| First Author | Zhang Y | Year | 2013 |
| Journal | Diabetes | Volume | 62 |
| Issue | 4 | Pages | 1159-66 |
| PubMed ID | 23223021 | Mgi Jnum | J:208594 |
| Mgi Id | MGI:5563744 | Doi | 10.2337/db12-0670 |
| Citation | Zhang Y, et al. (2013) Amyloid-beta induces hepatic insulin resistance in vivo via JAK2. Diabetes 62(4):1159-66 |
| abstractText | Amyloid-beta (Abeta), a natural product of cell metabolism, plays a key role in the pathogenesis of Alzheimer's disease (AD). Epidemiological studies indicate patients with AD have an increased risk of developing type 2 diabetes mellitus (T2DM). Abeta can induce insulin resistance in cultured hepatocytes by activating the JAK2/STAT3/SOCS-1 signaling pathway. Amyloid precursor protein and presenilin 1 double-transgenic AD mouse models with increased circulating Abeta level show impaired glucose/insulin tolerance and hepatic insulin resistance. However, whether Abeta induces hepatic insulin resistance in vivo is still unclear. Here we show C57BL/6J mice intraperitoneally injected with Abeta42 exhibit increased fasting blood glucose level, impaired insulin tolerance, and hepatic insulin signaling. Moreover, the APPswe/PSEN1dE9 AD model mice intraperitoneally injected with anti-Abeta neutralizing antibodies show decreased fasting blood glucose level and improved insulin sensitivity. Injection of Abeta42 activates hepatic JAK2/STAT3/SOCS-1 signaling, and neutralization of Abeta in APPswe/PSEN1dE9 mice inhibits liver JAK2/STAT3/SOCS-1 signaling. Furthermore, knockdown of hepatic JAK2 by tail vein injection of adenovirus inhibits JAK2/STAT3/SOCS-1 signaling and improves glucose/insulin tolerance and hepatic insulin sensitivity in APPswe/PSEN1dE9 mice. Our results demonstrate that Abeta induces hepatic insulin resistance in vivo via JAK2, suggesting that inhibition of Abeta signaling is a new strategy toward resolving insulin resistance and T2DM. |
