Global prevalence of obesity and type 2 diabetes are rapidly increasing to pandemic proportions. A novel supplement composed of 5 plant extracts from olive leaf, bilberry, artichoke,... Show moreGlobal prevalence of obesity and type 2 diabetes are rapidly increasing to pandemic proportions. A novel supplement composed of 5 plant extracts from olive leaf, bilberry, artichoke, chrysanthellum, and black pepper was designed to prevent type 2 diabetes development in people at risk. It was previously shown to improve body weight and glucose control in preclinical rodent models, with these effects being accompanied by increased fecal energy excretion and in vitro inhibition of several digestive enzymes. Thus, we hypothesized that, in mice fed a high-fat diet (HFD), a single dose of this botanical supplementation would decrease the responses to oral fat and carbohydrate tolerance tests, and that chronic supplementation would result in increased fecal triglyceride content. We showed that acute administration in HFD-fed mice (1.452 g/kg body weight) markedly reduced circulating triglycerides following an oral lipid gavage, whereas glycemic responses to various carbohydrate tests were only mildly affected. When incorporated into the food (2.5%) of HFD-fed mice, chronic supplementation prevented body weight gain and improved glucose homeostasis and lipid tolerance. Fecal free fatty acid content, but not triglyceride, was significantly increased in supplemented animals, suggesting reduced lipid absorption in the digestive tract. Congruently, this botanical supplementation downregulated several genes associated with fatty acid transport whose expression was increased by HFD, principally in the jejunum. This study provides novel insights as for the mode of action behind the antiobesity effect of this plant-based supplementation, in HFD-fed mice. Show less
Glucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new treatment option for obesity and type 2 diabetes. Treatment has been shown to result in in weight loss and improved glycemic... Show moreGlucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new treatment option for obesity and type 2 diabetes. Treatment has been shown to result in in weight loss and improved glycemic control. In this thesis, the effects of treatment on the different adipose tissue depots and on cardiac function are described. In a randomised controlled trial, we treated patients with type 2 diabetes from South Asian descent, a population with increased risk to develop type 2 diabetes and cardiovascular disease compared to Western Europeans, with liraglutide, a GLP-1 receptor agonist, or placebo, and studied these subjects with MRI. We concluded that liraglutide and possibly other GLP-1 receptor agonists can be a good strategy to reduce the volume of visceral adipose tissue. This reduction was accompanied by a significant improvement of glycemic control. Lastly, we provided evidence that liraglutide does not improve cardiac function and myocardial tissue characteristics and thus does not improve diabetic cardiomyopathy. In addition, in another study, we studied the mechanism behind GLP-1 receptor agonism induced weight loss and concluded that liraglutide induces weight loss in humans by decreasing energy intake rather than by activating brown adipose tissue or increasing energy expenditure. Show less
Aims/hypothesis Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study... Show moreAims/hypothesis Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes.Methods One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals.Results Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAF(Afr)]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9x10(-9)); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAF(Afr)=0.0536), was associated with a reduced response to metformin (p=2.4x10(-8)), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA(1c) of 0.08% and non-carriers had an HbA(1c) increase of 0.01% after 1 year of treatment (p=3.3x10(-3)). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6x10(-5)), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology.Conclusions/interpretation We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. Show less
Aims/hypothesisThe aim of this study was to identify differentially expressed long non-coding RNAs (lncRNAs) and mRNAs in whole blood of people with type 2 diabetes across five different clusters:... Show moreAims/hypothesisThe aim of this study was to identify differentially expressed long non-coding RNAs (lncRNAs) and mRNAs in whole blood of people with type 2 diabetes across five different clusters: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), mild diabetes (MD) and mild diabetes with high HDL-cholesterol (MDH). This was to increase our understanding of different molecular mechanisms underlying the five putative clusters of type 2 diabetes.MethodsParticipants in the Hoorn Diabetes Care System (DCS) cohort were clustered based on age, BMI, HbA1c, C-peptide and HDL-cholesterol. Whole blood RNA-seq was used to identify differentially expressed lncRNAs and mRNAs in a cluster compared with all others. Differentially expressed genes were validated in the Innovative Medicines Initiative DIabetes REsearCh on patient