Introduction Little is known about the comparative effects of sodium glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), or dipeptidyl peptidase-4... Show moreIntroduction Little is known about the comparative effects of sodium glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), or dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of acute kidney injury (AKI) in routine care, which may differ from the controlled setting of trials.Methods Observational study comparing risks of AKI among new users of SGLT2i, GLP1-RA or DPP-4i in the region of Stockholm, Sweden, during 2008-2018. AKI was defined by ICD-10 codes and creatinine-based KDIGO criteria. We used inverse probability of treatment weighting (IPTW) to adjust for 60 potential confounders, weighted Kaplan-Meier curves and Cox regression to estimate hazard ratios and absolute risks.Results We included 17,407 participants who newly initiated DPP-4i (N = 10,605), GLP1-RA (N = 4448) or SGLT2i (N = 2354). Mean age was 63 years (39% women) and median (IQR) eGFR was 89 (73-100) ml/min/1.73 m(2). During a median follow-up of 2.5 years, 1411 participants experienced AKI. SGLT2i users had the lowest incidence rate of AKI, 18.3 [CI 95% 14.1-23.4] per 1000 person years, followed by GLP1-RA (22.5; 19.9-25.3) and DPP-4i (26.6; 25-28.2). The weighted 3-year absolute risk for AKI was 5.79% [3.63-8.52] in the SGLT2i group, compared with 7.03% [5.69-8.69] and 7.00% [6.43-7.58] in the GLP1-RA and DPP-4i groups, respectively. The adjusted hazard ratio was 0.73 [CI 95% 0.45-1.16] for SGLT2i vs. DPP-4i, and 0.98 [CI 95% 0.82-1.18] for GLP1-RA vs. DPP-4i.Conclusion This study of routine care patients initiating novel glucose-lowering drugs showed similar occurrence of AKI between therapies, and suggests lower risk for SGLT2i. Show less
Dong, X.; Strudwick, M.; Wang, W.Y.S.; Borlaug, B.A.; Geest, R.J. van der; Ng, A.C.C.; ... ; Ng, A.C.T. 2022
Purpose: We hypothesize that both increased myocardial steatosis and interstitial fibrosis contributes to subclinical myocardial dysfunction in patients with increased body mass index and diabetes... Show morePurpose: We hypothesize that both increased myocardial steatosis and interstitial fibrosis contributes to subclinical myocardial dysfunction in patients with increased body mass index and diabetes mellitus. Background: Increased body weight and diabetes mellitus are both individually associated with a higher incidence of heart failure with preserved ejection fraction. However, it is unclear how increased myocardial steatosis and interstitial fibrosis interact to influence myocardial composition and function. Methods: A total of 100 subjects (27 healthy lean volunteers, 21 healthy but overweight volunteers, and 52 asymptomatic overweight patients with diabetes) were prospectively recruited to measure left ventricular (LV) myocardial steatosis (LV-myoFat) and interstitial fibrosis (by extracellular volume [ECV]) using magnetic resonance imaging, and then used to determine their combined impact on LV global longitudinal strain (GLS) analysis by 2-dimensional (2D) speckle tracking echocardiography on the same day. Results: On multivariable analysis, both increased body mass index and diabetes were independently associated with increased LV-myoFat. In turn, increased LV-myoFat was independently associated with increased LV ECV. Both increased LV-myoFat and LV ECV were independently associated with impaired 2D LV GLS. Conclusion: Patients with increased body weight and patients with diabetes display excessive myocardial steatosis, which is related to a greater burden of myocardial interstitial fibrosis. LV myocardial contractile function was determined by both the extent of myocardial steatosis and interstitial fibrosis, and was independent of increasing age. Further study is warranted to determine how weight loss and improved diabetes management can improve myocardial composition and function. Show less
