Irs2, or insulin receptor substrate protein-2, is a crucial mediator of insulin signaling and may regulate other pathways as well. It is a major component of the insulin/insulin-like growth factor-1 signaling pathway [2,3]. This pathway is essential for maintaining various physiological functions, such as glucose homeostasis, cell growth, and differentiation. Genetic models, like knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying its functions.

In cardiac function, cardiomyocyte-restricted deletion of Irs2 (cIRS2-KO) in mice makes the hearts more susceptible to pressure overload-induced cardiac dysfunction and prone to catecholamine-sensitive ventricular tachycardia and reperfusion ventricular tachycardia. This is due to sarcoplasmic reticulum dysfunction caused by over-activation of the AKT1/NOS3/CaMKII/RyR2 signaling pathway [1]. In male mice lacking Irs2 (Irs2 -/-/6J), there are hippocampus-associated behavioral alterations, along with aberrant changes in energy and nutrient sensors and reduced core body temperature [2]. In pancreatic beta-cells, IRS2 is involved in regulating the total functional beta-cell mass, with overexpression studies in isolated islets showing its role in beta-cell proliferation and protection against apoptosis [3].

In conclusion, Irs2 is essential for maintaining normal physiological functions in multiple organs. The Irs2 KO/CKO mouse models have revealed its critical roles in cardiac adaptation to stress, hippocampus-related behaviors, and pancreatic beta-cell mass regulation, providing valuable insights into related disease mechanisms such as cardiac arrhythmias, cognitive impairments, and diabetes-related conditions.