In dit onderzoek hebben we de rol van thromboinflammatie onderzocht in verschillende hoog-risico populaties, zoals mensen met type 2 diabetes mellitus (T2DM) en patiënten met ernstige COVID-19, als... Show moreIn dit onderzoek hebben we de rol van thromboinflammatie onderzocht in verschillende hoog-risico populaties, zoals mensen met type 2 diabetes mellitus (T2DM) en patiënten met ernstige COVID-19, als ook naar verhoogd risico bij vrouwen in de Nederlandse samenleving. Thromboinflammatie is de verbinding tussen de gelijktijdige activatie van de stollingsroute en immuunrespons welke een belangrijke trigger vormt voor bloedvat schade, prominent in microvasculaire gezondheid. Als eerste laten we zien dat er genderspecifieke associaties zijn tussen het activatie potentieel van de stollingsroute en microvasculaire gezondheid met betrekking tot eventueel ontwikkelen van hartfalen. Het mechanisme van T2DM progressie varieert bij verschillende etniciteiten en we hebben aangetoond dat veranderingen in cholesterol functie (HDL) en lipiden profiel in het bloed een van de onderliggende mechanismen kunnen zijn die leiden tot versnelde ziekte progressie bij Zuid-Aziaten van Nederlandse afkomst met T2DM in vergelijk met Nederlandse blanke Europeanen met T2DM. Met nieuwe geavanceerde technieken vonden we ook dat bij patiënten met ernstige COVID-19 factoren in het bloed aanwezig zijn die schade aan de kleine bloedvaten en verhoogde stollingsactiviteit teweegbrengen. Ook bij deze patiënten zagen we dat veranderingen in HDL compositie een belangrijke rol in de ernst van de ziekte speelt. Samen geven de resultaten het belang aan van thromboinflammatie in verhoogd-risico populaties in versneld ontwikkelen van hartfalen, T2DM en COVID-19. Het onderzoek laat de noodzaak zien van vroege detectie in het proces, waarbij vroegtijdige interventies kunnen lijden tot preventie of het beter managen van het thromboinflammatoire ziekteproces.*************************************************************************In this study, we investigated the role of thromboinflammation in various high-risk populations, including individuals with type 2 diabetes mellitus (T2DM) and patients with severe COVID-19, as well as the increased risk in women in Dutch society. Thromboinflammation refers to the simultaneous activation of the clotting pathway and immune response, which is a significant trigger for vascular damage, particularly in microvascular health.Firstly, we demonstrated sex-specific associations between coagulation parameters and microvascular health. The mechanism of T2DM progression varies among different ethnicities, and we found that changes in cholesterol function (HDL) and lipid profiles in the blood could be underlying mechanisms leading to accelerated disease progression in South Asians of Dutch descent with T2DM compared to Dutch white Caucasian with T2DM.Using advanced techniques, we also identified factors in the blood of patients with severe COVID-19 that contribute to small blood vessel damage and increased clotting activity. We observed that changes in HDL composition played an important role in the severity of the disease in these patients.Overall, our results highlight the importance of thromboinflammation in high-risk populations in the accelerated development of heart failure, T2DM, and COVID-19. The research emphasizes the need for early detection in the process, where timely interventions can lead to prevention or better management of the thromboinflammatory disease process. Show less
