University of Groningen
Risk variables for the development of obesity and type 2 diabetes
van der Meer, Tom
DOI:
10.33612/diss.170143787
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2021
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van der Meer, T. (2021). Risk variables for the development of obesity and type 2 diabetes. University of
Groningen. https://doi.org/10.33612/diss.170143787
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General introduction and thesis outline
Chapter one
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Introduction
The rise of obesity and type 2 diabetes
Over the past decades, obesity has been rising at an alarming rate. Since 1975, the worldwide prevalence of obesity (having a body-mass index [BMI] of at least 30kg/ m2) has increased 3.4-fold to 10.8% in men, and 2.3-fold to 14.9% in women in 2014 (1).
According to the World Health Organisation (WHO), obesity is responsible for 2.8 million deaths each year (2). It causes changes in lipid metabolism, which lead to an increased risk for the development of cardiovascular diseases and type 2 diabetes (3). The close link between obesity and type 2 diabetes contributed to a fourfold increase in prevalence of type 2 diabetes during the same time period (4). Therefore, the WHO has included obesity and type 2 diabetes in its global action plan, with a target of halting the rise of type 2 diabetes and obesity at its 2010 level (5).
Energy balance and metabolism
The rise in obesity has been largely considered to be the consequence of a positive energy balance (3). On one hand the caloric intake through food and beverage consumptions has risen while on the other hand energy expenditure in the form of physical activity has decreased. Moreover, the amount of sedentary time has increased. This disbalance leads to a surplus of energy, which is stored as triglycerides in adipose tissue. A chronic energy surplus leads to an increase in adipose tissue and is defined as overweight (BMI > 25 kg/m2) or obesity.
Diabetes is characterized by elevated blood glucose concentrations, and is usually diagnosed based on a fasting plasma glucose concentration of at least 7.0 mmol/L (≥ 11.1 mmol/L when not fasted) (6). In type 2 diabetes, high blood glucose is caused by a combined effect of a (relative) deficiency of the hormone insulin and a resistance to its action. Insulin is produced by the
β
-cells in the pancreas and decreases blood glucose concentrations by promoting the uptake of glucose from the blood into tissue, suppressing the endogenous production of glucose by the liver, and suppressing the breakdown of fat (lipolysis) in adipocytes. When the biological effects of insulin are less than expected, one speaks of insulin resistance. In a physiological setting, the pancreas is able to react to insulin resistance by secreting a larger volume of the hormone. However, the progression of insulin resistance leads to increased blood concentrations of glucose and free fatty acids. These factors, together with genetic predisposition, (adiposity-induced) inflammation and adipocytokines in turn lead toβ
-cell dysfunction and the development of type 2 diabetes (7). In contrast to type 1 diabetes,β
-cells retain a small part of their function. Therefore, type 2 diabetes can be reversible. The development of type 2 diabetes has been associated with a multitude of different risk variables ranging from lifestyle variables, anthropometrics and biomarkers (8). Therefore, it has been labelled as a complex, multifactorial disease.Chapter 1
12
Endocrine disrupting chemicals
During the period that the incidence in obesity and type 2 diabetes exploded, a plethora of man-made substances have been introduced in our environment. Several of these chemical compounds have the potency to interact with the human hormonal system. These so-called endocrine disrupting chemicals (EDCs) include a large variety of different substances. Parabens, bisphenols and phthalates have in common that even though having lipophilic properties, they are quickly metabolized into more water-soluble chemicals. These chemicals in turn are easily excreted via the kidneys from the body. Due to their short half-lives of less than 24 hour, these chemicals are considered to be non-persistent (9–11). In contrast, persistent EDCs are often more resilient to metabolization, making it harder to excrete these chemicals. For example, polychlorinated biphenyls (PCBs) contain chlorine atoms, which make hydroxylation by the liver much harder and leads to half-live times of months to decades (12). As a result, PCBs are still widely detected in blood regardless of the fact that they have been banned in 1985 (13). Even though non-persistent EDCs are easily metabolized and excreted, their use in a wide variety of daily used consumer products has led to an ubiquitous exposure around the world (14–17). Yet, this makes it possible to effectively regulate exposure, which has been exemplified by changes in exposure over the past decades (16–18).
