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Diabetes. 2013 Apr;62(4):1159-66. doi: 10.2337/db12-0670. Epub 2012 Dec 6.

Amyloid-β induces hepatic insulin resistance in vivo via JAK2.

Author information

1
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Abstract

Amyloid-β (Aβ), 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). Aβ 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 Aβ level show impaired glucose/insulin tolerance and hepatic insulin resistance. However, whether Aβ induces hepatic insulin resistance in vivo is still unclear. Here we show C57BL/6J mice intraperitoneally injected with Aβ42 exhibit increased fasting blood glucose level, impaired insulin tolerance, and hepatic insulin signaling. Moreover, the APPswe/PSEN1dE9 AD model mice intraperitoneally injected with anti-Aβ neutralizing antibodies show decreased fasting blood glucose level and improved insulin sensitivity. Injection of Aβ42 activates hepatic JAK2/STAT3/SOCS-1 signaling, and neutralization of Aβ 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 Aβ induces hepatic insulin resistance in vivo via JAK2, suggesting that inhibition of Aβ signaling is a new strategy toward resolving insulin resistance and T2DM.

PMID:
23223021
PMCID:
PMC3609589
DOI:
10.2337/db12-0670
[Indexed for MEDLINE]
Free PMC Article

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