"The insulin receptor (INSR) exists as two alternatively spliced isoforms, INSR-A and INSR-B, differing by a 12–amino acid sequence encoded by exon 11. Although >400 studies report functional differences, their distinct physiological roles in vivo remain unclear. To address this, we generated mice lacking INSR-A (homologous recombination) or INSR-B (CRISPR/Cas9).
No significant metabolic differences were observed between male WT and INSR-A-/- mice. Female INSR-A-/- mice showed reduced triglyceride (TG) excursion on lipid tolerance tests (LTT) and lower glycemic excursion on oral glucose tolerance tests (OGTT), consistent with enhanced hepatic INSR phosphorylation.
In contrast, INSR-B-/- mice exhibited higher refed and post-LTT TGs, increased fat mass, reduced lean mass, and lower fasting non-esterified fatty acids (NEFAs). Radiotracer studies revealed increased hepatic retention of 14C-oleic acid and reduced 3H-triolein in perigonadal adipose tissue. Hepatic INSR phosphorylation during refeeding was reduced.
Whole-body adiposity in INSR-B-/- mice increased markedly with age. Aging females also showed lower fasting NEFAs and higher glucose. Under a high-fat diet, male INSR-B-/- mice developed impaired fasting glycemia with reduced hepatic INSR phosphorylation.
In summary, deletion of INSR-A modestly affects glucose and lipid tolerance in females, whereas deletion of INSR-B leads to elevated postprandial TGs and age- and diet-induced metabolic dysfunction."