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
Rapid socio-economic growth accelerates urbanization in Indonesia, which changes many aspect of human lives, and potentially affect disease prevalence and outcome. This thesis aims to investigate... Show moreRapid socio-economic growth accelerates urbanization in Indonesia, which changes many aspect of human lives, and potentially affect disease prevalence and outcome. This thesis aims to investigate the impacts of urbanization on human health, especially metabolic health and allergic disease, by incorporating many aspects of scientific investigation. Our cluster-randomized-controlled trial showed that, helminth infection, a characteristic feature of rural areas, and anthelmintic treatment, could significantly affect metabolic profiles and hormones. Thus, the ongoing deworming program in Indonesia require in parallel, monitoring of the metabolic health. Additionally, based on our prospective cohort study and analysis on a large scale nationally representative data, although Indonesian rural populations have relatively better metabolic profiles compared to urban, lifelong residence in rural areas does not protect their community members from adverse metabolic changes due to urbanization. Next, we observed that majority of individuals with diabetes in Indonesia were undiagnosed and untreated, especially in rural populations, which warrants extensive action plan from all related stakeholders. Lastly, high-dimensional data analyses on the systemic and nasal mucosal immune profiles revealed a stronger inflammatory immune responses in the nasal mucosal of Indonesian urban young adults with allergic rhinitis compared to their rural counterparts. Show less
Bone morphogenetic protein (BMP)-9, a member of the TGF beta-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly... Show moreBone morphogenetic protein (BMP)-9, a member of the TGF beta-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context.We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO-and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients' samples.In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplemen-tation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis. 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
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
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
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 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
The prevalence of obesity, defined as a body mass index (BMI) > 30 kg/m2, is increasing to epidemic proportions. In 2014, 11% of men and 15% of women worldwide were obese. Thus, more than... Show moreThe prevalence of obesity, defined as a body mass index (BMI) > 30 kg/m2, is increasing to epidemic proportions. In 2014, 11% of men and 15% of women worldwide were obese. Thus, more than half a billion adults worldwide are classed as obese. The fundamental cause of obesity is an imbalance between energy intake (excessive intake of energy-dense foods) and energy expenditure (reduced physical activity). People with obesity are at risk for a range of chronic conditions including cardiovascular disease (CVD) and nonalcoholic fatty liver disease (NAFLD). Furthermore, obesity is a major risk factor for the development of type 2 diabetes, which is one of the most common chronic diseases in nearly all countries. According to the World Health Organization, the global prevalence of diabetes in 2014 was estimated to be 9%, of which 90% was comprised of type 2 diabetes. This thesis focuses on cardiovascular and cerebral dimensions and function in people with obesity and type 2 diabetes. State-of-the-art imaging techniques are used to investigate links between the heart, liver, abdominal fat, and brain to elucidate parts of the complex relationships between these organs. Show less
In modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the... Show moreIn modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the circadian system in mice and in humans. Circadian rhythms are orchestrated by ~20,000 neurons in the central clock in the suprachiasmatic nuclei (SCN) in the brain. In mice, a complete abolishment of central clock-driven rhythms resulted in obesity and severe hepatic insulin resistance. An attenuation of rhythms resulted in decreased muscle strength, osteoporosis-like bone changes and transient changes in the immune system. In humans, short sleeping obese individuals with a preference for evening activities ("evening chronotypes") had increased cardiovascular risk factors. Their neurocognitive function was often impaired and could be improved with sleep extension. Insufficient sleep was also associated with an increased risk for osteopenia and sarcopenia. Taken together, disrupted circadian rhythms and insufficient sleep associate with a spectrum of unfavorable health outcomes. Studies described in the thesis provide insight in potential strategies to improve rhythms and sleep: by appropriately timed behavior (active behavior during the active phase; rest during the rest phase), light exposure (light during the subjective day; darkness at night) as well as caffeine intake. Show less
