Links Between Epigenetics and Diabetes/Obesity
The debate is not genes versus the environment anymore. Now, we wonder how the environment can affect how genes control the function of cells (gene expression). Some environmental exposures can affect gene expression through epigenetic or other processes. Epigenetic processes may be involved in the development of diabetes and obesity. The possibility that these changes can be passed down from one generation to the next has profound implications. How to reverse epigenetic changes is an important ongoing area of research.
Gene Expression: Turning Genes On and Off
Genes are not only responsible for static, inherited characteristics such as eye color; they also guide how cells function throughout life. Genes carry the instructions that our cells use for making proteins, and it is these proteins that carry out most of the functions of the cell. Every cell in our bodies contain the same genes, yet these cells may have vastly different functions. For example, the beta cells in the pancreas make the protein hormone insulin (at least, in people who do not have type 1 diabetes); cells called lymphocytes make antibodies; nerve cells carry nerve signals. These differing functions depend on which genes are "switched on" in that cell type. The cell's job, based on that switching on or off, is called "gene expression." Cells differ, then, not because they contain different genes (they don't), but because they express genes differently. Whether a gene is switched on or off can depend on the type of cell, its surroundings, its age, and external signals.
For example, a pancreatic beta cell senses glucose in the blood, which triggers it to produce the protein insulin. The gene that codes for insulin is activated (expressed), and it produces insulin. The beta cell then releases insulin into the blood stream.
This diagram shows two major kinds of epigenetic modifications, DNA methylation (top left) and histone modifications (bottom and bottom right).
Here's the technical explanation: "DNA methylation involves the transfer of a methyl group from S-adenosylhomocysteine to the 5´ position of the cytosine ring, most often on cytosines followed by guanines in the DNA sequence. This results in the formation of 5-methylcytosine. Histone modifications are another major type of epigenetic modification, and involve the post-translational transfer of, for example, methyl, acetyl, ubiquitin, or phosphate groups to specific amino acid residues on the N-terminal tail of the histone proteins. The N-terminal tails protrude from the center of the nucleosome core (shown on right) and are accessible for these types of modifications. A linker histone (H1) is bound to DNA outside the nucleosome and is thought to help keep the DNA correctly positioned in relation to the nucleosome core." Got that?
Source: Breton et al. 2017, EHP.
Epigenetics: Gene "Packaging"
Each person's DNA sequence differs slightly from other people's. DNA sequence can affect gene expression and gene function, and contribute to a person's susceptibility to various diseases. Changes in gene expression can result from changes to the DNA sequence (mutations are one example of changes to DNA sequence).
Changes in gene expression can also result from epigenetic changes, which are changes in gene function that do not involve changes to the DNA sequence. These changes involve alterations in how the DNA is "packaged" in our cells (Hewagama and Richardson 2009). How genes are wrapped up and packaged can help determine whether or not they can be turned on (expressed) and produce their proteins. In other words, epigenetic changes can lead to changes in gene expression.
There are different types of epigenetic changes, including histone modifications, DNA methylation, and changes to mitochondrial DNA. Exposure to various environmental factors can influence all of these.
Genes AND the Environment
It's not genes VERSUS the environment anymore; it is how they interact. Epigenetics involves interactions between genes and the environment; it looks at how the environment can affect genes, turning them on or off. It also looks at how the environment affects development. As an individual develops from an embryo into an adult, genes guide this development. If genes are changed via epigenetics in early development, these changes can be permanent-- they can be passed down as a cell divides. Epigenetic change in adults tend to be more transient.
Health and disease are determined by interactions between our genes and the environment. Researchers are looking into how environmental factors can affect how genes guide the function of cells, and how this process can lead to disease. What about diabetes? What role does epigenetics play in diabetes? Throughout life, environmental factors can interact with genetic factors via epigenetics to influence the risk of various types of diabetes (Tremblay and Hamet, 2019).
Type 2 Diabetes and Obesity
We already know which genes are associated with type 2 diabetes; now scientists are figuring out that epigenetic changes of these genes are also important for type 2 diabetes. Epigenetic changes are associated with diabetes-related measurements (Kriebel et al. 2016). These changes may even be able to help predict who will go on to develop type 2 diabetes (Toperoff et al. 2012). One factor linked to epigenetics is microRNAs, and these in turn are linked to the development of diabetes via insulin resistance and/or beta cell function (Feng et al. 2016). DNA methylation is another epigenetic change linked to type 2 diabetes development (Ahmed et al. 2020). Kim and Kulkarni (2020) review the epigenetic changes linked to the adaptation of beta cells to insulin resistance in type 2 diabetes.