straTification (IMI DIRECT) study. Expression quantitative trait loci (eQTLs) for differentially expressed RNAs were obtained from a publicly available dataset. To estimate the causal effects of RNAs on traits, a two-sample Mendelian randomisation analysis was performed using public genome-wide association study (GWAS) data.ResultsEleven lncRNAs and 175 mRNAs were differentially expressed in the MOD cluster, the lncRNA AL354696.2 was upregulated in the SIDD cluster and GPR15 mRNA was downregulated in the MDH cluster. mRNAs and lncRNAs that were differentially expressed in the MOD cluster were correlated among each other. Six lncRNAs and 120 mRNAs validated in the IMI DIRECT study. Using two-sample Mendelian randomisation, we found 52 mRNAs to have a causal effect on anthropometric traits (n=23) and lipid metabolism traits (n=10). GPR146 showed a causal effect on plasma HDL-cholesterol levels (p = 2×10–15), without evidence for reverse causality.Conclusions/interpretationMultiple lncRNAs and mRNAs were found to be differentially expressed among clusters and particularly in the MOD cluster. mRNAs in the MOD cluster showed a possible causal effect on anthropometric traits, lipid metabolism traits and blood cell fractions. Together, our results show that individuals in the MOD cluster show aberrant RNA expression of genes that have a suggested causal role on multiple diabetes-relevant traits. Show less
Aims/hypothesisObesity is a major risk factor for type 2 diabetes. However, body composition differs between women and men. In this study we investigate the association between diabetes status and... Show moreAims/hypothesisObesity is a major risk factor for type 2 diabetes. However, body composition differs between women and men. In this study we investigate the association between diabetes status and body composition and whether this association is moderated by sex.MethodsIn a population-based cohort study (n=7639; age 40–75 years, 50% women, 25% type 2 diabetes), we estimated the sex-specific associations, and differences therein, of prediabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes (reference: normal glucose metabolism [NGM]) with dual-energy x-ray absorptiometry (DEXA)- and MRI-derived measures of body composition and with hip circumference. Sex differences were analysed using adjusted regression models with interaction terms of sex-by-diabetes status.ResultsCompared with their NGM counterparts, both women and men with prediabetes and type 2 diabetes had more fat and lean mass and a greater hip circumference. The differences in subcutaneous adipose tissue, hip circumference and total and peripheral lean mass between type 2 diabetes and NGM were greater in women than men (women minus men [W–M] mean difference [95% CI]: 15.0 cm2 [1.5, 28.5], 3.2 cm [2.2, 4.1], 690 g [8, 1372] and 443 g [142, 744], respectively). The difference in visceral adipose tissue between type 2 diabetes and NGM was greater in men than women (W–M mean difference [95% CI]: −14.8 cm2 [−26.4, −3.1]). There was no sex difference in the percentage of liver fat between type 2 diabetes and NGM. The differences in measures of body composition between prediabetes and NGM were generally in the same direction, but were not significantly different between women and men.Conclusions/interpretationThis study indicates that there are sex differences in body composition associated with type 2 diabetes. The pathophysiological significance of these sex-associated differences requires further study. Show less
Background: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1... Show moreBackground: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown. Results: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3. Conclusions: These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit. Show less
Ouden, H. den; Vos, R.C.; Pieterse, A.H.; Rutten, G.E.H.M. 2022
Aims: To analyse the performance of a Shared Decision Making (SDM) intervention, we assessed perceived and experienced SDM in General Practitioners (GPs) and patients with type 2 diabetes (T2DM)... Show moreAims: To analyse the performance of a Shared Decision Making (SDM) intervention, we assessed perceived and experienced SDM in General Practitioners (GPs) and patients with type 2 diabetes (T2DM).Methods: Cluster-Randomised Controlled Trial (cRCT) testing the effect of a decision aid. Opinions and experienced role regarding SDM were assessed in 72 patients and 18 GPs with the SDM-Q-9 (range 0-45) and Control Preferences Scale (CPS, 0-5), and observed SDM with the OPTION5 (0-20). SDM at baseline was compared to 24 months' follow-up using paired t-tests.Results: At baseline, perceived levels of SDM did not significantly differ between GPs and patients with T2DM (difference of 2.3, p = 0.24). At follow-up, mean patients' perceived level of SDM was 7.9 lower compared to baseline (p < 0.01), whereas GPs' opinions had not changed significantly. After both visits, mean CPS scores differed significantly between patients and GPs. OPTION5 scores ranged between 6 and 20.Conclusion: Patients and GPs perceived similar baseline levels of SDM. Two years later, patients perceived less SDM, while GPs did not change their opinion. SDM was appropriate immediately after training, but perhaps GPs fell back in old habits over time. We recommend repeated SDM training. Show less