Figure 1. Potential risk variables for the development of obesity and type 2 diabetes. Obesity and type 2 diabetes have been associated with a wide range of biomarkers, anthropometrics, genetic predisposition, lifestyle determinants and exposure to environmental chemicals.
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Parabens have antimicrobial properties and are therefore used as preservatives in a large variety of personal care products (e.g. cosmetics, soap, loations), food products and medication. Bisphenols and phthalates function as plasticisers (i.e. promote flexibility and elasticity of products) and are used in a wide range of products including food and beverage packaging, toys, paper receipts, medical devices and medication. Routes of exposure depend on the application of the EDC and include ingestion, inhalation and transdermal application. Several studies have shown a clear link between some EDCs and food intake, while exposure to others appears to occur via other routes (19–21).
The hormonal system plays a central role in metabolism and uses hormones (i.e. messengers) which bind to receptors (i.e. receivers) to induce an effect. EDCs can influence this system by mimicking the actions of specific hormones, or by binding to their receptors while not initiating a response (i.e. competitive antagonism). Parabens are known for their estrogenic effects, and adverse effects on lipid metabolism have been described in vitro and in vivo (22,23). Bisphenol A is one of the most thoroughly investigated EDCs so far. It possesses both estrogenic and anti-androgenic properties (24,25), and exposure has been shown to cause metabolic abnormalities in vivo including an increase in insulin resistance and a reduction of overall energy metabolism (26,27). As the use of bisphenol A has been restricted by the European Union (28) and consumer awareness has grown, replacements such as bisphenol F and bisphenol S have been introduced. However, these analogues have been proven to hold an endocrine disrupting potential similar to bisphenol A (29). Phthalates possess anti-androgenic properties and have been shown to promote adipogenesis (30–33). In line with the obesogenic and diabetogenic potentials observed in experimental studies, a number of epidemiological studies have found significant associations between higher concentrations of endocrine disrupting chemicals and adverse metabolic effects. For example, being exposed to higher paraben concentrations was associated with a higher BMI (34), and exposure to higher levels of bisphenol A and
Figure 2. Chemical structure of hormones and endocrine disrupting chemicals. Natural hormones such as Estradiol are responsible for a wide range of physiological processes including energy metabolism. These processes can be influenced by endocrine disrupting chemicals such as bisphenol A. As bisphenol A mimics the hormonal effect of estradiol while not having a similar structure, it is labelled as a xeno-estrogen. Even though bisphenols and polychlorinated biphenyls have a similar structure, the chlorine atoms of biphenyls make it much harder for the human body to metabolize and excrete these chemicals. Bisphenol A, lacking these atoms, is easily metabolized and excreted and thus labelled as non-persistent, whereas polychlorinated biphenyl is a persistent endocrine disrupting chemical.
Chapter 1
14
phthalates was associated with weight gain over time (35,36). Moreover, higher exposure to parabens, bisphenols, and phthalates has been associated with the development of type 2 diabetes (37–39).
In humans, parabens, bisphenols and phthalates can be measured in different tissues. These EDCs have been detected in adipose tissue, general brain tissue, blood and urine. Yet, it remains unknown how organs who play a key role in our metabolism are exposed to these chemicals. For example, hunger and satiety are regulated by the hypothalamus, so local exposure specifically in this part of the brain could have effects throughout the entire body. As these EDCs are metabolised and excreted fairly quickly, their concentrations in the blood tend to vary over the day. Therefore, measurement of these chemicals in urine which has been collected over time (preferably 24 hour) makes for a reliable proxy of recent exposure (40–42).
