Review
Epigenetic mechanisms in the development of type 2 diabetes

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Type 2 diabetes (T2D) is a disorder of complex genetics influenced by interactions between susceptible genetic loci and environmental perturbations. Intrauterine growth retardation is one such environmental perturbation linked to the development of T2D in adulthood. An abnormal metabolic intrauterine milieu affects fetal development by permanently modifying expression of key genes regulating β-cell development (Pdx1) and glucose transport (Glut4) in muscle. Epigenetic regulation of gene expression is one mechanism by which genetic susceptibility and environmental insults can lead to T2D. Therefore, therapeutic agents targeting epigenetic gene regulation can ultimately be used to treat T2D; however, there is much to be learned about genome-wide epigenetic programming of health and disease before these therapies can be used in patient care.

Introduction

The incidence of type 2 diabetes (T2D) has rapidly increased over the past several decades and is now reaching epidemic proportions across the globe. In fact, incidence of T2D is estimated to reach 366 million throughout the world by 2030 [1]. Simple Mendelian inheritance patterns have failed to describe the genetics of T2D, in that studies have identified single nucleotide polymorphisms linked to the development of T2D, but no disease-causing mutations have been discovered. Recent genome-wide association studies identified at least 17 genetic loci associated with T2D [2], suggesting that T2D is a complex genetic disorder influenced by interactions between multiple susceptible genetic loci and environmental perturbations.

Environmental contributions to the development of T2D potentially include exposures such as a suboptimal in utero environment, low birth weight, obesity, inactivity and advancing age [3]. These environmental perturbations can lead to a disease phenotype by affecting gene expression through epigenetic modifications. Epigenetic changes are defined as mitotically heritable alterations in gene expression that are not related to changes in DNA sequence. One of the key environmental perturbations associated with T2D is exposure to an adverse intrauterine milieu, such as intrauterine growth retardation (IUGR). An adverse intrauterine milieu affects fetal development by modifying gene expression of both pluripotent cells that are rapidly replicating and terminally differentiated cells that replicate poorly. Whether the effect(s) of exposure to an altered intrauterine milieu extend into adulthood depends on whether the cells are undergoing differentiation, proliferation and/or functional maturation at the time of that exposure.

There are several examples where human exposure to an abnormal intrauterine milieu leads to abnormalities in glucose homeostasis and ultimately T2D. For example, pregnant women exposed to the Dutch Hunger Winter, the period in late World War II during which daily caloric intake was limited to 400–800 kcal, delivered infants with lower birth weights. By age 50, these offspring had impaired glucose tolerance compared to offspring who were in utero either the year before or after the famine [4]. Another epidemiological study from Hertfordshire, UK found that men who were the smallest at birth (<2.5 kg) were seven times more likely to have glucose intolerance or T2D than those who were heaviest at birth [5]. Permanent changes in the phenotype of the offspring suggest that IUGR is associated with stable changes in gene expression, potentially as a result of epigenetic modifications. Here, we provide a general review of epigenetics and discuss the possible causal role of chromatin remodeling in the development of T2D.

Section snippets

Chromatin structure, DNA methylation and gene expression

Epigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene expression from one generation of cells to the next 6, 7, 8, 9, 10, 11, 12, 13, 14. There are at least two distinct mechanisms through which epigenetic information can be inherited: histone modifications and DNA methylation.

Maternal nutritional supplementation and epigenetic modifications in offspring

The role of environmental regulation of epigenetic phenomena in offspring has been established by experiments performed in agouti mice (reviewed in Ref. [20]). Wild type expression of the Agouti protein results in a phenotypic brown coat color in the mouse. In this mouse model, an endogenous retrovirus-like transposon sequence is inserted close to the gene coding for the Agouti protein. An unmethylated retrotransposon promoter overrides the wild type agouti promoter, resulting in ectopic agouti

Chromatin remodeling and oxidative stress

Exposure to oxidative stress can directly mediate both DNA methylation and chromatin remodeling in multiple disease models and thus could be a mechanism by which aberrant epigenetic programming leads to T2D 15, 16, 17, 18, 19, 20, 21, 22, 23, 24. In addition to targeted DNA methylation changes in response to external stimuli, random DNA methylation changes also occur during aging in several tissue types and are associated with increased oxidative stress 16, 23. Such changes in DNA methylation

Epigenetic regulation of gene expression in fetal growth retardation

Several studies suggest that uteroplacental insufficiency, the most common cause of IUGR in the developed world, induces epigenetic modifications in offspring 35, 36, 37, 38. Fetal growth retardation can be induced by bilateral uterine artery ligation in the pregnant rat [39]. Following this, pups are born spontaneously with decreased levels of glucose, insulin, insulin-like growth factor 1 and amino acids [39]. Diabetes develops in these animals at approximately 15–26 weeks of age with

Chromatin remodeling in the β-cell of IUGR rats

Pdx-1 is a homeodomain-containing transcription factor that plays a critical role in the early development of both the endocrine and exocrine pancreas and in the later differentiation and function of the β-cell. As early as 24 h after the onset of growth retardation, Pdx-1 mRNA levels are reduced by more than 50% in IUGR fetal rats. Suppression of Pdx-1 expression persists after birth and progressively declines in the IUGR animal, implicating an epigenetic mechanism.

A change in histone

Chromatin remodeling in muscle of IUGR rats

Reduced glucose transport in muscle is a trademark of insulin resistance in IUGR offspring 47, 48. Under normal physiological circumstances, glucose transport occurs by facilitated diffusion, a rate-limiting step in glucose utilization [49]. This process of glucose transport is mediated by a family of structurally related membrane-spanning glycoproteins, termed facilitative glucose transporters (GLUTs; Slc2 family of transport proteins; reviewed in Ref. [50]). Of the isoforms cloned to date,

Histone modifications in vascular epithelium exposed to hyperglycemia

The previous examples describing the relationship between chromatin remodeling and its contribution to the development of T2D focused on the IUGR animal model. We focused on this model because it is the only system that has thus far been able to link specific chromatin modifications to changes in gene expression relevant to alterations in glucose homeostasis in vivo. Brasacchio et al. describe how transient hyperglycemia in vitro induces changes in histone methylation at the promoter of

T2D therapeutic agents targeting chromatin remodeling

Drugs that are currently used to treat patients with T2D have been shown to reverse epigenetic modifications in vitro. Treating INS1 (832/13) β-cells (a rat insulinoma cell line) or dispersed mouse islets with incretin hormones such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic-peptide 1 (GIP) increased global acetylation of histone H3 at lysine residues 9 and 18 and increased phosphorylation at serine 10 in a concentration-dependent manner [55]. These histone

Concluding remarks

The studies described above clearly show that environmental effects can induce epigenetic alterations, ultimately affecting expression of key genes linked to the development of T2D including genes critical for pancreatic development and β-cell function, peripheral glucose uptake and insulin resistance, and atherosclerosis. Recent progress in understanding epigenetic programming of gene function has led to the development of novel therapeutic agents with epigenetic targets in diseases such as

Acknowledgments

Dr. Rebecca Simmons is supported by the National Institutes of Health grant #DK55704. Dr. Pinney is supported by the National Institutes of Health Training Grant K12HD0432545.

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