In this thesis, we evaluated the acute and more long-term effects of different weight loss strategies; pure calorie restriction by very low calorie diet and gastric banding, versus the drastic... Show moreIn this thesis, we evaluated the acute and more long-term effects of different weight loss strategies; pure calorie restriction by very low calorie diet and gastric banding, versus the drastic surgical procedure Roux-en-Y gastric bypass. Moreover, we found differences between NGT and T2DM subjects at baseline, which enable us to better be able to dissect the subsequent effects of the procedures. To our surprise, and in contrast to previous studies, we observed no additional effect of the RYGB as compared to calorie restriction, on our main outcome parameters: postprandial glucose, insulin and the gut peptide levels three weeks after surgery. Furthermore, both restrictive and RYGB induced weight loss resulted in comparable effects on the lipidome, circulating thyroid hormone levels and the autonomic nervous system. For these outcome parameters, it seems that calorie restriction is the common denominator of the effect of the different weight loss strategies on the short term. Clearly distinct effects of RYGB, however, were seen on bile salt, FGF21 and glucagon levels in response to food intake. Although neither the exact mechanisms, nor the eventual metabolic effect are as yet clear, the gut-liver-pancreas axis may be an important mediator of the effect of the RYGB Show less
Mutsert, R. de; Heijer, M. den; Rabelink, T.J.; Smit, J.W.A.; Romijn, J.A.; Jukema, J.W.; ... ; Rosendaal, F.R. 2013
The introduction of systems biology in combination with the profiling of numerous biochemical components (e.g. lipid metabolites, herbal products) enables the study of living systems from a... Show moreThe introduction of systems biology in combination with the profiling of numerous biochemical components (e.g. lipid metabolites, herbal products) enables the study of living systems from a holistic perspective. In this thesis we explored systems biology-based platforms to investigate the therapeutic effects of chemical drugs and herbal medicines on animal models with high-fat diet-induced obesity and genetic manipulated diabetes. The aim of the work was to better understand the working mechanisms of both treatments on metabolic syndrome from a holistic point of view and to evaluate the potentials of __omics__ technologies to this effort. Our results showed that lipidomics approach with appropriate bioinformatics tools are essential to describe the global, dynamic metabolic response of living systems, e.g. from homeostasis via sub-optimal health and ultimately to dysfunction. These studies pointed hints to disco ver lipid biomarkers in relation to health promotion and disease prevention and facilitated the understanding of the complex regulatory mechanisms in humans or animals. Particularly, the introduction of the systems biology view will not only provide in-depth insights into the multi-target synergetic effects (which have hardly been used in modern drug discovery) but also can bridge Chinese Medicine (multi-target therapy) and Western Medicine (molecular pharmacology). Show less
Overgewicht en obesitas kunnen leiden tot insulineresistentie (type 2 diabetes mellitus) en hyperlipidemie, een risicofactor voor atherosclerose (aderverkalking). Obesitas gaat ook gepaard met de... Show moreOvergewicht en obesitas kunnen leiden tot insulineresistentie (type 2 diabetes mellitus) en hyperlipidemie, een risicofactor voor atherosclerose (aderverkalking). Obesitas gaat ook gepaard met de ontwikkeling van een chronische ontsteking in vetweefsel en lever. Met dit promotieonderzoek laten we met behulp van onderzoek in muizen zien dat ontsteking een belangrijke rol speelt in het metabolisme en transport van vetten. We bekijken ook welk effect dit heeft op de ontwikkeling van atherosclerose en type 2 diabetes. In het eerste deel van dit promotieonderzoek laten we zien dat ontsteking een belangrijke rol speelt in vetmetabolisme en atherosclerose. De ontstekingsremmer aspirine zorgde voor een verlaging van de hoeveelheid vet in het bloed. Activatie van een onsteking in de lever leidde juist tot een verhoging van vet in het bloed, wat de ontwikkeling van atherosclerose in de vaatwand verergerde. In het tweede deel van dit promotieonderzoek bestuderen we het belang van het inflammasoom/caspase-1 complex (betrokken bij ontstekingsprocessen) in obesitas, insulineresistentie en vetmetabolisme. We laten zien dat muizen die een deel van dit eiwit-complex missen, beschermt zijn tegen de ontwikkeling van obesitas en insulineresistentie. Het inflammasoom/caspase-1 complex lijkt daarmee een potentieel target voor de behandeling van obesitas, insulineresistentie en type 2 diabetes. Show less
Nowadays, obesity has reached epidemic proportions globally. It can lead to several chronic diseases, including insulin resistance/type 2 diabetes mellitus. Feeding behaviour is regulated in the... Show moreNowadays, obesity has reached epidemic proportions globally. It can lead to several chronic diseases, including insulin resistance/type 2 diabetes mellitus. Feeding behaviour is regulated in the hypothalamus of the brain by two opposing pathways: NPY/AgRP neurons vs. POMC/CART neurons. In addition, there are numerous peripheral signals, deriving from stomach, gut, pancreas and adipose tissue, that act on the hypothalamus and thereby contribute to the regulation of food intake. The aim of the studies we have performed, was to investigate the effects of some of these neuropeptides and peripheral signals that affect these neuropeptides, on insulin action. Our experiments showed, that NPY can cause insulin resistance, specifically in the liver. The POMC pathway can improve insulin-mediated glucose disposal and does not affect hepatic insulin sensitivity. Therefore, both pathways are not completely opposing each other’s effects, but seem to have a different tissue-specific effect. Experiments with gut hormones like PYY and ghrelin showed that these hormones affect insulin sensitivity as well. Also leptin, and specifically leptin signalling in the brain, was found to be important for insulin sensitivity. In conclusion, this work showed that neuropeptides/hormones that are involved in the regulation of food intake also affect insulin sensitivity. Show less