The research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and... Show moreThe research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and glucocorticoids.Leptin plays an important role during TB infection and has a huge impact on insulin sensitivity in zebrafish larvae. Similarly to what has been observed in the murine model, leptin deficiency in zebrafish increased the bacterial burden and mortality during the infection, leading to hyperglycemia and the development of insulin resistance. In addition, a novel SHP-1/SHP-2 inhibitor, NSC-87877, was shown to represent a promising anti-diabetic drug that can be used for further DM2 research, as it is able to rescue the phenotype of the leptin-deficient zebrafish and to restore glucose transport to the tissues. In contrast to metformin, NSC-87877 can act at very early developmental stages and inhibits the function of SHP-1 and factors that underlay impaired glucose metabolism, whereas metformin is mostly known to improve insulin sensitivity. Additionally, treatment with the glucocorticoid beclomethasone attenuates the metabolic changes associated with the infection, and transcriptional alterations induced by beclomethasone treatment suggest that genes involved in glucose metabolism, insulin and leptin signaling all play an important role in the modulation of the metabolism.Our data show that zebrafish larvae represent an interesting model system to investigate the complex pathology of TB, and the studies described in this thesis in which this model has been used have provided novel insights into the molecular mechanisms underlying wasting syndrome and the possibilities for adjunctive glucocorticoid therapy to alleviate this metabolic state. Show less
Aims/hypothesis: Renal GLUT2 is increased in diabetes, thereby enhancing glucose reabsorption and worsening hyperglycaemia. Here, we determined whether loss of Glut2 (also known as Slc2a2)... Show moreAims/hypothesis: Renal GLUT2 is increased in diabetes, thereby enhancing glucose reabsorption and worsening hyperglycaemia. Here, we determined whether loss of Glut2 (also known as Slc2a2) specifically in the kidneys would reverse hyperglycaemia and normalise body weight in mouse models of diabetes and obesity. Methods: We used the tamoxifen-inducible CreERT2-Lox system in mice to knockout Glut2 specifically in the kidneys (Ks-Glut2 KO) to establish the contribution of renal GLUT2 to systemic glucose homeostasis in health and in insulin-dependent as well as non-insulin-dependent diabetes. We measured circulating glucose and insulin levels in response to OGTT or IVGTT under different experimental conditions in the Ks-Glut2 KO and their control mice. Moreover, we quantified urine glucose levels to explain the phenotype of the mice independently of insulin actions. We also used a transcription factor array to identify mechanisms underlying the crosstalk between renal GLUT2 and sodium-glucose cotransporter 2 (SGLT2). Results: The Ks-Glut2 KO mice exhibited improved glucose tolerance and massive glucosuria. Interestingly, this improvement in blood glucose control was eliminated when we knocked out Glut2 in the liver in addition to the kidneys, suggesting that the improvement is attributable to the lack of renal GLUT2. Remarkably, induction of renal Glut2 deficiency reversed hyperglycaemia and normalised body weight in mouse models of diabetes and obesity. Longitudinal monitoring of renal glucose transporters revealed that Sglt2 (also known as Slc5a2) expression was almost abolished 3 weeks after inducing renal Glut2 deficiency. To identify a molecular basis for this crosstalk, we screened for renal transcription factors that were downregulated in the Ks-Glut2 KO mice. Hnf1 alpha (also known as Hnf1a) was among the genes most downregulated and its recovery restored Sglt2 expression in primary renal proximal tubular cells isolated from the Ks-Glut2 KO mice. Conclusions/interpretation: Altogether, these results demonstrate a novel crosstalk between renal GLUT2 and SGLT2 in regulating systemic glucose homeostasis via glucose reabsorption. Our findings also indicate that inhibiting renal GLUT2 is a potential therapy for diabetes and obesity. Show less
Mahe, G.; Brodmann, M.; Capodanno, D.; Ceriello, A.; Cuisset, T.; Delgado, V.; ... ; Valensi, P. 2022
Aims: This survey aimed to evaluate the current management and screening of coronary artery disease and peripheral artery disease in people with type 2 diabetes mellitus (T2DM) in Europe, utilizing... Show moreAims: This survey aimed to evaluate the current management and screening of coronary artery disease and peripheral artery disease in people with type 2 diabetes mellitus (T2DM) in Europe, utilizing the 2013 ESC/EASD (European Society of Cardiology/European Association for the Study of Diabetes) guidelines as a benchmark. Methods: The PADDIA/CADDIA survey is a European medical research collaboration targeting cardiologists, vascular physicians, diabetologists and general practitioners from Austria, Belgium, France, Germany, Italy, Netherlands and United Kingdom. Results: The questionnaire was completed by