Aims/hypothesis: Numerous genome-wide association studies have been performed to understand the influence of genetic variation on type 2 diabetes etiology. Many identified risk variants are located... Show moreAims/hypothesis: Numerous genome-wide association studies have been performed to understand the influence of genetic variation on type 2 diabetes etiology. Many identified risk variants are located in non-coding and intergenic regions, which complicates understanding of how genes and their downstream pathways are influenced. An integrative data approach will help to understand the mechanism and consequences of identified risk variants. Methods: In the current study we use our previously developed method CONQUER to overlap 403 type 2 diabetes risk variants with regulatory, expression and protein data to identify tissue-shared disease-relevant mechanisms. Results: One SNP rs474513 was found to be an expression-, protein- and metabolite QTL. Rs474513 influenced LPA mRNA and protein levels in the pancreas and plasma, respectively. On the pathway level, in investigated tissues most SNPs linked to metabolism. However, in eleven of the twelve tissues investigated nine SNPs were linked to differential expression of the ribosome pathway. Furthermore, seven SNPs were linked to altered expression of genes linked to the immune system. Among them, rs601945 was found to influence multiple HLA genes, including HLA-DQA2, in all twelve tissues investigated. Conclusion: Our results show that in addition to the classical metabolism pathways, other pathways may be important to type 2 diabetes that show a potential overlap with type 1 diabetes. Show less
To improve primary diabetes care in the Netherlands, in 2007 a ‘care group’ system is initiated. We first studied the association between adherence to a structured diabetes protocol and patient... Show moreTo improve primary diabetes care in the Netherlands, in 2007 a ‘care group’ system is initiated. We first studied the association between adherence to a structured diabetes protocol and patient outcomes. We then investigated what practices actually require when seeking to adjust care to patient needs. With that aim in mind, we explored the effect of dispensing with protocol and the key conditions for successful implementation of self-management interventions. Finally, we measured patient outcomes with regard to treatment satisfaction, quality of life and monitoring.A structured care protocol has added value for people with diabetes; the proportion of people having recommended monitoring increases sharply. Practices likely undergo an intensive learning process when they join a care group and appear to reach the same as experienced practice within a year. When comparing the HbA1 levels of people with recommended and incomplete monitoring, we found that the HbA1c levels in people with recommended monitoring are significantly circa 2 mmol/mol lower compared to incomplete monitoring. In other words, recommended monitoring is far more than merely an administrative procedure; it actually reflects better real-world HbA1c levels. Differences in HbA1c level between people with recommended versus incomplete monitoring were greater in vulnerable populations, to the extent of approximately 3 mmol/mol, whereas a circa 1 mmol/mol difference was found in the intermediate category. In other words, within a care group setting people in the deprived category derive the most benefit from recommended monitoring.Protocol-free care provided room for reflection concerning ‘tailored care’; varying self-management interventions were chosen Our study revealed three key conditions for successful implementation of self-management interventions. Considering that patient satisfaction and monitoring decreased, this thesis ends with a roadmap consisting of several recommendations to improve and tailor diabetes care in general practice. Show less
Akpinar, E.O.; Liem, R.S.L.; Nienhuijs, S.W.; Greve, J.W.M.; Marang-van de Mheen, P.J.; Dutch Audit Treatment Obesity Res 2021
Background: Bariatric surgery among patients with obesity and type 2 diabetes (T2D) can induce complete remission. However, it remains unclear whether sleeve gastrectomy (SG) or Roux-en-Y gastric... Show moreBackground: Bariatric surgery among patients with obesity and type 2 diabetes (T2D) can induce complete remission. However, it remains unclear whether sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) has better T2D remission within a population-based daily practice.Objectives: To compare patients undergoing RYGB and SG on the extent of T2D remission at the 1-year follow-up.Setting: Nationwide, population-based study including all 18 hospitals in the Netherlands providing metabolic and bariatric surgery.Methods: Patients undergoing RYGB and SG between October 2015 and October 2018 with 1 year of complete follow-up data were selected from the mandatory nationwide Dutch Audit for Treatment of Obesity (DATO). The primary outcome is T2D remission within 1 year. Secondary outcomes include >= 20% total weight loss (TWL), obesity-related co-morbidity reduction, and postoperative complications with a Clavien-Dindo (CD) grade >= III within 30 days. We compared T2D remission between RYGB and SG groups using propensity score matching to adjust for confounding by indication.Results: A total of 5015 patients were identified from the DATO, and 4132 (82.4%) had completed a 1-year follow-up visit. There were 3350 (66.8%) patients with a valid T2D status who were included in the analysis (RYGB = 2623; SG = 727). RYGB patients had a lower body mass index than SG patients, but were more often female, with higher gastroesophageal reflux disease and dyslipidemia rates. After adjusting for these confounders, RYGB patients had increased odds of achieving T2D remission (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.14-2.1; P<.01). Groups were balanced after matching 695 patients in each group. After matching, RYGB patients still had better odds of T2D remission (OR, 1.91; 95% CI, 1.27-2.88; P<.01). Also, significantly more RYGB patients had >= 20%TWL (OR, 2.71; 95% CI, 1.96-3.75; P<.01) and RYGB patients had higher dyslipidemia remission rates (OR, 1.96; 95% CI, 1.39-2.76; P<.01). There were no significant differences in CD >= III complications.Conclusion: Using population-based data from the Netherlands, this study shows that RYGB leads to better T2D remission rates at the 1-year follow-up and better metabolic outcomes for patients with obesity and T2D undergoing bariatric surgery in daily practice. (C) 2021 American Society for Bariatric Surgery. Published by Elsevier Inc. Show less
Aims/hypothesis Five clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes. In the current study we replicate and... Show moreAims/hypothesis Five clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes. In the current study we replicate and cross-validate these type 2 diabetes clusters in three large cohorts using variables readily measured in the clinic.Methods In three independent cohorts, in total 15,940 individuals were clustered based on age, BMI, HbA(1c), random or fasting C-peptide, and HDL-cholesterol. Clusters were cross-validated against the original clusters based on HOMA measures. In addition, between cohorts, clusters were cross-validated by re-assigning people based on each cohort's cluster centres. Finally, we compared the time to insulin requirement for each cluster.Results Five distinct type 2 diabetes clusters were identified and mapped back to the original four All New Diabetics in Scania (ANDIS) clusters. Using C-peptide and HDL-cholesterol instead of HOMA2-B and HOMA2-IR, three of the clusters mapped with high sensitivity (80.6-90.7%) to the previously identified severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) clusters. The previously described ANDIS mild age-related diabetes (MARD) cluster could be mapped to the two milder groups in our study: one characterised by high HDL-cholesterol (mild diabetes with high HDL-cholesterol [MDH] cluster), and the other not having any extreme characteristic (mild diabetes [MD]). When these two milder groups were combined, they mapped well to the previously labelled MARD cluster (sensitivity 79.1%). In the cross-validation between cohorts, particularly the SIDD and MDH clusters cross-validated well, with sensitivities ranging from 73.3% to 97.1%. SIRD and MD showed a lower sensitivity, ranging from 36.1% to 92.3%, where individuals shifted from SIRD to MD and vice versa. People belonging to the SIDD cluster showed the fastest progression towards insulin requirement, while the MDH cluster showed the slowest progression.Conclusions/interpretation Clusters based on C-peptide instead of HOMA2 measures resemble those based on HOMA2 measures, especially for SIDD, SIRD and MOD. By adding HDL-cholesterol, the MARD cluster based upon HOMA2 measures resulted in the current clustering into two clusters, with one cluster having high HDL levels. Cross-validation between cohorts showed generally a good resemblance between cohorts. Together, our results show that the clustering based on clinical variables readily measured in the clinic (age, HbA(1c), HDL-cholesterol, BMI and C-peptide) results in informative clusters that are representative of the original ANDIS clusters and stable across cohorts. Adding HDL-cholesterol to the clustering resulted in the identification of a cluster with very slow glycaemic deterioration. Show less
Ritter, R. de; Sep, S.J.S.; Kallen, C.J.H. van der; Greevenbroek, M.M.J. van; Jong, M. de; Vos, R.C.; ... ; Stehouwer, C.D.A. 2021
Background Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal... Show moreBackground Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular measures. Methods In a population-based cohort study of individuals aged 40-75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders. Results Men with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 mu m (1.22;7.36)) and less retinal arteriolar dilatation (difference: - 0.74% (- 1.22; - 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 mu m (- 3.50;4.07) and: - 0.52% (- 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation. Conclusions Our findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications. Show less
Beulens, J.W.J.; Yauw, J.S.; Elders, P.J.M.; Feenstra, T.; Herings, R.; Slieker, R.C.; ... ; Heijden, A.A. van der 2021