Exposures to various environmental factors during early life development can play a role in the later development of type 2 diabetes, involving epigenetic mechanisms. There is substantial evidence that a variety of environmental factors, including exposure to environmental chemicals, may impair fetal development, thereby leading to adipose tissue and pancreatic beta cell dysfunction, contributing to later diabetes (reviewed by Fernandez-Twinn et al. 2019; Vaiserman and Lushchak, 2019).
Epigenetic changes may help to explain why identical twins do not always get the same disease. For example, differing epigenetic patterns have been found in identical twins where one has type 2 diabetes and the other does not. These changes were associated with glucose tolerance (Bork-Jensen et al. 2015).
When fathers have pre-diabetes, there are changes in their sperm that give their children an increased risk of diabetes. There are also changes in their sperm that may be transmitted for two generations (Wei et al. 2015). Epigenetic changes in the mothers may play a role as well (Ge et al. 2014).
Epigenetics may help to explain some curious findings relating to type 2 diabetes. Children who suffered through the Dutch famine of 1944-5 grew up to have an increased risk of type 2 diabetes later in life (van Abeelen et al. 2012). If mothers experienced the famine while pregnant, their offspring show impaired insulin secretion and lower glucose tolerance in their 50s (de Rooij et al. 2006a; de Rooij et al. 2006b; Ravelli et al. 1998). It is likely that epigenetics play a role in this pattern. Persistent epigenetic changes have been found in those who were in the womb during the famine, as compared to their siblings who were not (Heijmans et al. 2008).
Laboratory studies in animals also show epigenetic changes that precede type 2 diabetes (Ouni et al. 2020).
There are a lot of environmental factors linked to obesity, including diet, the built environment, socio-economic factors, and many more. Obesity-associated genes may interact with these various factors via epigenetic mechanisms (Nicolaidis, 2019). Some of the environmental exposures that are linked to epigenetic changes that may contribute to obesity include nutrition, gut microbiota, and chemical exposures (Lopomo et al. 2016). Impaired fat cell function due to environmental factors can lead to epigenetic changes linked to obesity and metabolic syndrome (Pant et al. 2021).
In animals, the mother's diet during gestation helps to determine the metabolism of the offspring later in life. The offspring may be more likely to be obese, for example, as well as have epigenetic changes in their genes that control metabolism. A study in humans has found that a substantial portion (over 25%) of a person's metabolic disease risk (obesity and type 2 diabetes are metabolic diseases) can be predicted by the prenatal environment, and associated with certain epigenetic changes (Godfrey et al. 2011). Epigenetic patterns are also associated with childhood obesity, including from the prenatal/birth period (Relton et al. 2012; Lillycrop et al. 2017), and early childhood (Clarke-Harris et al. 2014). Early life exposure to chemicals are linked to obesity and metabolic syndrome in adulthood as well, via epigenetic changes (Almeida et al. 2019).
A large study found that body mass index was linked to epigenetic changes in the blood and fatty tissue of Europeans (Dick et al. 2014). For an article about this study and related research, see Epigenomics starts to make its mark, published by Nature (Callaway, 2014).
In general obesity is linked to a number of diseases of the pancreas (in addition to diabetes), such as pancreatitis and pancreatic cancer. The environmental chemicals that accumulate in fatty tissue play a role in these diseases, via mechanisms involving epigenetics (Di Ciaula and Portincasa 2014).
Type 1 Diabetes
What might epigenetic processes have to do with type 1 diabetes? Epigenetic changes of many types are associated with changes in gene expression and the development of type 1 diabetes, supporting the role of epigenetics in type 1 diabetes development (Dang et al. 2013; Bansal and Pinney 2017; Esposito et al. 2019; Jerram et al. 2017; Johnson et al. 2020; Luo et al. 2020; Miao et al. 2018; Miao et al. 2012; Paul et al. 2016; Rakyan et al. 2011; Scherm et al. 2019; Scherm and Daniel 2020; Snowhite et al. 2017; Stankov et al. 2013; Stefan et al. 2014; Syed et al. 2020; Taheri et al. 2020; Wang et al. 2017; Xie et al. 2020; Zhang et al. 2021; Zullo et al. 2017). Epigenetic changes have been found in adults with type 1 diabetes as well (Li et al. 2011). And epigenetic changes induced by maternal factors during pregnancy may affect the risk of type 1 diabetes in the offspring (reviewed by Barchetta et al. 2021). Using epigenetic changes, researchers have been able to prevent and cure diabetes in non-obese diabetic (NOD) mice (Jayaraman et al. 2013).