Patiënts with type 2 diabetes mellitus (T2DM) are at increased risk of heart failure: diabetic cardiomyopathy. This condition is characterized by a thickened cardiac muscle of the left ventricle... Show morePatiënts with type 2 diabetes mellitus (T2DM) are at increased risk of heart failure: diabetic cardiomyopathy. This condition is characterized by a thickened cardiac muscle of the left ventricle that impairs its adequate filling with blood. The cause of diabetic cardiomyopathy is probably related to insuline resistance and impaired cardiac energy metabolism by accumulation of toxic lipids in the cells of cardiac muscle. Magnetic resonance (MR) imaging and MR spectroscopy of the heart can be used to characterize and investigate diabetic cardiomyopathy and its treatment.This thesis describes studies aimed at improving MR techniques on the one hand. While, on the other hand, MR is applied to investigate the efficacy of pharmacologic and lifestyle interventions to treat diabetic cardiomyopathy. The effect of the diabetes drug liraglutide on diabetic cardiomyopathy was studied in a randomized placebo-controlled trial. Liraglutide reduced filling pressure of the left ventricle, which in time could be a beneficial effect in terms of preservation of cardiac health. In addition, it was found that liraglutide did not reduce ectopic fat accumulation in visceral abdominal fat, the liver and the heart, despite significantly reduced body weight as compared tot the placebo-treated group.Furthermore, the effect of a lifestyle intervention aimed at healthy nutrition and physical exercise was investigated in patients with insulin-dependent T2DM. In twelve weeks, patients required less insulin, and fat accumulation in the liver and heart was significantly reduced. Despite these improvements, the endogenous insulin-production and heart function did not change. These results suggest that these patients with T2DM had irreversible end-organ damage.In conclusion, this thesis shows that the application of advanced MR techniques can help to better understand diabetic cardiomyopathy and its treatment. Thereby hopefully leading to an improved cardiovascular prognosis of patients with T2DM. Show less
Aims/hypothesis: Mitochondrial dysfunction, which can be approximated by blood mitochondrial DNA copy number (mtDNACN), has been implicated in the pathogenesis of type 2 diabetes mellitus. Thus far... Show moreAims/hypothesis: Mitochondrial dysfunction, which can be approximated by blood mitochondrial DNA copy number (mtDNACN), has been implicated in the pathogenesis of type 2 diabetes mellitus. Thus far, however, insights from prospective cohort studies and Mendelian randomisation (MR) analyses on this relationship are limited. We assessed the association between blood mtDNA-CN and incident type 2 diabetes using multivariable-adjusted regression analyses, and the associations between blood mtDNA-CN and type 2 diabetes and BMI using bi-directional MR .Methods: Multivariable-adjusted Cox proportional hazard models were used to estimate the association between blood mtDNA-CN and incident type 2 diabetes in 285,967 unrelated European individuals from UK Biobank free of type 2 diabetes at baseline. Additionally, a cross-sectional analysis was performed to investigate the association between blood mtDNA-CN and BMI. We also assessed the potentially causal relationship between blood mtDNA-CN and type 2 diabetes (N=898,130 from DIAG RAM, N=215,654 from FinnGen) and BMI (N=681,275 from GIANT) using bi-directional two-sample MR. Results: During a median follow-up of 11.87 years, 15,111 participants developed type 2 diabetes. Participants with a higher level of blood mtDNA-CN are at lower risk of developing type 2 diabetes (HR 0.90 [95% CI 0.89, 0.92]). After additional adjustment for BMI and other confounders, these results attenuated moderately and remained present. The multivariable-adjusted crosssectional analyses showed that higher blood mtDNA-CN was associated with lower BMI (-0.12 [95% CI -0.14, -0.10]) kg/m(2). In the bi-directional MR analyses, we found no evidence for causal associations between blood mtDNA-CN and type 2 diabetes, and blood mtDNA-CN and BMI in either direction. Conclusions/interpretation: The results from the present study indicate that the observed association between low blood mtDNACI\ and higher risk of type 2 diabetes is likely not causal. Show less
