Insulin resistance is a common metabolic disorder that occurs when body cells—particularly in skeletal muscle, liver, and adipose tissue—lose their normal responsiveness to insulin. As a result, glucose uptake becomes inefficient, leading to elevated blood glucose levels. Biochemical Mechanism Under physiological conditions, insulin binds to its membrane receptor, activating an intracellular signaling cascade that includes insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt). This pathway ultimately promotes the translocation of the glucose transporter (GLUT4) to the cell membrane, facilitating glucose entry into the cell. In insulin resistance, defects occur within these signaling pathways due to multiple contributing factors, including: Obesity and visceral fat accumulation Chronic low-grade inflammation Oxidative stress Altered intracellular phosphorylation signaling These alterations reduce receptor sensitivity to insulin. Consequently, pancreatic β-cells increase insulin secretion as a compensatory mechanism, often resulting in hyperinsulinemia. Clinical Significance Insulin resistance is strongly associated with several major health conditions, including: Type 2 diabetes mellitus Metabolic syndrome Cardiovascular diseases Non-alcoholic fatty liver disease (NAFLD) Persistent insulin resistance may eventually lead to β-cell dysfunction and impaired insulin secretion, culminating in overt diabetes. Diagnosis and Biomarkers Insulin resistance can be evaluated through: Fasting insulin measurement HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) Oral glucose tolerance test (OGTT) Ongoing research is exploring molecular biomarkers related to inflammation, oxidative stress, and mitochondrial dysfunction to improve early detection and therapeutic targeting. Conclusion Insulin resistance represents a pivotal early event in the development of metabolic diseases. Understanding its molecular and biochemical mechanisms is essential for developing effective preventive and therapeutic strategies. Al-Mustaqbal University – Ranked First Among Iraqi Private Universities