The genetics of diabetes and its complications in older adults

Population studies demonstrate that up to 25% of the U.S. population over the age of 65 years has diabetes, making it one of the most common genetic diseases in the United States (1). In addition, it is a major contributing factor to many chronic medical conditions and to the development of disability in older adults (2,3). The prevalence of diabetes increases with age, with the vast majority of cases of diabetes in older adults consisting of type 2 diabetes mellitus (T2DM) (1). While progress toward the understanding of the environmental, physiological, and molecular and genetic basis of diabetes in older adults has been made over the past several years, substantial gaps in knowledge remain, in part because of the complex and heterogeneous nature of diabetes (4,5). Type 1 DM (T1DM) usually develops in childhood or early adulthood and is due to the autoimmune destruction of insulin-secreting beta cells in the pancreas. Although T1DM is found in older adults, it is uncommon for older adults to develop new onset T1DM. The etiology of T2DM in older adults is more complex, with increased insulin resistance and impaired insulin secretion being the key predisposing features of this disorder (1). In fact, T2DM appears to be a complex of multiple metabolic alterations that in sum ultimately contribute to the development of hyperglycemia and the diagnosis of diabetes (4). Aging-related changes in body composition and activation of inflammatory pathways with related declines in lean body mass and increased fat mass profoundly influence these metabolic processes (6). In addition, age-related environmental factors including declines in activity, chronic medical conditions, and pharmaceutical interventions likely alter insulin sensitivity in older adults as well. Given that the vast majority of cases of diabetes that impact older adults are T2DM, the main focus of this chapter will be on genes that contribute to T2DM and related endophenotypes as well as epigenetic mechanisms that influence the development of this disease in older adults. Gene variants that may influence diabetic complications and the utility of some diabetes therapies will also be covered, as will the clinical relevance of this type of research.