Objective: To examine the relationship between risk factors for low patient activation and change in patient activation, well-being, and health outcomes in people with type 2 diabetes mellitus ... Show moreObjective: To examine the relationship between risk factors for low patient activation and change in patient activation, well-being, and health outcomes in people with type 2 diabetes mellitus (T2DM). Method: A longitudinal prospective study was conducted with measurements at baseline and 20-week follow-up among 603 people with T2DM participating in a group-based walking intervention. Patient activation and risk factors were assessed using online questionnaires. Health outcomes were assessed in participants' general practices. Results: No association was found between risk factors for activation and change in patient activation. Patient activation significantly increased (t(602) = 2.53, p = 0.012) and was associated with an increase in emotional well-being (beta = 0.22), exercise behavior (beta = 0.17), general diet behavior (beta = 0.20), and a reduction in BMI (beta = -0.28), weight (beta = -0.29), and HbA1c (beta = -0.27). Conclusion: Favorable changes in patient activation, self-management, well-being, and health outcomes occurred during a walking intervention, despite highly prevalent risk factors for low activation and less engagement in self-management. Practice implications: Group-based walking interventions might empower people with T2DM to begin taking a larger role in their self-care and improve (mental) health outcomes. Vulnerable groups of patients (with multiple risk factors for low activation) can change and presumably need this kind of interventions to be able to change. Show less
This thesis shows the potential utility of imaging biomarkers of the heart, kidneys, and visceral adiposity in the clinical management of cardiorenal syndrome and type 2 diabetes. We explored the... Show moreThis thesis shows the potential utility of imaging biomarkers of the heart, kidneys, and visceral adiposity in the clinical management of cardiorenal syndrome and type 2 diabetes. We explored the methods to quantify visceral fat, and demonstrated the potential clinical implications of a special compartment of visceral fat, renal sinus fat. We summarized the current role of imaging techniques in the clinical management of cardiorenal syndrome, and evaluated the preclinical MRI-derived imaging biomarkers in a group of patients with type 4 cardiorenal syndrome. Our findings could potentially benefit the clinical care for patients with metabolic disorders and/or cardiorenal syndrome. Continuous technical developments in quantitative imaging will increase the potential for applying imaging biomarkers in the management of reno-cardiometabolic diseases, and contribute to achieving the goals of personalized medicine. Show less
Aims We aimed to compare renal sinus fat volume assessed by MRI between patients with type 2 diabetes and healthy volunteers, and investigate the association between renal sinus fat and metabolic... Show moreAims We aimed to compare renal sinus fat volume assessed by MRI between patients with type 2 diabetes and healthy volunteers, and investigate the association between renal sinus fat and metabolic traits.Methods In this cross-sectional study, renal sinus fat and parenchyma volumes measured on abdominal MRI were compared between patients and controls using analysis of covariance. Associations of renal parameters with clinical characteristics were analyzed using linear regression analysis.Results A total of 146 participants were enrolled, consisting of 95 type 2 diabetes patients (57.2 +/- 8.8 years, 49.5% male) and 51 controls (54.0 +/- 9.2 years, 43.1% male). Patients with diabetes demonstrated larger sinus fat volumes (15.4 +/- 7.5 cm(3) vs. 10.3 +/- 7.1 cm(3), p < 0.001) and sinus fat-parenchyma ratio than controls. In the total population, renal sinus fat was positively associated with HbA1c, abdominal VAT, cholesterol and triglycerides, after adjustment for age, sex, ethnicity and type 2 diabetes. In type 2 diabetes patients, increased sinus fat volume was significantly associated with urinary albumin-to-creatinine ratio.Conclusion Renal sinus fat volume is positively associated with several metabolic risk factors including HbA1c level and urinary albumin-to-creatinine ratio in type 2 diabetes patients, indicating a potential role of renal sinus fat in the development of diabetic nephropathy. Future studies are needed to investigate whether sinus fat volume can serve as an early biomarker for diabetic nephropathy. Show less