We know that certain genes either increase or decrease the risk of type 1 diabetes. Certain HLA genes, for example, are often associated with an increased risk. The function of these HLA genes relates to the immune system. Meanwhile, a variety of epigenetic processes may play a role in type 1 diabetes development by controlling the expression/function of these genes, and thereby affecting the immune system attack on the beta cells (Xie et al. 2014). Epigenetic differences may also help explain why genetically identical twins do not always both develop type 1 diabetes (Xiang et al. 2017; Giwa et al. 2020).
There is evidence that environmental factors can modify the immune system via epigenetic mechanisms to cause other autoimmune diseases as well. This evidence raises the possibility that epigenetic processes may also contribute to the development of type 1 diabetes and other autoimmune diseases via their effects on autoimmunity (Chen et al. 2017; Greer and McCombe, 2012; Hewagama and Richardson 2009; Javierre et al. 2011; Nielsen and Tost, 2013; Picascia et al. 2015; Wang et al. 2017; Wu et al. 2019; Wu et al. 2018; Zhang et al. 2020). Regarding immune system diseases, "Genetics loads the gun and epigenetics pulls the trigger." (Bellanti, 2019). Exposure to various environmental chemicals during development can affect the immune system and promote autoimmunity later in life (Blossom and Gilbert, 2018).
MacFarlane et al. (2009) propose a number of possible ways that epigenetic processes could influence the development of type 1 diabetes. For example, epigenetic mechanisms can influence not only the immune system, but also beta cell development, maintenance, and regeneration. Planas et al. (2010) discuss gene expression changes in type 1 diabetes. In the pancreas, there is overexpression of inflammatory immune response genes. There is some consistency of gene expression changes in people with various autoimmune diseases; these changes largely affect the immune system these diseases, affecting differing target organs (the target organ in type 1 is the pancreas).
In fact, drugs that modify epigenetics in a positive manner can stop the development of type 1 diabetes in mice, reduce inflammation, and promote beta cell regeneration (Fu et al. 2014).
Also, researchers are identifying epigenetic markers that can be used to help identify people at high risk of developing type 1 diabetes (Erener et al. 2017). Or, to help identify levels of beta cell death (Zhang et al. 2017).
Beta Cell Function
Epigenetic changes are also linked to residual beta cell function and better blood sugar control in people newly diagnosed with type 1 diabetes (Neilsen et al. 2012; Samandari et al. 2017). There is debate and research ongoing about how exactly epigenetic factors affect beta cells (e.g., Eliasson 2017; Sims et al. 2017). For example, epigenetic mechanisms play a role in how the pancreas and beta cells develop and function (Astro and Adamo, 2018; Coskun et al. 2018; Xu et al. 2020).
Gestational diabetes is believed to be a result of interactions between genetic, epigenetic, and environmental factors. Complex genetic and epigenetic mechanisms can contribute to the development of gestational diabetes (reviewed by Rosik et al. 2019, also see Zhu et al. 2020). Epigenetic changes caused by endocrine disrupting chemicals are likely involved in the development of gestational diabetes (reviewed by Kunysz et al. 2021).
Diabetes Management and Complications
Epigenetic mechanisms also likely play a role in the development of complications from diabetes (Gastoł et al. 2020; Rodriguez and El-Osta 2018; Wu and Miller 2017). High blood sugar (as well as inflammation and other factors) can cause epigenetic changes that result in the expression of numerous genes relating to inflammation, clearance of oxidative stress, and other effects associated with various diabetes complications (Agardh et al. 2015; Chen et al. 2016; Karachanak-Yankova et al. 2016; Reddy et al. 2015; Wegner et al. 2014). Epigenetic changes have been associated with various diabetes complications, including kidney disease (Caramori et al. 2015) and retinopathy (Kowlulu 2017). In fact, we may be able to use epigenetic markers to predict the development of complications in people with diabetes (e.g., Argyropoulos et al. 2015).
Do Epigenetic Changes Affect the Endocrine System?
Yes. Epigenetic processes can control hormone production and release, blood and tissue levels of hormones, and response to hormones. Zhang and Ho (2011) have written a review of this topic. Hormones can also cause epigenetic changes, as endocrine disrupting chemicals do as well (Alavian-Ghavanini and Rüegg 2018).
