Insulin receptor (INSR), CD220 belongs to the receptor tyrosine kinase (RTK) family. It is a key membrane protein that mediates insulin signal transduction. It is mainly expressed in tissues such as liver, muscle, and fat. It mediates insulin signals, regulates metabolism and cell growth, and is related to tumors.
Expression distribution of INSR
INSRs are primarily expressed in insulin's metabolic target tissues, primarily in the liver, skeletal muscle, and adipose tissue, directly mediating insulin's metabolic regulatory effects (e.g., glucose uptake and glycogen synthesis). However, they are also expressed in peripheral nerves, kidneys, alveoli, pancreatic acini, placental vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes, and skin. This broad expression pattern reflects the central role of insulin in maintaining systemic metabolic homeostasis, cell growth, and tumorigenesis.
(Data source: Uniprot)
Functions of INSR
Core of metabolic regulation: After binding to insulin, it activates downstream signaling pathways, promotes glucose uptake (transported to the cell membrane through GLUT4), glycogen synthesis, protein synthesis, and maintains blood sugar homeostasis.
Cell growth and differentiation: Participates in cell proliferation, differentiation and survival, and affects tissue development (e.g., pituitary development during embryonic period depends on the regulation of transcription factor Pax6).
Neurological function: Recent studies have found that it is expressed in brain neural stem cells and is crucial to stem cell lifespan and brain function (such as neuron regeneration), and may be associated with neurodegenerative diseases such as Alzheimer's disease.
Action in adipocytes: In adipocytes, this receptor inhibits lipolysis.
The structure of INSR
INSR , encoded by the INSR gene, is a type I transmembrane protein with a length of 1382 amino acids and a molecular weight of approximately 156 kDa . It belongs to the tyrosine kinase receptor family. The INSR precursor protein is hydrolyzed into α and β chains, forming an α₂β₂ heterotetramer, with the subunits linked by disulfide bonds. The tetrameric INSR binds insulin via non-homologous regions of the two α chains, primarily through the C-terminal region of the first INSR α chain. The leucine-rich N-terminal residues of the other INSR α chain also contribute to this insulin-binding site. A second insulin-binding site is formed by residues at the junction of type III fibronectin domains 1 and 2. The βsubunit possesses tyrosine protein kinase (TPK) activity, and the intracellular region contains an ATP binding site and an autophosphorylation site.
(Data source : AlphaFold)
Signaling pathways of INSR
The PI3K-AKT pathway: phosphorylation of the IRS → activation of PI3K → production of PIP3 → activation of AKT → promotion of GLUT4 vesicle transport to the membrane, increased glucose uptake, inhibition of apoptosis (phosphorylation of BAD) , and regulation of gluconeogenesis and lipases (via FOX transcription factors) . Abnormal mechanisms: Oxidative stress or hyperphosphorylation of serine/threonine residues in the IRS can inhibit this pathway, leading to insulin resistance .
Ras-MAPK pathway: drives cell growth and differentiation and is associated with tumorigenesis (e.g. glioblastoma relies on INSR for survival) .
(Data source: James DE, et al. Nat Rev Mol Cell Biol. 2021.)
INSR and Disease
Type 2 diabetes: The core mechanism is insulin resistance, that is, the target cells' sensitivity to insulin decreases, leading to increased blood sugar (accounting for more than 90% of diabetes worldwide) .
Severe inherited diabetes: (a) Type A insulin resistance syndrome (e.g., Rabson-Mendenhall syndrome): Mutations in the INSR gene lead to receptor inactivation, resulting in extreme insulin resistance, hyperglycemia, and acanthosis nigricans . (b) Donohue syndrome: Lethal INSR mutations, associated with developmental malformations and shortened lifespan.
Autoimmune diseases: Type B insulin resistance syndrome: Anti-INSR antibodies block signal transduction, leading to alternating hyperglycemia and hypoglycemia.
Metabolic syndrome: Insulin resistance promotes dyslipidemia, hypertension, and atherosclerosis.
Neurodegenerative diseases: Impaired INSR signaling in the brain may exacerbate Alzheimer's disease (brain insulin resistance hypothesis).
(Data source: James DE, et al. Nat Rev Mol Cell Biol. 2021.)
Targeted therapy for INSR
Insulin degludec is a biosimilar targeting the insulin receptor (INSR) developed by Jilin Huisheng Biopharmaceutical Co,.Ltd. Its primary mechanism of action is as an INSR agonist, mimicking the effects of insulin by directly binding to the insulin receptor and activating downstream signaling pathways for the treatment of type 2 diabetes. It was approved for marketing in China on August 5, 2024.
Insulin degludec (Degall) is a biosimilar drug targeting the INSR developed by Jilin Huisheng Biopharmaceutical Co,.Ltd. Its primary mechanism of action is similar to that of insulin degludec, as both are INSR agonists and are used to treat type 2 diabetes. It was approved for marketing in China on July 30, 2024.
The insulin glargine biosimilar is an INSR-targeted drug developed by Hefei Tianmai Biotechnology Development Co., Ltd. Its mechanism of action is an INSR agonist. It was approved for marketing in China on June 18, 2024.
