The article by Samuel and Shulman reviews the pathogenesis of insulin resistance, focusing on the integration of signaling pathways and substrate flux. Insulin resistance arises from chronic energy surpluses, leading to ectopic lipid accumulation in liver and skeletal muscle. This accumulation triggers pathways that impair insulin signaling, reducing muscle glucose uptake and hepatic glycogen synthesis. Muscle insulin resistance precedes liver insulin resistance, diverting glucose to the liver, which increases de novo lipogenesis and hyperlipidemia. Macrophage infiltration into white adipose tissue (WAT) further increases lipolysis, enhancing hepatic triglyceride synthesis and hyperlipidemia. Insulin signaling in WAT is defective due to inflammation, and therapies targeting ectopic lipid storage and macrophage-induced lipolysis can reverse the root causes of type 2 diabetes (T2D). The review also discusses the role of insulin in nutrient storage, the regulation of hepatic glucose and lipid metabolism, and the cellular mechanisms of muscle, liver, and adipose insulin resistance. It highlights the importance of substrate-driven processes in hepatic insulin resistance and the potential of weight loss and exercise as therapeutic strategies.The article by Samuel and Shulman reviews the pathogenesis of insulin resistance, focusing on the integration of signaling pathways and substrate flux. Insulin resistance arises from chronic energy surpluses, leading to ectopic lipid accumulation in liver and skeletal muscle. This accumulation triggers pathways that impair insulin signaling, reducing muscle glucose uptake and hepatic glycogen synthesis. Muscle insulin resistance precedes liver insulin resistance, diverting glucose to the liver, which increases de novo lipogenesis and hyperlipidemia. Macrophage infiltration into white adipose tissue (WAT) further increases lipolysis, enhancing hepatic triglyceride synthesis and hyperlipidemia. Insulin signaling in WAT is defective due to inflammation, and therapies targeting ectopic lipid storage and macrophage-induced lipolysis can reverse the root causes of type 2 diabetes (T2D). The review also discusses the role of insulin in nutrient storage, the regulation of hepatic glucose and lipid metabolism, and the cellular mechanisms of muscle, liver, and adipose insulin resistance. It highlights the importance of substrate-driven processes in hepatic insulin resistance and the potential of weight loss and exercise as therapeutic strategies.