Type 2 diabetes mellitus (T2DM) develops through the interplay of insulin resistance and progressive beta-cell dysfunction. Beyond genetic predisposition, epigenetic regulation provides a mechanistic link between environmental exposures (e.g., overnutrition, physical inactivity, inflammation) and durable changes in gene expression in pancreatic islets and insulin-sensitive tissues (skeletal muscle, adipose tissue, and liver). Accordingly, this review aims to synthesize current evidence on the epigenetic mechanisms underlying T2DM and its complications, with a particular focus on epigenetically targeted therapeutic strategies. We summarize major epigenetic processes, including DNA and RNA methylation, histone post-translational modifications, and non-coding RNAs, and discuss how these alterations remodel chromatin and transcriptional programs under metabolic stress. A key concept is "metabolic memory," whereby transient hyperglycemia or lipotoxicity can induce persistent epigenetic signatures that sustain dysfunctional cellular phenotypes, partly shaped by mitochondrial metabolism and Krebs cycle intermediates regulating chromatin-modifying enzymes. Importantly, several epigenetic alterations demonstrate partial reversibility following lifestyle modification, metabolic surgery, or pharmacological intervention (e.g., DNA methyltransferase inhibition), underscoring their therapeutic relevance. Finally, we address translational challenges, including limited access to human tissues and inadequate modeling of chronic metabolic stress, which currently constrain clinical exploitation of epigenetic targets in T2DM.

Type 2 diabetes (T2D) is a chronic metabolic disorder primarily affecting the metabolism of glucose in the body. It is characterized by polyphagia, polydipsia, polyuria, fatigue, and persistent hyperglycemia. It occurs mainly because of two major factors, namely, dysregulated insulin secretion from pancreatic β-cells and/or reduced sensitivity of insulin-responsive tissues to insulin, i.e., insulin resistance. The process of insulin secretion and insulin signaling is complex, requiring the involvement of distinct membrane receptors. Sulfonylureas are a class of antidiabetic drugs which exert their antidiabetic action by stimulating sulfonylurea receptors on the pancreatic β-cells. Other cellular mechanisms mediated by receptors, such as insulin receptor, glucagon-like peptide-1 receptor, free fatty acid receptors, and peroxisome proliferator-activated receptor-γ, also serve as potential therapeutic targets for a number of conventional and novel antidiabetic agents. In this review article, we discuss the significance of these receptors in the therapeutic regulation of T2D. We also lay emphasis on the need for the development of novel antidiabetic agents, several of which are currently advancing through clinical research to determine their potential for antidiabetic mediation through these receptors.

Diabetic peripheral neuropathy (DPN) is the most common chronic complication of type 2 diabetes (T2D) and a major predisposing factor for the development of diabetic foot, one of the most devastating diabetes-related conditions associated with substantial morbidity and mortality. To date, no pharmacological therapy has been shown capable of preventing, halting, or reversing neuropathic damage. We report the case of a 57-year-old man with T2D and obesity (BMI 35.2 kg/m[2]) who presented with symptoms and signs of DPN, including a neuropathy symptom score (NSS) of 3/9, a neuropathy disability score (NDS) of 3/10, and a vibration perception threshold (VPT) of 22 volts (V) bilaterally. In vivo corneal confocal microscopy (CCM) was performed to further evaluate small fiber involvement. Despite adequate glycemic control (HbA1c 6.6%), semaglutide was initiated to optimize metabolic status and promote weight loss. After 6 months of treatment, both BMI and HbA1c had improved, while NSS, NDS, and VPT remained unchanged. Repeat CCM demonstrated improvement across all corneal nerve parameters. This case suggests that semaglutide-associated metabolic improvement, or a direct semaglutide effect on small fiber integrity, may contribute to early regeneration of small nerve fibers in DPN. Further studies are urgently needed to determine whether semaglutide has a therapeutic role in the management of DPN.