INSR

INSR refers to the gene that encodes the insulin receptor, a transmembrane receptor tyrosine kinase essential for insulin signaling and glucose homeostasis. In humans, the INSR gene is located on chromosome 19p13.3. The receptor plays a central role in mediating the metabolic actions of insulin and in coordinating growth-related signaling.

The insulin receptor is a disulfide-linked heterotetramer consisting of two alpha subunits and two beta subunits. The extracellular alpha subunits form the insulin-binding site, while the beta subunits span the cell membrane and contain the intracellular tyrosine kinase domain responsible for receptor autophosphorylation and downstream signaling. The receptor is activated when insulin binding induces conformational changes that enable autophosphorylation of specific tyrosine residues, creating docking sites for signaling proteins.

The INSR gene produces two main isoforms, A and B, generated by alternative splicing of exon 11. Isoform A is more prevalent in fetal tissues and certain cancers and can bind IGF-II with relatively high affinity, whereas isoform B is more common in adult metabolic tissues such as liver, muscle, and adipose tissue, where it preferentially mediates insulin’s metabolic effects.

Signaling downstream of the activated receptor involves the IRS proteins, leading to two major pathways. The PI3K-AKT pathway promotes glucose uptake (via GLUT4 translocation), glycogen synthesis, and lipid synthesis. The MAPK pathway contributes to growth and mitogenic signaling. The receptor also forms hybrid complexes with the IGF1 receptor, enabling cross-talk between insulin and IGF signaling.

Clinical significance includes severe insulin resistance caused by INSR mutations (e.g., Donohue syndrome and Rabson-Meltzner syndrome). Partial loss-of-function variants contribute to type 2 diabetes and metabolic syndrome.