Research ArticleMetabolism

Overproduction of inter-α-trypsin inhibitor heavy chain 1 after loss of Gα13 in liver exacerbates systemic insulin resistance in mice

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Science Translational Medicine  09 Oct 2019:
Vol. 11, Issue 513, eaan4735
DOI: 10.1126/scitranslmed.aan4735

Targeting ITIH1 in metabolic disease

The liver releases secretory proteins in response to metabolic stress. Kim et al. report a decrease in Gα13 in the liver of mice and humans with diabetes. Secretome analysis enabled identification of a specific protein (ITIH1) highly secreted by liver in association with insulin resistance and consequent hyperglycemia. Glycosyl modification of ITIH1 facilitated its deposition on the hyaluronan surrounding mouse adipose tissue and skeletal muscle, making a physical barrier between insulin and its receptor. Neutralization of secreted ITIH1 prevented systemic insulin resistance and ameliorated glucose intolerance in mice. This finding may contribute to developing a new strategy to treat metabolic diseases.

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