Epigenetic modifiers of islet function and mass Dario F. De Jesus 1, 2 and Rohit N. Kulkarni 1, 3 1 Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA 2 Graduate Program in Areas of Basic and Applied Biology (GABBA), Abdel Salazar Biomedical Sciences Institute, University of Porto, 5000 Porto, Portugal 3 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA Type 2 diabetes (T2D) is associated with insulin resis- tance in target tissues including the b-cell, leading to significant b-cell loss and secretory dysfunction. T2D is also associated with aging, and the underlying mecha- nisms that increase susceptibility of an individual to develop the disease implicate epigenetics: interactions between susceptible loci and the environment. In this review, we discuss the effects of aging on b-cell function and adaptation, besides the significance of mitochondria in islet bioenergetics and epigenome. We highlight three important modulators of the islet epigenome, namely: metabolites, hormones, and the nutritional state. Unra- veling the signaling pathways that regulate the islet epigenome during aging will help to better understand the development of disease progression and to design novel therapies for diabetes prevention. Diabetes – an environmental and genetic multifactorial disease Diabetes mellitus is increasing worldwide with a global prevalence of 6.4% in the adult population (aged 20–79 years), and new cases of diabetes are predicted to be higher in developing countries (69%), compared with developed nations (20%) [1]. It is a metabolic disease that affects virtually all tissues in the body, and is characterized by uncontrolled hyperglycemia and tissue-specific complica- tions in the untreated state. Type 1 diabetes (T1D) is caused by an autoimmune attack targeting the insulin- producing pancreatic b-cells, while type 2 diabetes (T2D) is associated with aging, early development of insulin resis- tance, and a deteriorating b-cell function [2]. The underly- ing mechanisms responsible for changes in b-cell function, glucose tolerance, and insulin sensitivity are areas of intensive investigation. Among the diverse factors that impact the disease, environmental stimuli have been reported to shape epigenetic signatures of different tissue types, and contribute to the disease process [3]. In this review, we will briefly outline the basic epigenetic princi- ples and focus on their relevance in the aging-associated b- cell dysfunction in T2D. We will also discuss the impor- tance of epigenetic regulation of b-cell adaptation and the importance of metabolic, hormonal and nutritional factors that contribute to the b-cell epigenome. Epigenetics and aging Common to virtually all living organisms, aging is broadly defined as a time-dependent loss of homeostatic structure and function [4]. Although genomic instability is an impor- tant hallmark of aging and is characterized by increased accumulation of nuclear and mitochondrial DNA muta- tions [5], there are no functional studies reporting a direct effect of a mutation on the life-span of an organism [4]. Thus, an important question in the field has been to determine how the accumulation of mutations contribute to a phenotype associated with aging. Beyond the genome, epigenetics emerges as a complementary and dynamic mechanism by which the environment can directly affect the life-span of an organism. First coined by Conrad H. Waddington, epigenetics is defined as ‘the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states’ [6]. Epigenetics is also defined as the science that studies the changes in gene expression, without an alteration in the nucleotide sequence. Epigenetic altera- tions can be further transmitted in a cell-to-cell manner (mitosis) or through generations (meiosis). The most wide- ly studied epigenetic modifications include: DNA methyl- ation (Box 1), chromatin modification (Box 2), and non- coding RNA expression (Box 2). Epigenetics changes associated with diabetes Diabetes is a multifactorial and complex disease influenced by both genetic and environmental factors (Box 3). The concordance rate in adult-onset of T1D is low (<20%), suggesting that factors other than genetics are implicated in the development of this complex autoimmune disease [7]. Indeed, epigenome-wide association studies (EWAS) are beginning to identify differently methylated cytosine– phosphate–guanine (CpG) dinucleotides that precede the onset of T1D and implicate a role for epigenetics [8]. While insulin resistance is strongly associated with obesity and aging, the overt development of T2D in both states is triggered by an inability of the b-cells to compen- sate by increasing insulin secretion and/or enhancing cell mass. Notably, a majority of the genes associated with T2D are related to b-cell function [9], and new rare monogenic forms of diabetes and individual loci conferring risk for Review 1043-2760/ ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tem.2014.08.006 Corresponding author: Kulkarni, R.N. (Rohit.Kulkarni@joslin.harvard.edu). 628 Trends in Endocrinology and Metabolism, December 2014, Vol. 25, No. 12