Environmental Factors That Can Affect Gene Expression
Exposing a fetus, infant, or child to a chemical or nutritional (or other) stressor during development can affect the risk of disease development even into adulthood. The mechanisms involved are probably epigenetics (Boekelheide et al. 2012). For example, if a mother has impaired glucose tolerance during pregnancy, her offspring show epigenetic changes related to growth (Desgagné et al. 2014). A number of environmental exposures can affect epigenetics, including (but not limited to) obesity, physical activity, under or over nutrition, stress, and toxic chemicals (Barrès and Zierath, 2016). High glucose levels can also lead to epigenetic changes, and thereby damage beta cells (Lin et al. 2017).
Scientists have shown that many chemical exposures can lead to epigenetic changes. They have also found similar or the same epigenetic changes in people suffering from certain diseases. Whether these exposures actually lead to disease via these epigenetic changes remains to be determined (Baccarelli and Bollati 2009).
Environmental Chemicals Can Affect Gene Expression
At very low (A) and higher (B) doses, arsenic exposure can increase (red) or decrease (green) gene expression. Many of these genes are related to the immune system.
Chemicals considered here that have been found to affect gene expression include arsenic, bisphenol A, persistent organic pollutants, phthalates, heavy metals, trichloroethylene, and air pollutants (most of these are reviewed in Baccarelli and Bollati (2009) and Chung and Herceg (2020)). Many epigenetic changes caused by these chemicals are linked to diabetes and obesity, and some are transmitted over multiple generations (reviewed by Lehle and McCarrey, 2020).
Both nutrition and environmental chemicals can affect epigenetic processes. Lee et al. (2009) propose that researchers consider both of these factors in tandem, since many chemicals contaminate food items. They also propose that epigenetic mechanisms may be involved in the associations between persistent organic pollutants (POPs) and type 2 diabetes. Two recent studies have found human evidence that certain epigenetic changes are associated with levels of POPs, at both high levels of exposure (Rusiecki et al. 2008) and at low levels (Kim et al. 2010). These specific changes are not necessarily related to diabetes development, but do provide evidence that POPs can affect epigenetic processes. A review discusses how nutrition can impact the toxicity of environmental chemicals in the body, sometimes via epigenetic mechanisms (Hoffman et al. 2017). Another review discusses various endocrine disrupting chemicals as well as nutrition, and how epigenetic processes play a role in the later-life development of metabolic diseases (like type 2 diabetes) following early life exposure (Greco et al. 2019).
In laboratory studies of cells, numerous chemicals have been found to affect the growth and development of fat cells, accompanied by epigenetic changes (Bastos Sales et al. 2013).
In a review of how environmental chemicals can affect gene expression, Edwards and Myers (2007) point out that chemically induced changes in gene expression are associated with a variety of diseases, including diabetes. Some of these changes occur early in development, e.g., in utero, possibly contributing to disease later in life. Chemical exposures may contribute to disease depending on genetic background, developmental stage, timing, duration, and interactions of mixtures of chemicals. One chemical may have multiple mechanisms of action, and individuals may have differing sensitivities to exposures depending on their genetic background (Edwards and Myers 2007).
A human study found that exposures to various environmental chemicals were linked to epigenetic changes in certain genes, and these genes were linked to a variety of metabolic traits like diabetes, obesity, metabolic syndrome, high blood pressure, and insulin resistance (Lu et al. 2020).
Exposure During Development
Indeed, the effects of environmental exposures seem to be more severe and permanent if they occur during development. This may be due to epigenetic processes. Research into this topic is now booming, in relation to all sorts of diseases, diabetes included. Here is one example: researchers found that exposure to high blood sugar in the womb (when a pregnant woman has type 1 diabetes) leads to an increased risk of kidney dysfunction in her children when they are adults, and that this outcome is associated with epigenetic changes (Gautier et al. 2015). Whether those changes caused the problem is not yet clear and is still being investigated. There are many studies like this throughout this website. Smith and Ryckman (2015) review the human and animal evidence that epigenetic changes due to environmental exposures in the womb (diet, maternal obesity, and pregnancy complications) may contribute to diabetes, obesity, and metabolic syndrome in adults. Sosa-Larios et al. (2015) review the animal evidence of epigenetic mechanisms involved in the development of the pancreas in the womb-- these changes can lead to beta cell dysfunction later in life.
Researchers are also finding that small epigenetic changes may have large effects, and may be important for children's health (Barrett et al. 2017; Breton et al. 2017). Scientists are in the process of determining how exactly epigenetic changes may be a mechanism whereby early life exposures could lead to later life disease, in current and future generations (Barouki et al. 2018).