Aims Data on the effect of liraglutide on glycemic endpoints in people with T2DM using multiple daily insulin injections (MDI) are scarce, especially in the context of ethnicity. Methods This is a... Show moreAims Data on the effect of liraglutide on glycemic endpoints in people with T2DM using multiple daily insulin injections (MDI) are scarce, especially in the context of ethnicity. Methods This is a secondary analysis of the placebo-controlled randomized clinical "MAGNA VICTORIA" trials in Western European (WE) and South Asian (SA) people with T2DM. Participants had inadequate glycemic control despite using metformin and/or sulfonylurea derivatives and/or insulin. Participants were assigned to liraglutide (1.8 mg) or placebo for 6 months, in addition to standard care. The primary endpoint number of participants reaching target HbA1c was compared for liraglutide versus placebo in the complete dataset and MDI-treated participants using Chi-square test. Liraglutide's efficacy in WE and SA was compared using a generalized linear model. Results Forty-five subjects were randomized to liraglutide and 51 to placebo. In each group, one participant did not complete the study. Liraglutide-treated patients reached target HbA1c more frequently: 23/45 (51%) vs 11/51 (22%), relative probability 2.4 (1.3-4.3), p = 0.002. Subgroup analysis in 43 MDI participants showed that the proportion reaching target HbA1c using liraglutide was significantly higher than in placebo: 9/22 (41%) vs 1/21 (5%), p = 0.005. There was no difference between WE and SA in terms of liraglutide efficacy (p = 0.18). Conclusions Liraglutide treatment resulted in increased chance of reaching target HbA1c as compared to placebo. Liraglutide efficacy was sustained in participants using MDI regimens and those of SA descent. Liraglutide should be considered for T2DM people with inadequate glycemic control despite MDI. Show less
Bos, M.M.; Noordam, R.; Bennett, K.; Beekman, M.; Mook-Kanamori, D.O.; Dijk, K.W. van; ... ; Heemst, D. van 2020
Introduction Several plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus. Objectives We aimed to identify plasma metabolites associated with different... Show moreIntroduction Several plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus. Objectives We aimed to identify plasma metabolites associated with different indices of early disturbances in glucose metabolism and insulin sensitivity. Methods This cross-sectional study was conducted in a subsample of the Leiden Longevity Study comprising individuals without a history of diabetes mellitus (n = 233) with a mean age of 63.3 +/- 6.7 years of which 48.1% were men. We tested for associations of fasting glucose, fasting insulin, HOMA-IR, Matsuda Index, Insulinogenic Index and glycated hemoglobin with metabolites (Swedish Metabolomics Platform) using linear regression analysis adjusted for age, sex and BMI. Results were validated internally using an independent metabolomics platform (Biocrates platform) and replicated externally in the independent Netherlands Epidemiology of Obesity (NEO) study (Metabolon platform) (n = 545, mean age of 55.8 +/- 6.0 years of which 48.6% were men). Moreover, in the NEO study, we replicated our analyses in individuals with diabetes mellitus (cases: n = 36; controls = 561). Results Out of the 34 metabolites, a total of 12 plasma metabolites were associated with different indices of disturbances in glucose metabolism and insulin sensitivity in individuals without diabetes mellitus. These findings were validated using a different metabolomics platform as well as in an independent cohort of non-diabetics. Moreover, tyrosine, alanine, valine, tryptophan and alpha-ketoglutaric acid levels were higher in individuals with diabetes mellitus. Conclusion We found several plasma metabolites that are associated with early disturbances in glucose metabolism and insulin sensitivity of which five were also higher in individuals with diabetes mellitus. Show less