Aims/hypothesis Approximately 25% of people with type 2 diabetes experience a foot ulcer and their risk of amputation is 10-20 times higher than that of people without type 2 diabetes. Prognostic... Show moreAims/hypothesis Approximately 25% of people with type 2 diabetes experience a foot ulcer and their risk of amputation is 10-20 times higher than that of people without type 2 diabetes. Prognostic models can aid in targeted monitoring but an overview of their performance is lacking. This study aimed to systematically review prognostic models for the risk of foot ulcer or amputation and quantify their predictive performance in an independent cohort.Methods A systematic review identified studies developing prognostic models for foot ulcer or amputation over minimal 1 year follow-up applicable to people with type 2 diabetes. After data extraction and risk of bias assessment (both in duplicate), selected models were externally validated in a prospective cohort with a 5 year follow-up in terms of discrimination (C statistics) and calibration (calibration plots).Results We identified 21 studies with 34 models predicting polyneuropathy, foot ulcer or amputation. Eleven models were validated in 7624 participants, of whom 485 developed an ulcer and 70 underwent amputation. The models for foot ulcer showed C statistics (95% CI) ranging from 0.54 (0.54, 0.54) to 0.81 (0.75, 0.86) and models for amputation showed C statistics (95% CI) ranging from 0.63 (0.55, 0.71) to 0.86 (0.78, 0.94). Most models underestimated the ulcer or amputation risk in the highest risk quintiles. Three models performed well to predict a combined endpoint of amputation and foot ulcer (C statistics >0.75).Conclusions/interpretation Thirty-four prognostic models for the risk of foot ulcer or amputation were identified. Although the performance of the models varied considerably, three models performed well to predict foot ulcer or amputation and may be applicable to clinical practice. Show less
Background The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be... Show moreBackground The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D. Methods Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts. Results We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling. Conclusions Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D. Show less
Aims/hypothesis The aims of this study were to identify all published prognostic models predicting retinopathy risk applicable to people with type 2 diabetes, to assess their quality and accuracy,... Show moreAims/hypothesis The aims of this study were to identify all published prognostic models predicting retinopathy risk applicable to people with type 2 diabetes, to assess their quality and accuracy, and to validate their predictive accuracy in a head-to-head comparison using an independent type 2 diabetes cohort. Methods A systematic search was performed in PubMed and Embase in December 2019. Studies that met the following criteria were included: (1) the model was applicable in type 2 diabetes; (2) the outcome was retinopathy; and (3) follow-up was more than 1 year. Screening, data extraction (using the checklist for critical appraisal and data extraction for systemic reviews of prediction modelling studies [CHARMS]) and risk of bias assessment (by prediction model risk of bias assessment tool [PROBAST]) were performed independently by two reviewers. Selected models were externally validated in the large Hoorn Diabetes Care System (DCS) cohort in the Netherlands. Retinopathy risk was calculated using baseline data and compared with retinopathy incidence over 5 years. Calibration after intercept adjustment and discrimination (Harrell's C statistic) were assessed. Results Twelve studies were included in the systematic review, reporting on 16 models. Outcomes ranged from referable retinopathy to blindness. Discrimination was reported in seven studies with C statistics ranging from 0.55 (95% CI 0.54, 0.56) to 0.84 (95% CI 0.78, 0.88). Five studies reported on calibration. Eight models could be compared head-to-head in the DCS cohort (N = 10,715). Most of the models underestimated retinopathy risk. Validating the models against different severities of retinopathy, C statistics ranged from 0.51 (95% CI 0.49, 0.53) to 0.89 (95% CI 0.88, 0.91). Conclusions/interpretation Several prognostic models can accurately predict retinopathy risk in a population-based type 2 diabetes cohort. Most of the models include easy-to-measure predictors enhancing their applicability. Tailoring retinopathy screening frequency based on accurate risk predictions may increase the efficiency and cost-effectiveness of diabetic retinopathy care. Registration PROSPERO registration ID CRD42018089122 Show less