Exposure to environmental chemicals in the womb is also a concern. A review of the role of epigenetics in early life exposures to obesogenic chemicals finds that the first potential markers for obesity can be detected even at birth (Stel and Legler, 2015). Exposure to toxic chemicals in the womb are linked to epigenetic changes in the placenta (reviewed by Addo et al. 2020).
Transgenerational Effects: You Are What Your Grandfather Ate?
It used to be thought that epigenetic changes were wiped out in early development. It turns out that this does not always happen. While most epigenetic changes are erased during development, some may survive. When chemical exposures occur at precise times during development, transgenerational changes can occur (Schmidt 2013).
Epigenetic changes induced by embryonic exposure to a pesticide, including immune system abnormalities as well as high cholesterol levels, were passed down for four generations in rats (Anway et al. 2006). Epigenetic changes that are passed to the next generation have been proposed as one of the processes leading to the development of type 2 diabetes (Portha 2005).
Now scientists are finding that prenatal exposure to environmental chemicals can lead to epigenetic changes and effects that are passed down through multiple generations via the sperm-- including obesity (Guerrero-Bosagna et al. 2014). For example, fetal DDT, jet fuel, or glyphosate (Roundup) exposure promote obesity-- in the great-grandchildren of the rats who were exposed (Ben Maamar et al. 2020; Kubsad et al. 2019; Skinner et al. 2013; Tracey et al. 2013).
If chemicals or other environmental factors can result in epigenetic changes in humans that can be passed down to subsequent generations, the implications are daunting. Curiously, epigenetic changes may also be able to skip a generation. And yet, there is also evidence that epigenetic changes can be erased from one generation to the next, probably depending on genetic background, gender, age, diet, duration of exposure, and timing. Little is known about persistent exposures over multiple generations, how epigenetic changes could be reversed, or when they might be permanent (Gabory et al. 2009).
Effects Across Generations
When a pregnant woman is exposed to an environmental chemical, the exposure extends not only to herself (F0) and her unborn child (F1), but also to the germ cells of her granddaughter developing within the fetus (F2). The F3 generation (her great-granddaughter) is the first generation not directly exposed. Animal studies have demonstrated chemical effects that extend to the F3 and later generations, while human studies have shown effects through the F2 generation.
Figure by Joseph Tart/EHP, from Schmidt 2013, EHP.
To read a good article on transgenerational epigenetic research, see Uncertain inheritance: Transgenerational effects of environmental exposures, published in Environmental Health Perspectives (Schmidt 2013). Desai et al. (2015) review the human and animal evidence on the role of epigenetics (due to nutrition and chemicals) in the transgenerational transmission of obesity and metabolic syndrome. Nilsson and Skinner (2015) review how epigenetic changes lead to transgenerational changes (of numerous health effects) and how these changes can lead to disease in adults.
And yes, the effects of environmental exposure of fathers, not just mothers, can be transmitted via epigenetics. There's even a name for that, the Paternal Origins of Health and Disease (POHaD) (a variation of DOHaD, Developmental Origins of Health and Disease), complete with a symposium and calls for research on the topic (Soubry 2018). New research is actively investigating just exactly how "fathers matter" (Braun et al. 2017). Reviews summarize how epigenetic changes to sperm caused by various environmental factors, including chemicals, might lead to metabolic disease in offspring (Siddeek et al. 2018; Sharp and Lawlor, 2019).
Additional reviews also address how epigenetic changes (in sperm or eggs), caused by nutrition or environmental chemicals, can lead to obesity and other metabolic problems in offspring and in future generations (King and Skinner 2020).
Researchers are now looking into whether we can find epigenetic markers in sperm that would be a sign of ancestral exposures to environmental chemicals (Nilsson et al. 2020).
Can Epigenetic Changes Be Reversed?
This is an important question. It appears that epigentic changes can be reversed, sometimes, under certain circumstances, but scientists are still trying to figure out those circumstances. One study found that exposure to a high-fat diet in the womb led to epigenetic changes and health effects (glucose intolerance, weight gain, metabolic syndrome) over multiple generations in mice. A normal diet after the in utero exposure diminished these effects, and a normal diet in the womb for 3 generations completely eliminated the effects (Masuyama et al. 2015).
Li et al. (2019) review how an "epigenetics diet," which includes bioactive dietary compounds such as isothiocyanates in broccoli, genistein in soybeans, resveratrol in grapes, epigallocatechin-3-gallate in green tea, and ascorbic acid in fruits, has been shown to affect epigenetics and benefit health.
To see these and additional references on epigenetics and diabetes/obesity, as well as articles on how various environmental factors can influence epigenetics or gene expression, see my PubMed collection, Epigenetics.