Background and aim: Non-alcoholic fatty liver disease (NAFLD) is defined as a liver fat content >= 5.56%. It is of clinical interest to know the prevalence of NAFLD in people with a combination... Show moreBackground and aim: Non-alcoholic fatty liver disease (NAFLD) is defined as a liver fat content >= 5.56%. It is of clinical interest to know the prevalence of NAFLD in people with a combination of metabolic risk factors. We aimed to examine the prevalence of NAFLD, including groups with metabolic risk factors.Methods and results: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity (NEO) study, liver fat content was assessed using proton magnetic resonance spectroscopy (H-MRS). Participants with excessive alcohol consumption or missing values were excluded, leaving a total of 1570 participants for the analyses. Mean (SD) age of the population was 55 years, BMI 25.9 (4.0) kg/m(2) and 46% were men. The prevalence of NAFLD was 27% (95% CI 24-30). The prevalence of NAFLD was increased in participants with hypertriglyceridemia (57%, 52-63), obesity (62%, 58-66) and diabetes (69%, 61-77). The prevalence of NAFLD was highest in those with diabetes and obesity (79%, 71-87), obesity and hypertriglyceridemia (81%, 76-86) and with diabetes and hypertriglyceridemia (86%, 77-95). NAFLD was also present in 12% (8-16) of participants without overweight.Conclusions: The prevalence of NAFLD in a middle-aged population in the Netherlands in 2010 was 27%. The prevalence of NAFLD is particularly increased in individuals with diabetes, obesity, and hypertriglyceridemia. This information may help clinicians and general practitioners in the risk stratification of their patients in daily practice.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
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
This review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and... Show moreThis review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and autoimmunity. Multiple therapeutic approaches using existing pharmaceuticals are possible from a rationale in which T cell metabolism forms the hub in dampening the T cell component of autoimmunity in metabolic diseases. Future research into the effects of a metabolically aberrant micro-environment on T cell metabolism and its potential as a therapeutic target for immunomodulation could lead to novel treatment strategies for metabolic disease-associated autoimmunity. Show less
This review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and... Show moreThis review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and autoimmunity. Multiple therapeutic approaches using existing pharmaceuticals are possible from a rationale in which T cell metabolism forms the hub in dampening the T cell component of autoimmunity in metabolic diseases. Future research into the effects of a metabolically aberrant micro-environment on T cell metabolism and its potential as a therapeutic target for immunomodulation could lead to novel treatment strategies for metabolic disease-associated autoimmunity. Show less
This review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and... Show moreThis review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and autoimmunity. Multiple therapeutic approaches using existing pharmaceuticals are possible from a rationale in which T cell metabolism forms the hub in dampening the T cell component of autoimmunity in metabolic diseases. Future research into the effects of a metabolically aberrant micro-environment on T cell metabolism and its potential as a therapeutic target for immunomodulation could lead to novel treatment strategies for metabolic disease-associated autoimmunity. Show less
This review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and autoim...Show moreThis review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and autoimmunity. Multiple therapeutic approaches using existing pharmaceuticals are possible from a rationale in which T cell metabolism forms the hub in dampening the T cell component of autoimmunity in metabolic diseases. Future research into the effects of a metabolically aberrant micro-environment on T cell metabolism and its potential as a therapeutic target for immunomodulation could lead to novel treatment strategies for metabolic disease-associated autoimmunity. Show less
This review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and... Show moreThis review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and autoimmunity. Multiple therapeutic approaches using existing pharmaceuticals are possible from a rationale in which T cell metabolism forms the hub in dampening the T cell component of autoimmunity in metabolic diseases. Future research into the effects of a metabolically aberrant micro-environment on T cell metabolism and its potential as a therapeutic target for immunomodulation could lead to novel treatment strategies for metabolic disease-associated autoimmunity. Show less
Obesity is characterized by excessive fat storage and is associated with various diseases like cardiovascular disease (CVD) and type 2 diabetes (DM2), thereby being a serious problem of public... Show moreObesity is characterized by excessive fat storage and is associated with various diseases like cardiovascular disease (CVD) and type 2 diabetes (DM2), thereby being a serious problem of public health. Excessive energy intake is an important cause of obesity since excess energy is primarily stored as fat. The stored fat is mobilized again during fasting in the form of fatty acids (FA). These FA are re-esterified in the liver in triglycerides (TG) that are secreted in VLDL particles to deliver FA to peripheral tissues where they can be used for energy. One of the current views of the cause of diseases related to obesity is the (mis)handling of TG derived FA. Therefore it is important to understand pathways involved in the uptake, distribution, oxidation and storage of TG. In this thesis we have evaluated the effect of different interventions on VLDL-TG metabolism to gain a better understanding of its complex regulation. For these studies we used APOE*3-Leiden (E3L) and E3L.CETP transgenic mice that have a human-like lipoprotein metabolism and respond to lipid-modifying drugs in a ways similar to humans. 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