sixty-three physicians, of whom 75% declared assessing the cardiovascular risk of people with T2DM mostly without using a risk score (59%). More than 90% of the panel, check HbA1c, blood pressure and low-density lipoprotein cholesterol targets in their patients with T2DM and coronary or peripheral artery disease. For 94% the presence of T2DM influence their patients' management, by optimizing blood glucose, blood pressure and low-density lipoprotein cholesterol control. Only 37% considered screening for lower extremity peripheral artery disease among their T2DM patients and 35% among those with cardiovascular disease. Conclusions: Physicians mostly follow the ESC/EASD 2013 guidelines, but when it comes to screening for additional conditions including coronary artery disease or peripheral artery disease, or intensifying the antithrombotic regimen there is need for better guidance. (C) 2022 Elsevier B.V. All rights reserved. Show less
In this thesis, I study 1) metabolic alterations in tuberculosis related to wasting syndrome in human patients as well as in rodent and fish animal models. 2) effects of the mutation of the leptin... Show moreIn this thesis, I study 1) metabolic alterations in tuberculosis related to wasting syndrome in human patients as well as in rodent and fish animal models. 2) effects of the mutation of the leptin gene on cachexia and diabetes in rodent and zebrafish animal models. 3) how tuberculosis infection and resulting metabolic reprogramming are dependent on leptin signaling in mice and zebrafish larvae. Show less
Kunneman, M.; Branda, M.E.; Ridgeway, J.L.; Tiedje, K.; May, C.R.; Linzer, M.; ... ; Shah, N.D. 2021
Purpose: To determine the effectiveness of a shared decision-making (SDM) tool versus guideline-informed usual care in translating evidence into primary care, and to explore how use of the tool... Show morePurpose: To determine the effectiveness of a shared decision-making (SDM) tool versus guideline-informed usual care in translating evidence into primary care, and to explore how use of the tool changed patient perspectives about diabetes medication decision making. Methods: In this mixed methods multicenter cluster randomized trial, we included patients with type 2 diabetes mellitus and their primary care clinicians. We compared usual care with or without a within-encounter SDM conversation aid. We assessed participant-reported decisions made and quality of SDM (knowledge, satisfaction, and decisional conflict), clinical outcomes, adherence, and observer-based patient involvement in decision-making (OPTION12-scale). We used semi-structured interviews with patients to understand their perspectives. Results: We enrolled 350 patients and 99 clinicians from 20 practices and interviewed 26 patients. Use of the conversation aid increased post-encounter patient knowledge (correct answers, 52% vs. 45%, p = 0.02) and clinician involvement of patients (Mean between-arm difference in OPTION12, 7.3 (95% CI 3, 12); p = 0.003). There were no between-arm differences in treatment choice, patient or clinician satisfaction, encounter length, medication adherence, or glycemic control. Qualitative analyses highlighted differences in how clinicians involved patients in decision making, with intervention patients noting how clinicians guided them through conversations using factors important to them. Conclusions: Using an SDM conversation aid improved patient knowledge and involvement in SDM without impacting treatment choice, encounter length, medication adherence or improved diabetes control in patients with type 2 diabetes. Future interventions may need to focus specifically on patients with signs of poor treatment fit. Show less
In chapters 2, 3 and 4, novel biomarkers IGFPB7, TIMP-2 and long noncoding RNAs were studied in order to find new diagnostic possibilities for early recognition and diagnosis of injury in native... Show moreIn chapters 2, 3 and 4, novel biomarkers IGFPB7, TIMP-2 and long noncoding RNAs were studied in order to find new diagnostic possibilities for early recognition and diagnosis of injury in native and transplanted kidneys. In chapter 2, diabetic nephropathy was found to be associated with higher levels of circulating TIMP-2, which did not normalize after simultaneous pancreas-kidney transplantation. In chapter 3, we found that four circulating long noncoding RNAs associated with diabetic nephropathy and did normalize after simultaneous pancreas-kidney transplantation. In chapter 4, acute rejection in kidney transplant recipients