Amyloid-β Induces Hepatic Insulin Resistance by Activating JAK2/STAT3/SOCS-1 Signaling Pathway

Epidemiological studies indicate that patients with Alzheimer's disease (AD) have an increased risk of developing type 2 diabetes mellitus (T2DM), and experimental studies suggest that AD exacerbates T2DM, but the underlying mechanism is still largely unknown. This study aims to investigate whether amyloid-beta (A beta), a key player in AD pathogenesis, contributes to the development of insulin resistance, as well as the underlying mechanism. We find that plasma A beta 40/42 levels are increased in patients with hyperglycemia. APPswe/PSEN1dE9 transgenic AD model mice with increased plasma A beta 40/42 levels show impaired glucose and insulin tolerance and hyperinsulinemia. Furthermore, A beta impairs insulin signaling in mouse liver and cultured hepatocytes. A beta can upregulate suppressors of cytokine signaling (SOCS)-1, a well-known insulin signaling inhibitor. Knockdown of SOCS-1 alleviates A beta-induced impairment of insulin signaling. Moreover, JAK2/STAT3 is activated by A beta, and inhibition of JAK2/STAT3 signaling attenuates A beta-induced upregulation of SOCS-1 and insulin resistance in hepatocytes. Our results demonstrate that A beta induces hepatic insulin resistance by activating JAK2/STAT3/SOCS-1 signaling pathway and have implications toward resolving insulin resistance and T2DM. Diabetes 61:1434-1443, 2012