Aims and thesis outline
The primary aim of Part I of this thesis was to quantify exposure to parabens, bisphenols and phthalates in the Dutch population and to determine whether these endocrine disruptors play a role in the development of obesity and type 2 diabetes.
As mentioned, the hypothalamus plays a central role in the regulation of several aspects of our metabolism. As it regulates food intake (e.g. hunger, satiety) and energy expenditure via circulating neuropeptide hormones, the blood-brain barrier is more permeable to allow for these hormones to pass (3). However, this makes the hypothalamus more susceptible for hormone-like chemicals as well. It has been shown that exposure to bisphenols increases hypothalamic neurogenesis in zebrafish (43). Although EDCs have been detected in human adipose tissue, liver and brain samples (44), it is unknown if they can permeate the hypothalamus, and if concentrations are higher compared to regular brain tissue. In Chapter 2 we investigated the potential of parabens and bisphenols to cross the blood-brain barrier into white matter tissue and hypothalamus tissue in normal weight and obese individuals.
As it is not possible to obtain human brain tissue to study effects of EDCs in live humans, we measured EDC concentrations in urine samples. In order to be able to measure a large amount of urine samples with high precision, we developed two high-throughput liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) methods for which we present the details of the development and interlaboratory validation in Chapter 3. These methods have been used by us to quantify the presence of parabens, bisphenols and phthalates in urine samples.
Although exposure to EDCs has been proven to be ubiquitous across the globe, very little is known about exposure in the Netherlands. So far, bisphenols and phthalates have primarily been quantified in pregnant women (45–47). Using our newly validated methods, we assessed the exposure of EDCs in a Dutch general population in Chapter 4. Further, we investigated cross-sectional associations with cardiometabolic traits while taking the well-known classical risk variables (i.e. caloric intake and physical activity) into account.
1
More persistent EDCs have been shown to be stored in adipose tissue and are released in response to weight loss, leading to higher circulating concentrations (48–50). In case of obesogenic chemicals, these higher concentrations could in turn stimulate weight gain. The concept of losing weight, which leads to higher exposures to obesogenic chemicals and in turn to weight gain has been labelled as the yo-yo effect. Parabens, bisphenols and phthalates are lipophilic compounds, and have been detected in adipose tissue. Yet, it is unknown whether weight loss (i.e. in which people lose a certain amount of adipose tissue) affects the exposure to these EDCs. In Chapter 5, we aimed to gain insights in the obesogenic effects of EDCs and their release from adipose tissue in a dynamic setting of weight loss. As weight loss was achieved by caloric restriction, we also attempted to elicit whether the source of EDC exposure was of a food-related nature.
In Chapter 6, we investigated the diabetogenic potential of EDCs by testing associations between EDCs and the 5-year development of type 2 diabetes. Using repeated measurements, we further investigated what the effect is on the associations between EDCs and type 2 diabetes when basing exposure to EDCs on measurements at one or both timepoints.
Exposure to EDCs has been shown to change over the years (16–18). Therefore, we elaborate on our previous findings in Chapter 7, in which we assessed the change in exposure to EDCs between 2009 and 2016. As previous studies have shown poor consistency of EDC measurements in spot urine over a range of multiple years (51,52), we additionally investigated between- and within-person temporal correlations of 24 hour urine samples in a pre-diabetic population.
To put our findings from the previous chapter in perspective, we broadened our vision in Part II to other risk variables for the development of type 2 diabetes. In Chapter 8 we used a data-driven approach to assess and contextualize associations between a large set of 134 potential risk variables and the development of type 2 diabetes. As these risk variables have led to over a hundred different prediction models (53,54), we subsequently untangled risk prediction for the development of type 2 diabetes by assessing robustness, unique risk prediction and effect size stability. In Chapter 9, we provided a general discussion to elaborate on the findings of the previous chapters and point out future perspectives. Chapter 10 contains appendices, including a Dutch summary, acknowledgments, a section about the author, and a list of publications.
Chapter 1
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