resulted in higher circulating LNC-EPHA6 levels. In chapter 5, clinical parameters and single antigen bead assay for measurement of donor specific antibodies were evaluated in the context of antibody-mediated rejection. Female recipients who received a kidney transplant from their spouse were especially at risk for acute antibody-mediated rejection and a single antigen bead assay is more sensitive to detect antibodies in this group than the standard diagnostic strategy. In chapter 6, mesenchymal stromal cell therapy is studied in a randomized controlled trial to evaluate the potential for prevention of acute rejection and fibrosis in transplanted kidneys. MSC therapy resulted in similar fibrosis scores and rejection rates. Show less
Background Leptin plays a critical role in the regulation of metabolic homeostasis. However, the molecular mechanism and cross talks between leptin and metabolic pathways leading to metabolic... Show moreBackground Leptin plays a critical role in the regulation of metabolic homeostasis. However, the molecular mechanism and cross talks between leptin and metabolic pathways leading to metabolic homeostasis across different species are not clear. This study aims to explore the effects of leptin in mice and zebrafish larvae by integration of metabolomics and transcriptomics. Different metabolomic approaches including mass spectrometry, nuclear magnetic resonance (NMR) and high-resolution magic-angle-spinning NMR spectrometry were used to investigate the metabolic changes caused by leptin deficiency in mutant ob/ob adult mice and lepb(-/-) zebrafish larvae. For transcriptome studies, deep RNA sequencing was used. Results Thirteen metabolites were identified as common biomarkers discriminating ob/ob mice and lepb(-/-) zebrafish larvae from their respective wild type controls: alanine, citrulline, ethanolamine, glutamine, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, putrescine, serine and threonine. Moreover, we also observed that glucose and lipid levels were increased in lepb(-/-) zebrafish larvae compared to the lepb(+/+) group. Deep sequencing showed that many genes involved in proteolysis and arachidonic acid metabolism were dysregulated in ob/ob mice heads and lepb mutant zebrafish larvae compared to their wild type controls, respectively. Conclusions Leptin deficiency leads to highly similar metabolic alterations in metabolites in both mice and zebrafish larvae. These metabolic changes show similar features as observed during progression of tuberculosis in human patients, mice and zebrafish larvae. In addition, by studying the transcriptome, we found similar changes in gene regulation related to proteolysis and arachidonic acid metabolism in these two different in vivo models. Show less
Heparanase is the predominant enzyme that cleaves heparan sulfate, the main polysaccharide in the extracellular matrix. While the role of heparanase in sustaining the pathology of autoimmune... Show moreHeparanase is the predominant enzyme that cleaves heparan sulfate, the main polysaccharide in the extracellular matrix. While the role of heparanase in sustaining the pathology of autoimmune diabetes is well documented, its association with metabolic syndrome/type 2 diabetes attracted less attention. Our research was undertaken to elucidate the significance of heparanase in impaired glucose metabolism in metabolic syndrome and early type 2 diabetes. Here, we report that heparanase exerts opposite effects in insulin-producing (i.e., islets) vs. insulin-target (i.e., skeletal muscle) compartments, sustaining or hampering proper regulation of glucose homeostasis depending on the site of action. We observed that the enzyme promotes macrophage infiltration into islets in a murine model of metabolic syndrome, and fosters beta-cell-damaging properties of macrophages activated in vitro by components of diabetogenic/obese milieu (i.e., fatty acids). On the other hand, in skeletal muscle (prototypic insulin-target tissue), heparanase is essential to ensure insulin sensitivity. Thus, despite a deleterious effect of heparanase on macrophage infiltration in islets, the enzyme appears to have beneficial role in glucose homeostasis in metabolic syndrome. The dichotomic action of the enzyme in the maintenance of glycemic control should be taken into account when considering heparanase-targeting strategies for the treatment of diabetes. Show less