Background Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and... Show moreBackground Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and length of follow-up. Here, we characterize glycemic variability over time and whether its relation to diabetes-related complications and mortality is independent from diabetes- and follow-up duration. Materials and methods Individuals with type 2 diabetes (n = 6770) from the Hoorn Diabetes Care System cohort were included in this study. The coefficient of variation (CV) was calculated over 5-year sliding intervals. People divided in quintiles based on their CV. Cox proportional hazard models were used to investigate the role of glycemic CV as risk factor in diabetes-related complications and mortality. Results The coefficient of variation of glucose (FG-CV) increased with time, in contrast to HbA1c (HbA1c-CV). People with a high FG-CV were those with an early age of diabetes onset (Delta(Q5-Q1) = - 2.39 years), a higher BMI (Delta(Q5-Q1) = + 0.92 kg/m(2)), an unfavorable lipid profile, i.e. lower levels of HDL-C (Delta(Q5-Q1) = - 0.06 mmol/mol) and higher triglycerides (Delta(Q5-Q1) =+ 1.20 mmol/mol). People with the highest FG-CV in the first 5-year interval showed an increased risk of insulin initiation, retinopathy, macrovascular complications and mortality independent of mean glycemia, classical risk factors and medication use. For HbA1c, the associations were weaker and less consistent. Conclusions Individuals with a higher FG-CV have an unfavorable metabolic profile and have an increased risk of developing micro- and macrovascular complications and mortality. The association of HbA1c-CV with metabolic outcomes and complications was less consistent in comparison to FG-CV. Show less
Schaft, N. van der; Schoufour, J.D.; Nano, J.; Kiefte-de Jong, J.C.; Muka, T.; Sijbrands, E.J.G.; ... ; Voortman, T. 2019
Aims/hypothesisAnimal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing... Show moreAims/hypothesisAnimal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing system for energy metabolism is well established, but little is known about the diurnal regulation of (clock) gene expression in obese individuals with type 2 diabetes. In this study we aimed to identify key disturbances in the diurnal rhythms of the white adipose tissue transcriptome in obese individuals with type 2 diabetes.MethodsIn a case-control design, we included six obese individuals with type 2 diabetes and six healthy, lean control individuals. All participants were provided with three identical meals per day for 3days at zeitgeber time (ZT, with ZT 0:00 representing the time of lights on) 0:30, 6:00 and 11:30. Four sequential subcutaneous abdominal adipose tissue samples were obtained, on day 2 at ZT 15:30, and on day 3 at ZT 0:15, ZT 5:45 and ZT 11:15. Gene expression was measured using RNA sequencing.ResultsThe core clock genes showed reduced amplitude oscillations in the individuals with type 2 diabetes compared with the healthy control individuals. Moreover, in individuals with type 2 diabetes, only 1.8% (303 genes) of 16,818 expressed genes showed significant diurnal rhythmicity, compared with 8.4% (1421 genes) in healthy control individuals. Enrichment analysis revealed a loss of rhythm in individuals with type 2 diabetes of canonical metabolic pathways involved in the regulation of lipolysis. Enrichment analysis of genes with an altered mesor in individuals with type 2 diabetes showed decreased activity of the translation initiating pathway EIF2 signaling'. Individuals with type 2 diabetes showed a reduced diurnal rhythm in postprandial glucose concentrations.Conclusions/interpretationDiurnal clock and metabolic gene expression rhythms are decreased in subcutaneous adipose tissue of obese individuals with type 2 diabetes compared with lean control participants. Future investigation is needed to explore potential treatment targets as identified by our study, including clock enhancement and induction of EIF2 signalling.Data availabilityThe raw sequencing data and supplementary files for rhythmic expression analysis and Ingenuity Pathway Analysis have been deposited in NCBI Gene Expression Omnibus (GEO series accession number GSE104674). Show less
The main objective of this thesis is to improve the understanding of the role of helminth infections in the development of insulin resistance, hence type 2 diabetes, and to gain insight into the... Show moreThe main objective of this thesis is to improve the understanding of the role of helminth infections in the development of insulin resistance, hence type 2 diabetes, and to gain insight into the immunological mechanisms underlying this possible interaction. To this end, we initiated a large scale cluster randomized controlled trial, assessing the effect of anthelmintic treatment on insulin resistance and other metabolic, as well as immunological parameters, in a rural area of Indonesia. Deworming significantly reduced the prevalence of helminths, as well as infection intensity. Although treatment did not lead to an increase of whole-body insulin resistance at the community level, a significant increase in insulin resistance was observed among helminth-infected subjects. Furthermore, by comparing immune cells of helminth-infected Indonesians before and after treatment, we gained insight into the specific cell populations that participate in the type 2 and regulatory networks, and show that treatment affects specific cell subsets in these networks. Altogether, the studies described in this thesis show that helminth infections in humans, as well as the administration of helminth molecules in obese mice, have a beneficial effect on the insulin sensitivity, and have shed light on the immunomodulatory effects of helminths. Show less
