA and DFU with current SGLT2-I use and GLP1-RA use versus current SU use. The models were adjusted for age, sex, socio-economic variables, comorbidities and concomitant drug use. Results Current SGLT2-I use was not associated with a higher risk of LLA versus sulfonylureas {adjusted HR 1.10 [95% confidence interval (CI) 0.71–1.70]}. Current GLP1-RA use, on the other hand, was associated with a lower risk of LLA [adjusted HR 0.57 (95%CI 0.39–0.84)] compared to sulfonylureas. The risk of DFU was similar to that with sulfonylureas with both exposures of interest. Conclusion SGLT2-I use was not associated with a higher risk of LLA, but GLP1-RAs with a lower risk of LLA. Previous studies reporting a higher risk of LLA with SGLT2-I use compared to GLP1-RA use might have been looking at a protective GLP1-RA effect, rather than a harmful SGLT2-I effect.

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease (CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in PNPLA3, TM6SF2 and GCKR as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in PNPLA3 and TM6SF2 were found to protect against CAD, whereas variants in GCKR were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for PNPLA3 and TM6SF2, and lipid-raising for GCKR) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.

Both obesity and the metabolic syndrome are associated with increased risk of cardiovascular diseases and type 2 diabetes. Although both frequently occur together in the same individual, obesity and the metabolic syndrome can also develop independently from each other. The (patho)physiology of \"metabolically healthy obese\" (i.e. obese without metabolic syndrome) and \"metabolically unhealthy non-obese\" phenotypes (i.e. non-obese with metabolic syndrome) is not fully understood, but physical activity and sedentary behavior may play a role. To examine objectively measured physical activity and sedentary behavior across four groups: I) \"metabolically healthy obese\" (MHO); II) \"metabolically unhealthy obese\" (MUO); III)\"metabolically healthy non-obese\" (MHNO); and IV) \"metabolically unhealthy non-obese\" (MUNO). Data were available from 2,449 men and women aged 40-75 years who participated in The Maastricht Study from 2010 to 2013. Participants were classified into the four groups according to obesity (BMI≥30kg/m2) and metabolic syndrome (ATPIII definition). Daily activity was measured for 7 days with the activPAL physical activity monitor and classified as time spent sitting, standing, and stepping. In our study population, 562 individuals were obese. 19.4% of the obese individuals and 72.7% of the non-obese individuals was metabolically healthy. After adjustments for age, sex, educational level, smoking, alcohol use, waking time, T2DM, history of CVD and mobility limitation, MHO (n = 107) spent, per day, more time stepping (118.2 versus 105.2 min; p<0.01) and less time sedentary (563.5 versus 593.0 min., p = 0.02) than MUO (n = 440). In parallel, MHNO (n = 1384) spent more time stepping (125.0 versus 115.4 min; p<0.01) and less time sedentary (553.3 versus 576.6 min., p<0.01) than MUNO (n = 518). Overall, the metabolically healthy groups were less sedentary and more physically active than the metabolically unhealthy groups. Therefore, physical activity and sedentary time may partly explain the presence of the metabolic syndrome in obese as well as non-obese individuals.

Beyond antihyperglycemic effects, metformin may improve cardiovascular outcomes. Patients with type 2 diabetes often have an elevated plasma level of N-terminal pro B-type as a marker of (sub) clinical cardiovascular disease. We studied whether metformin was associated with a reduction in the serum level of N-terminal pro B-type natriuretic peptide (NT-proBNP) in these patients. In the HOME trial 390 insulin-treated patients with type 2 diabetes were randomized to 850 mg metformin or placebo three times daily. Plasma samples were drawn at baseline, 4, 17, 30, 43 and 52 months. In a post-hoc analysis we analyzed the change in NT-proBNP in both groups. We used a longitudinal mixed model analysis adjusting for age, sex and prior cardiovascular disease. In a secondary analysis we assessed a possible immediate treatment effect post baseline. Metformin did not affect NT-proBNP levels over time in the primary analysis (-1% [95%CI -4;3, p = 0.62]). In the secondary analysis there was also no sustained time independent immediate treatment effect (initial increase of 17% [95%CI 4;30, p = 0.006] followed by yearly decrease of -4% [95%CI -7;0, p = 0.07]). Metformin as compared to placebo did not affect NT-proBNP plasma levels in this 4.3-year placebo-controlled trial. Potential cardioprotective effects of metformin cannot be explained by changes in cardiac pressures or volumes to the extent reflected by NT-proBNP.

Aims/hypothesisWe aimed to examine associations of cardiometabolic risk factors, and (pre)diabetes, with (sensorimotor) peripheral nerve function.MethodsIn 2401 adults (aged 40–75 years) we previously determined fasting glucose, HbA1c, triacylglycerol, HDL- and LDL-cholesterol, inflammation, waist circumference, blood pressure, smoking, glucose metabolism status (by OGTT) and medication use. Using nerve conduction tests, we measured compound muscle action potential, sensory nerve action potential amplitudes and nerve conduction velocities (NCVs) of the peroneal, tibial and sural nerves. In addition, we measured vibration perception threshold (VPT) of the hallux and assessed neuropathic pain using the DN4 interview. We assessed cross-sectional associations of risk factors with nerve function (using linear regression) and neuropathic pain (using logistic regression). Associations were adjusted for potential confounders and for each other risk factor. Associations from linear regression were presented as standardised regression coefficients (β) and 95% CIs in order to compare the magnitudes of observed associations between all risk factors and outcomes.ResultsHyperglycaemia (fasting glucose or HbA1c) was associated with worse sensorimotor nerve function for all six outcome measures, with associations of strongest magnitude for motor peroneal and tibial NCV, βfasting glucose = −0.17 SD (−0.21, −0.13) and βfasting glucose = −0.18 SD (−0.23, −0.14), respectively. Hyperglycaemia was also associated with higher VPT and neuropathic pain. Larger waist circumference was associated with worse sural nerve function and higher VPT. Triacylglycerol, HDL- and LDL-cholesterol, and blood pressure were not associated with worse nerve function; however, antihypertensive medication usage (suggestive of history of exposure to hypertension) was associated with worse peroneal compound muscle action potential amplitude and NCV. Smoking was associated with worse nerve function, higher VPT and higher risk for neuropathic pain. Inflammation was associated with worse nerve function and higher VPT, but only in those with type 2 diabetes. Type 2 diabetes and, to a lesser extent, prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were associated with worse nerve function, higher VPT and neuropathic pain (p for trend <0.01 for all outcomes).Conclusions/interpretationHyperglycaemia (including the non-diabetic range) was most consistently associated with early-stage nerve damage. Nonetheless, larger waist circumference, inflammation, history of hypertension and smoking may also independently contribute to worse nerve function.