Dit proeschrift beschrijft het ontstaan van ziekte in de kleine bloedvaatjes bij vrouwen en geeft een moleculaire uitleg van de synthese en het werkingsmechanisme van microRNAs (kleine RNA... Show moreDit proeschrift beschrijft het ontstaan van ziekte in de kleine bloedvaatjes bij vrouwen en geeft een moleculaire uitleg van de synthese en het werkingsmechanisme van microRNAs (kleine RNA moleculen die gen expressie reguleren) daarin. Specifieke aandacht wordt gegeven aan het mechanisme waarmee het vrouwelijk hormoon oestrogeen de functie van bloedvaatjes en het hart reguleert door een effect op deze miRs. Ook wordt de vraag beantwoord of expressie van miRs in plasma van vrouwen bruikbaar is als diagnostische marker voor ziekte van de kleine bloedvaatjes. Dit is onder andere aangetoond in een studie in vrouwen met boezemfibrilleren (een ritmestoornis in het hart). Ook is bestudeerd in transvrouwen (man-naar-vrouw transgenders) hoe oestrogeen toediening (voor de transitie operatie) een risico op het ontwikkelen van suiker ziekte. Specifieke microRNAs werden gevonden die hierin een doorslaggevende rol spelen. Deze microRNAs werden vervolgens in muizen geremd waardoor muizen een vorm van suikerziekte ontwikkelden. Show less
Cardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the... Show moreCardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the interplay between genetic factors and lifestyle factors (eg sleep, nutrition, physical activity) with diseases such as cardiovascular disease and risk factors for cardiovascular disease (diabetes). For example, 12 blood biomarkers associated with insulin resistance have been identified, 5 of which are specifically much higher in subjects with diabetes. In addition, it appeared that a short sleep duration and poor sleep quality are associated with poorer lipids in the blood (eg cholesterol and LDL) and more insulin resistance. With regard to sleep, 59 new genetic variants have also been identified with regard to blood lipids (HDL, LDL, triglycerides). In addition, the results indicate that a better lifestyle can also help reduce the development of new cardiovascular diseases in people with an increased genetic risk. This is particularly interesting to prevent diseases in persons at high risk. All in all, this thesis has provided new insights into the various factors that are potentially important in the development of cardiovascular disease and diabetes. Show less
Diabetes mellitus type 2 (DM) is a major risk factor for developing active tuberculosis (TB) disease, yet the causal mechanisms driving this association remain largely elusive. As the incidence of... Show moreDiabetes mellitus type 2 (DM) is a major risk factor for developing active tuberculosis (TB) disease, yet the causal mechanisms driving this association remain largely elusive. As the incidence of DM is rising, especially in TB endemic countries, it is important to identify the relevant immunological and metabolic processes that underlie TB-DM comorbidity, because such insights will facilitate optimal treatment, diagnosis and prevention. In this thesis, we have started to unravel key factors underlying the association between TBand DM using two approaches. Firstly, we identified and analyzed human macrophage subsets and studied the interactions between these human cells and a major pathogen, Mycobacterium tuberculosis (Mtb), and the specific metabolic changes involved using well-controlled in vitro systems. Next, we employed metabolomics to determine the impact of concurrent TB-DM on circulating metabolites in patient cohorts ex vivo. In this thesis we present evidence derived from in vitro experiments and from ex vivo observational data which collectively suggest a pathogenic role of atherogenic lipid species during TB development. Show less
Background: Peripheral arterial occlusive disease (PAOD) and chronic venous insufficiency (CVI) in organ transplant recipients (OTR) can lead to harmful outcomes. We made an inventory of cutaneous... Show moreBackground: Peripheral arterial occlusive disease (PAOD) and chronic venous insufficiency (CVI) in organ transplant recipients (OTR) can lead to harmful outcomes. We made an inventory of cutaneous manifestations of PAOD and CVI in OTR in relation with diabetes and other potential risk factors.Methods: A prospective study in a single center was performed. OTR (n = 112) were included at the outpatient clinic to investigate clinical signs of PAOD and CVI. The most commonly associated risk factors were determined.Results: PAOD had been diagnosed in 15.6% and CVI in 30.0% of the patients. Diabetes was the cause of organ failure in 9.8% of the patients. Type 1 diabetes had been diagnosed in 8.9% and type 2 diabetes in 21.4% (59.1% newonset diabetes alter transplantation). Type 1 diabetes showed an increased risk for PAOD and limb amputation with hazard ratios of 11.0 (95%CI 3.0-40.2) and 9.1 (95%CI 1.4-58.6). Type 2 diabetes showed no increased risk.Conclusions: Patients with a history of type 1 diabetes were at high risk for PAOD even years after a simultaneous pancreas kidney transplantation and they should remain under dose observation for PAOD even though they are supposedly "cured" from their diabetes to prevent a harmful outcome. (C) 2020 Elsevier Inc. All rights reserved. Show less
