The insulin gene in humans and mice: evolution, regulation, and sex-specific mechanisms of diabetes susceptibility

Abstract

The insulin gene (INS) encodes a peptide hormone critical for glucose homeostasis, and its dysregulation underlies both type 1 and type 2 diabetes mellitus. This review compares the structural organization and functional regulation of the insulin gene in humans and mice, highlighting key species differences including the presence of two non-allelic insulin genes (Ins1 and Ins2) in mice versus a single INS gene in humans. Despite these differences, most preclinical diabetes research has historically been conducted in male mice, potentially concealing sex and species specific mechanisms. Additionally, this review examines the growing evidence for sex-specific differences in diabetes susceptibility. Recent single-cell multi-omics studies reveal that human pancreatic islets exhibit sex-specific chromatin accessibility and gene expression patterns, with autosomal sex differences emerging predominantly in type 2 diabetes. The protective effects of estrogen, mediated through estrogen receptor α signaling, contribute to enhanced insulin sensitivity and beta-cell function in premenopausal females. We argue that routine inclusion of both sexes and species aware interpretation of insulin gene studies are prerequisites for precision diabetology.