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
The scope of the current thesis is to obtain insight in immunological aspects of transplantation and diabetes. This thesis underscores the current concept of collaboration between the innate and... Show moreThe scope of the current thesis is to obtain insight in immunological aspects of transplantation and diabetes. This thesis underscores the current concept of collaboration between the innate and adaptive immune system by showing close interactions between both immune systems. Mannose binding lectin as a major recognition molecule of the lectin pathway and as a key protein of the immune system was studied in relation to its functional characteristics. Appreciating the Jekyll-and-Hyde character of MBL and the fact that MBL serum levels and functionality are under strict genetic control, MBL was studied under distinct pathological conditions. Chapter 2 describes molecular and biological aspects of mannose binding lectin and the interaction of MBL with the adaptive immune system. Chapter 3 focuses on the involvement of MBL in autoimmunity, by studying juvenile type 1 diabetic patients at disease onset. Chapter 4 addresses the role of the liver in production of serum MBL and evaluates the effect of MBL variant alleles on the susceptibility to infection after liver transplantation. Chapter 5 focuses on the effect of the adaptive immune system on islet transplantation, a novel treatment of type 1 diabetes. Show less
Buitinga, M.; Assen, F.; Hanegraaf, M.; Wieringa, P.; Hilderink, J.; Moroni, L.; ... ; Apeldoorn, A. van 2017
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
Pancreatic islet transplantation by a new method is introduced here : the isolation of islets in an organ preservation solution, the University of Wisconsin solution. A new concept allowing for the... Show morePancreatic islet transplantation by a new method is introduced here : the isolation of islets in an organ preservation solution, the University of Wisconsin solution. A new concept allowing for the first time large-scale isolation and transplantation of consistently near 100% pure islets of Langerhans in a preclinical dog model with fasting normoglycemia up to 3 years posttransplant. Detailed metabolic studies demonstrated normal insulin levels after meals with preservation of gut hormone action stimulating insulin secretion at the mild hyperglycemia after meals. The introduction of the University of Wisconsin solution organ preservation solution for islet isolation at the start of these studies in 1989 is a new concept … and has been shown by now in 2022 , world-wide , to make the future of islet isolation and transplantation methods for insulin-dependent diabetes mellitus (IDDM). Show less
The studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN... Show moreThe studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN output, can contribute to the development of insulin resistance. We also shown that insulin-stimulated glucose uptake by muscle and insulin-stimulated FA uptake by WAT is in part dependent on insulin action in the brain. These effects of circulating insulin on peripheral organs via the brain are abrogated by high-fat diet. These brain-dependent effects of insulin could reflect a similar situation for other hormones, for instance thyroid hormones. Furthermore, we demonstrate that topiramate improves insulin resistance by restoring insulin sensitivity in the brain, suggesting that therapeutical targets in the brain may offer challenging new approaches to treat insulin resistance of peripheral organs in T2DM. 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
The worldwide prevalence of obesity is steadily increasing. Obesity leads to insulin resistance and atherosclerosis, which are the pathologies underlying type 2 diabetes and cardiovascular disease,... Show moreThe worldwide prevalence of obesity is steadily increasing. Obesity leads to insulin resistance and atherosclerosis, which are the pathologies underlying type 2 diabetes and cardiovascular disease, respectively. Inflammation is an important factor connecting obesity to these disorders, but the exact mechanisms connecting obesity, the immune system, type 2 diabetes and cardiovascular disease are still under investigation. The research described in this thesis was performed 1) to gain more insight into the role of the immune system in obesity, dyslipidemia, insulin resistance and atherosclerosis, 2) to study whether inflammation contributes to the disadvantageous metabolic phenotype of a human population with a particularly high risk to develop type 2 diabetes and cardiovascular disease, and 3) to study the therapeutic potential of decreasing inflammation by pharmacological strategies to reduce obesity and improve glucose and lipid metabolism in pre-clinical models. The studies described in this thesis have increased our understanding of the role of inflammation in adipose tissue function and lipid metabolism during the development of type 2 diabetes and cardiovascular disease. Moreover, novel potential therapeutic strategies were identified to combat obesity, metabolic inflammation and associated metabolic disorders, such as treatment with interferons, salsalate and GPR120 agonists. Show less