Huang, Z.L.; Lum, E.; Jimenez, G.; Semwal, M.; Sloot, P.; Car, J. 2019
BackgroundSmartphone apps are becoming increasingly popular for supporting diabetes self-management. A key aspect of diabetes self-management is appropriate medication-taking. This study aims to... Show moreBackgroundSmartphone apps are becoming increasingly popular for supporting diabetes self-management. A key aspect of diabetes self-management is appropriate medication-taking. This study aims to systematically assess and characterise the medication management features in diabetes self-management apps and their congruence with best-practice evidence-based criteria.MethodsThe Google Play and Apple app stores were searched in June 2018 using diabetes-related terms in the English language. Apps with both medication and blood glucose management features were downloaded and evaluated against assessment criteria derived from international medication management and diabetes guidelines.ResultsOur search yielded 3369 Android and 1799 iOS potentially relevant apps; of which, 143 apps (81 Android, 62 iOS) met inclusion criteria and were downloaded and assessed. Over half 58.0% (83/143) of the apps had a medication reminder feature; 16.8% (24/143) had a feature to review medication adherence; 39.9% (57/143) allowed entry of medication-taking instructions; 5.6% (8/143) provided information about medication; and 4.2% (6/143) displayed motivational messages to encourage medication-taking. Only two apps prompted users on the use of complementary medicine. Issues such as limited medication logging capacity, faulty reminder features, unclear medication adherence assessment, and visually distracting excessive advertising were observed during app assessments.ConclusionsA large proportion of diabetes self-management apps lacked features for enhancing medication adherence and safety. More emphasis should be given to the design of medication management features in diabetes apps to improve their alignment to evidence-based best practice. Show less
Deseive, S.; Straub, R.; Kupke, M.; Broersen, A.; Kitslaar, P.H.; Stocker, T.J.; ... ; Hausleiter, J. 2019
Background: To investigate the impact of diabetes on coronary artery total plaque volume (TPV) and adverse events in long-term follow-up.Methods: One-hundred-and-eight diabetic patients were... Show moreBackground: To investigate the impact of diabetes on coronary artery total plaque volume (TPV) and adverse events in long-term follow-up.Methods: One-hundred-and-eight diabetic patients were matched to 324 non-diabetic patients, with respect to age, sex, body-mass index, hypertension, smoking habits, LDL and HDL cholesterol, family history for CAD as well as aspirin and statin medication. In all patients, TPV was quantified from coronary CT angiographies (CTA) using dedicated software. All-cause mortality, acute coronary syndrome and late revascularisation ( > 90 days) served as combined endpoint.Results: Patients were followed for 5.6 years. The endpoint occurred in 18 (16.7%) diabetic and 26 (8.0%) nondiabetic patients (odds ratio 2.3, p = 0.03). Diabetic patients had significantly higher TPV than non-diabetic patients (55.1 mm 3 [IQR: 6.2 and 220.4 mm(3)] vs. 24.9 mm 3 [IQR: 0 and 166.7 mm(3)], p = 0.02). A TPV threshold of 110.5 mm(3) provided good separation of diabetic and non-diabetic patients at higher and lower risk for adverse events. Noteworthy, diabetic and non-diabetic patients with a TPV < 110.5 mm(3) had comparable outcome (hazard ratio: 1.3, p = 0.59), while diabetic patients with TPV > 110.5 mm(3) had significantly higher incidence of adverse events (hazard ratio 2.3, p = 0.03) compared to non-diabetic patients with TPV > 110.5 mm(3). There was incremental prognostic value in diabetic and non-diabetic patients over the Framingham Risk Score (Integrated Discrimination Improvement: 0.052 and 0.012, p for both < 0.05).Conclusion: Diabetes is associated with significantly higher TPV, which is independent of other CAD risk factors. Quantification of TPV improves the identification of diabetic patients at higher risk for future adverse events. Show less
