Type 2 Diabetes Mellitus: Pathogenesis, Clinical Challenges, and Evolving Therapeutic Paradigms

Abstract

Type 2 Diabetes Mellitus (T2DM) is a progressive and multifactorial metabolic disorder defined by chronic hyperglycemia resulting from a combination of insulin resistance, inadequate insulin secretion, and dysfunction of glucose metabolism. It constitutes the vast majority of diabetes cases globally and is now recognized as a public health epidemic, largely driven by sedentary lifestyles, poor dietary habits, and rising rates of obesity. The increasing prevalence of T2DM poses a significant burden not only on individuals but also on healthcare systems worldwide due to its association with severe and potentially debilitating complications. T2DM is intricately linked with both microvascular complications—including diabetic retinopathy, nephropathy, and neuropathy—and macrovascular diseases such as coronary artery disease, stroke, and peripheral vascular disease. This review comprehensively examines the underlying pathophysiological mechanisms, including insulin resistance, β-cell dysfunction, altered incretin response, and glucagon dysregulation. It also discusses risk factors, genetic predisposition, and the role of the gut microbiome and epigenetic modifications. Clinical diagnosis of T2DM involves biochemical markers such as fasting glucose, HbA1c levels, and oral glucose tolerance tests, with emphasis on early detection to prevent complications. Management strategies include lifestyle modification, pharmacological therapy tailored to individual patient needs, and the integration of new treatment classes like SGLT2 inhibitors and GLP-1 receptor agonists, which also provide cardiovascular and renal protection. Emerging therapies, advancements in digital health technologies, and precision medicine are shaping the future of T2DM care, offering more personalized and effective treatment paradigms aimed at improving long-term outcomes and quality of life for patients.