This chapter explores the molecular mechanisms governing glucose homeostasis and insulin signaling, elucidating their dysregulation, which leads to insulin resistance and β cell failure. Maintaining blood glucose levels within the physiological range of 4–6 mM is critical, necessitating tight regulation of glucose intake, storage, mobilization, and breakdown. Insulin is central in these regulatory processes. Insulin resistance arises when normal insulin levels elicit an inadequate response in major insulin target tissues such as skeletal muscle, liver, and adipose tissue. Key factors contributing to insulin resistance include ectopic lipid accumulation, chronic inflammation, and ER stress. Furthermore, glucotoxicity and lipotoxicity induce oxidative stress, inflammatory responses, and ER stress in β cells, leading to their dysfunction and impaired insulin production. T2D is characterized by disrupted glucose and lipid homeostasis, affecting not only insulin production in β cells but also metabolism in the liver, muscle, and adipose tissue. The global prevalence of T2D is rapidly rising, and without proper management, it leads to decreased life expectancy due to microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications (myocardial infarction and cerebral stroke). Both genetic and environmental factors contribute to the disease's development. Despite extensive GWAS identifying risk genes, less than 10% of T2D heritability is understood. This emphasizes the significant role of epigenome-wide changes, both prenatal and in adult life, in the disease's pathogenesis.