Pathophysiology, Biochemistry, and Molecular Landscape of Insulin Resistance in Type 2 Diabetes

The pathophysiology of type 2 diabetes (T2D) remains poorly understood, largely because multiple early changes are obscure as they evolve during prolonged period of prediabetes. These changes are interconnected, involve feedback loops, and gradually develop in tissue-specific manner, ultimately leading to manifestation as overt diabetes. Insulin resistance (IR) and pancreatic β-cell dysfunction are regarded as central events driven by lipotoxicity and glucotoxicity. Understanding molecular mechanisms of their causes and consequences is essential for developing effective preventive and therapeutic strategies for T2D. This review describes the evolution of current perspectives on T2D pathophysiology, examines the mechanistic roles of lipotoxicity and glucotoxicity, and integrates current concepts on the molecular basis of IR. The hypotheses on the early events in prediabetes and potential role of IR in their progression toward overt T2D are discussed. A deeper understanding of T2D as a metabolic disease of biochemical origin may provide new insights into T2D prevention and major associated mortality risks, including cardiovascular complications and cancer.