Aims/hypothesis The aim of this work was to assess the effect of liraglutide on ectopic fat accumulation in individuals with type 2 diabetes mellitus. Methods This study is a pre-specified... Show moreAims/hypothesis The aim of this work was to assess the effect of liraglutide on ectopic fat accumulation in individuals with type 2 diabetes mellitus. Methods This study is a pre-specified subanalysis of the MAGNetic resonance Assessment of VICTOza efficacy in the Regression of cardiovascular dysfunction In type 2 diAbetes mellitus (MAGNA VICTORIA) study, with primary endpoints being the effects of liraglutide on left ventricular diastolic and systolic function. The MAGNA VICTORIA study was a single-centre, parallel-group trial in 50 individuals with type 2 diabetes mellitus (BMI >25 kg/m(2)) who were randomly assigned (1:1, stratified for sex and insulin use) to receive liraglutide 1.8 mg once daily or placebo for 26 weeks, added to standard care. Participants, study personnel and outcome assessors were blinded to treatment allocation. The secondary endpoints of visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT) and epicardial fat were measured with MRI. Hepatic triacylglycerol content (HTGC) and myocardial triacylglycerol content (MTGC) were quantified with proton MR spectroscopy. Between-group differences (change from baseline) were tested for significance using ANCOVA. Mean differences with 95% CIs were reported. Results The trial was completed in 2016. Twenty-four participants were randomised to receive liraglutide and 26 to receive placebo. One patient in the liraglutide group withdrew consent before having received the study drug and was not included in the intention-to-treat analysis. Liraglutide (n = 23) vs placebo (n = 26) significantly reduced body weight (liraglutide 98.4 +/- 13.8 kg to 94.3 +/- 14.9 kg; placebo 94.5 +/- 13.1 kg to 93.9 +/- 13.2 kg; estimated treatment effect -4.5 [95% CI -6.4, -2.6] kg). HbA(1c) declined in both groups without a significant treatment effect of liraglutide vs placebo (liraglutide 66.7 +/- 11.5 mmol/mol to 55.0 +/- 13.2 mmol/mol [8.4 +/- 1.1% to 7.3 +/- 1.2%]; placebo 64.7 +/- 10.2 mmol/mol to 56.9 +/- 6.9 mmol/mol [8.2 +/- 1.0% to 7.5 +/- 0.7%]; estimated treatment effect -2.9 [95% CI -8.1, 2.3] mmol/mol or -0.3 [95% CI -0.8, 0.2]%). VAT did not change significantly between groups (liraglutide 207 +/- 87 cm(2) to 203 +/- 88 cm(2); placebo 204 +/- 63 cm(2) to 200 +/- 55 cm(2); estimated treatment effect -7 [95% CI -24, 10] cm(2)), while SAT was reduced by a significantly greater extent with liraglutide than with placebo (liraglutide 361 +/- 142 cm(2) to 339 +/- 131 cm(2); placebo 329 +/- 107 cm(2) to 333 +/- 125 cm(2); estimated treatment effect -29 [95% CI -51, -8] cm(2)). Epicardial fat did not change significantly between groups (liraglutide 8.9 +/- 4.3 cm(2) to 9.1 +/- 4.7 cm(2); placebo 9.6 +/- 4.1 cm(2) to 9.6 +/- 4.6 cm(2); estimated treatment effect 0.2 [95% CI -1.5, 1.8] cm(2)). Change in HTGC was not different between groups (liraglutide 18.1 +/- 11.2% to 12.0 +/- 7.7%; placebo 18.4 +/- 9.4% to 14.7 +/- 10.0%; estimated treatment effect -2.1 [95% CI -5.3, 1.0]%). MTGC was not different after treatment with liraglutide (1.5 +/- 0.6% to 1.2 +/- 0.6%) vs placebo (1.3 +/- 0.5% to 1.2 +/- 0.6%), with an estimated treatment effect of -0.1 (95% CI -0.4, 0.2)%. There were no adjudicated serious adverse events. Conclusions/interpretation Compared with placebo, liraglutide-treated participants lost significantly more body weight. Liraglutide primarily reduced subcutaneous fat but not visceral, hepatic, myocardial or epicardial fat. Future larger studies are needed to confirm the results of this secondary endpoint study. Funding This study was funded by Novo Nordisk A/S (Bagsvaerd, Denmark). Show less
This thesis describes the clinical investigation of a novel treatment strategy for type 2 diabetes mellitus (t2dm) using an antisense oligonucleotide(aon)to inhibit the sglt2 receptor. Furthermore... Show moreThis thesis describes the clinical investigation of a novel treatment strategy for type 2 diabetes mellitus (t2dm) using an antisense oligonucleotide(aon)to inhibit the sglt2 receptor. Furthermore it describes skin effects of oligonucleotides Show less