Obesity, type 2 diabetes and cardiovascular diseases are major public health problems. South Asians are specifically at risk for the development of (cardio)metabolic diseases, due to a... Show moreObesity, type 2 diabetes and cardiovascular diseases are major public health problems. South Asians are specifically at risk for the development of (cardio)metabolic diseases, due to a combination of known and unknown risk factors. Since effective long-term treatment strategies are currently lacking, the search for additional risk factors and development of targeted treatment strategies to combat these (cardio)metabolic diseases is warranted. An attractive approach seems to be activation of energy-combusting brown adipose tissue (BAT), which can result in increased energy expenditure and improvement in glucose and lipid metabolism. In this thesis, we aimed to address two key objectives: 1) unravelling the underlying mechanisms that could explain the increased predisposition for metabolic disease in the South Asian population, and 2) identifying novel pharmacological strategies that activate BAT and increase energy expenditure in risk populations, including South Asians and individuals with overweight and prediabetes. The studies described in this thesis have highlighted some novel factors, such as endocannabinoids and angiopoitein-like-protein-4, that might in part explain to unbeneficial metabolic phenotype of South Asians. In addition, novel potential therapeutic strategies were identified to combat metabolic disease, such as treatment with a β3-adrenergic receptor agonist and a dipeptidyl-peptidase-4 inhibitor. Show less
Worldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of... Show moreWorldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of preventive and curative strategies for cardiometabolic disease is eagerly warranted. With the studies describes in this thesis, we aimed to disentangle the interwoven physiological, environmental and genetic factors that determine cholesterol and energy metabolism to increase our understanding of their contribution to cardiometabolic disease risk. The first part of this thesis focussed on the cholesteryl ester transfer protein (CETP). The lipid transfer properties of CETP induce a proatherogenic lipoprotein profile. Therefore, CETP inhibitory molecules have been developed and tested in clinical trials for their capability to improve the lipoprotein profile and reduce CVD risk. To fully understand the role of CETP in CVD, its physiology and biological function should be fully unravelled. The focus of the second part of this thesis was on the role of energy metabolism in cardiometabolic health. Specifically, we aimed to study the association of environmental and genetic factors, which were previously described to influence brown adipose tissue (BAT) activity, with energy expenditure and disease outcomes. Show less
The glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in diabetic kidney disease and beyond. In this... Show moreThe glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in diabetic kidney disease and beyond. In this thesis we studied structural and compositional changes of the endothelial glycocalyx upon diabetes in mice and in vitro. In glomerular capillaries, the endothelial glycocalyx contributes to the filtration barrier in the glomeruli. In diabetes the glycocalyx is damaged but can be restored via several pharmacological compounds that subsequently results in a shift from inflammatory towards anti-inflammatory macrophage function (chapter 2-3). In our model this appeared not to a result of changes in nitric oxide availability, affirming the potential overruling role for glomerular macrophages in glycocalyx degradation in diabetic nephropathy (chapter 4). Enzymatic cleavage of heparan sulfates reduced the total amount of luminal glycosaminoglycan content, but increased inflammatory heparan sulfate epitopes in vitro and in zebrafish (chapter 5). In chapter 6 we demonstrate that endothelial-specific loss of hyaluronan, another glycocalyx constituent, results in loss of endothelial barrier function. Overall, this thesis provides evidence that inhibition of glycocalyx degrading enzymes is a potent treatment option in diabetic nephropathy and other vascular diseases. Show less
