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
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
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
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
