Figure 1.

Subphenotypes of severe insulin resistance (SIR). Defects in insulin signaling can occur at the level of the insulin receptor (receptor-level, e.g., insulin receptoropathy, panel A) or pathways downstream of the insulin receptor (postreceptor, e.g., lipodystrophy, panel B) to cause SIR. Insulin receptoropathy is characterized by nonselective impairment of all signaling pathways downstream of the insulin receptor, whereas in lipodystrophy signaling through some pathways are impaired while other pathways remain intact. In both subphenotypes of SIR, hyperinsulinemia can cause signaling through receptors other than the insulin receptor through excess insulin binding to lower-affinity targets such as the IGF-1 receptor. Abbreviations: SIR, severe insulin resistance; INSR, insulin receptor; DNL, de novo lipogenesis; 11OA, 11-oxygenated androgen; GNG, gluconeogenesis; HA, hyperandrogenism.