Insulin Resistance and Diabetes

Abstract

In this chapter, we will describe the molecular principles of glucose homeostasis and insulin signaling as well as their dysregulation leading to insulin resistance and β cell failure. Since our blood glucose levels need to stay within a physiological range of 4–6 mM, glucose intake, storage, mobilization and breakdown are tightly regulated. Insulin plays a key role in these regulatory processes. When normal concentrations of insulin cause an insufficient response of the major insulin target tissues, such as skeletal muscle, liver and adipose tissue, insulin resistance has developed. Ectopic overload of lipids, chronic inflammatory response and ER stress are the main processes that can lead to insulin resistance. Moreover, glucotoxic and lipotoxic stress to β cells of the pancreas are mediated via inflammatory response, oxidative stress and ER stress eventually resulting in the failure of the cells, i.e., in the inability to produce insulin. We will describe diabetes as a disease of dysregulation of glucose and lipid homeostasis that does not only affect the insulin production in pancreatic β cells but also the metabolism in organs, such as liver, muscle and fat. Worldwide, the prevalence of T2D is rapidly increasing, which, when not properly treated, ultimately leads to reduced life expectancy due to microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (heart disease and stroke) complications. Both genetic and environmental factors contribute to the development of the disease. We will realize that despite large GWAS screening for risk genes less than 10% of the inheritance of T2D is understood. Therefore, epigenome-wide changes, both prenatal as well as in adult life, play an important role in the disease.