Snel, M.; Sleddering, M.A.; Peijl, I.D. van der; Romijn, J.A.; Pijl, H.; Meinders, A.E.; Jazet, I.M. 2012
Matrix metalloproteinases (MMPs) may play a pathophysiological role in the development of diabetic nephropathy (DN). We hypothesized that urinary MMP activity in patients with type 2 diabetes... Show moreMatrix metalloproteinases (MMPs) may play a pathophysiological role in the development of diabetic nephropathy (DN). We hypothesized that urinary MMP activity in patients with type 2 diabetes mellitus (T2DM) is related to a decline in renal function. We determined MMP-2, -8 and -9 activity in 24-h urine collections in relation to risk factors for ON in T2DM patients with (UA, n=27) and without albuminuria (NA, n=48) and controls (CO, n=28). MMP-8 and -9 levels were highest in UA patients (P<0.01). Of UA patients, 93% had at least one MMP increased, compared to 78% of NA patients and 46% of CO (P=0.001). Age, diabetes duration, BMI, systolic blood pressure, fasting plasma glucose, HbA1c and renal function were determinants of MMP-8 and -9 (P<0.05). In summary, MMP-8 and -9 are highest in T2DM UA patients. MMP-9, showed the strongest associations with clinical parameters related to DN. (C) 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Show less
In the studies comprising this thesis we evaluated the potential usefulness of cDNA microarray based gene expression profiling and 1H-NMR based metabolomics platforms as tools for the evaluation of... Show moreIn the studies comprising this thesis we evaluated the potential usefulness of cDNA microarray based gene expression profiling and 1H-NMR based metabolomics platforms as tools for the evaluation of novel PPAR_ and -_ agonists in future clinical __proof of concept studies__. We investigated the effects of rosiglitazone, (prototype PPAR_ agonist ) and ciprofibrate (prototype PPAR_ agonist) on global (target) tissue gene expression profiles and endogenous urinary and plasma metabolites of type 2 Diabetes Mellitus (T2DM) patients and healthy volunteers (HVs).The results from the transcriptomic analyses indicated that none of the genes in any of the tissues in either study group displayed a significant treatment response with either rosiglitazone of ciprofibrate vs. placebo at Bonferroni adjusted values and _=0.05. The results of the metabolomic analyses revealed significant rosiglitazone and ciprofibrate induced changes in endogenous urinary and plasma metabolite profiles of T2DM patients but not in HVs. We conclude that from the two molecular profiling platforms evaluated in this thesis, metabolomics currently appears to be the most promising platform for future application in clinical __proof of concept__ studies with novel PPAR agonist compounds in T2DM patients.In the studies comprising this thesis we evaluated the potential usefulness of cDNA microarray based gene expression profiling and 1H-NMR based metabolomics platforms as tools for the evaluation of novel PPAR_ and -_ agonists in future clinical __proof of concept studies__. We investigated the effects of rosiglitazone, (prototype PPAR_ agonist ) and ciprofibrate (prototype PPAR_ agonist) on global (target) tissue gene expression profiles and endogenous urinary and plasma metabolites of type 2 Diabetes Mellitus (T2DM) patients and healthy volunteers (HVs).The results from the transcriptomic analyses indicated that none of the genes in any of the tissues in either study group displayed a significant treatment response with either rosiglitazone of ciprofibrate vs. placebo at Bonferroni adjusted values and _=0.05. The results of the metabolomic analyses revealed significant rosiglitazone and ciprofibrate induced changes in endogenous urinary and plasma metabolite profiles of T2DM patients but not in HVs. We conclude that from the two molecular profiling platforms evaluated in this thesis, metabolomics currently appears to be the most promising platform for future application in clinical __proof of concept__ studies with novel PPAR agonist compounds in T2DM patients. Show less
