Insulin receptor signaling is crucial for glucose, lipid, and energy homeostasis, primarily in liver, skeletal muscle, and adipose tissue. Insulin and IGF-1 act through tyrosine kinase receptors, initiating a cascade of phosphorylation events that activate enzymes involved in metabolism and growth. Key signaling pathways include the PI3K-Akt and Grb2-SOS-Ras-MAPK pathways, which regulate cell proliferation, differentiation, and survival. Insulin resistance, a hallmark of type-2 diabetes, involves dysregulation of these pathways, often due to genetic mutations, obesity, or other metabolic disturbances. The insulin receptor (IR) and IGF-1 receptor (IGF-1R) are tetrameric proteins with α and β subunits. IR has two isoforms, IR-A and IR-B, with distinct tissue distributions and functions. IRS proteins, which act as scaffolds, are phosphorylated by activated receptors and recruit downstream signaling molecules. IRS-1 and IRS-2 have distinct roles in different tissues, with IRS-1 being critical for muscle and glucose metabolism, while IRS-2 is important for lipid metabolism and ERK activation. The PI3K-Akt pathway is central to insulin signaling, generating PIP3 to recruit and activate Akt, which regulates glucose transport, lipid synthesis, and cell survival. Akt also influences cell cycle and survival. The Grb2-SOS-Ras-MAPK pathway, independent of PI3K, controls cell proliferation and gene transcription. Negative regulators, such as phosphatases and inhibitory proteins, modulate insulin signaling, with PTP1B and PTEN playing key roles in reducing receptor activity and signaling. Insulin resistance can arise from various mechanisms, including lipotoxicity, inflammation, hyperglycemia, mitochondrial dysfunction, and ER stress. Genetic mutations in the insulin receptor or IRS proteins can cause severe insulin resistance. Environmental factors, such as obesity and high-fat diets, contribute to insulin resistance through lipid accumulation, inflammation, and oxidative stress. Understanding these pathways is essential for developing new therapies for diabetes and metabolic disorders.Insulin receptor signaling is crucial for glucose, lipid, and energy homeostasis, primarily in liver, skeletal muscle, and adipose tissue. Insulin and IGF-1 act through tyrosine kinase receptors, initiating a cascade of phosphorylation events that activate enzymes involved in metabolism and growth. Key signaling pathways include the PI3K-Akt and Grb2-SOS-Ras-MAPK pathways, which regulate cell proliferation, differentiation, and survival. Insulin resistance, a hallmark of type-2 diabetes, involves dysregulation of these pathways, often due to genetic mutations, obesity, or other metabolic disturbances. The insulin receptor (IR) and IGF-1 receptor (IGF-1R) are tetrameric proteins with α and β subunits. IR has two isoforms, IR-A and IR-B, with distinct tissue distributions and functions. IRS proteins, which act as scaffolds, are phosphorylated by activated receptors and recruit downstream signaling molecules. IRS-1 and IRS-2 have distinct roles in different tissues, with IRS-1 being critical for muscle and glucose metabolism, while IRS-2 is important for lipid metabolism and ERK activation. The PI3K-Akt pathway is central to insulin signaling, generating PIP3 to recruit and activate Akt, which regulates glucose transport, lipid synthesis, and cell survival. Akt also influences cell cycle and survival. The Grb2-SOS-Ras-MAPK pathway, independent of PI3K, controls cell proliferation and gene transcription. Negative regulators, such as phosphatases and inhibitory proteins, modulate insulin signaling, with PTP1B and PTEN playing key roles in reducing receptor activity and signaling. Insulin resistance can arise from various mechanisms, including lipotoxicity, inflammation, hyperglycemia, mitochondrial dysfunction, and ER stress. Genetic mutations in the insulin receptor or IRS proteins can cause severe insulin resistance. Environmental factors, such as obesity and high-fat diets, contribute to insulin resistance through lipid accumulation, inflammation, and oxidative stress. Understanding these pathways is essential for developing new therapies for diabetes and metabolic disorders.