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

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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.

Abstract

The impact of liver disease on whole-body glucose homeostasis is largely attributed to dysregulated release of secretory proteins in response to metabolic stress. The molecular cues linking liver to whole-body glucose metabolism remain elusive. We found that expression of G protein α-13 (Gα13) was decreased in the liver of mice and humans with diabetes. Liver-specific deletion of the Gna13 gene in mice resulted in systemic glucose intolerance. Comparative secretome analysis identified inter-α-trypsin inhibitor heavy chain 1 (ITIH1) as a protein secreted by liver that was responsible for systemic insulin resistance in Gna13-deficient mice. Liver expression of ITIH1 positively correlated with surrogate markers for diabetes in patients with impaired glucose tolerance or overt diabetes. Mechanistically, a decrease in hepatic Gα13 caused ITIH1 oversecretion by liver through induction of O-GlcNAc transferase expression, facilitating ITIH1 deposition on the hyaluronan surrounding mouse adipose tissue and skeletal muscle. Neutralization of secreted ITIH1 ameliorated glucose intolerance in obese mice. Our findings demonstrate systemic insulin resistance in mice resulting from liver-secreted ITIH1 downstream of Gα13 and its reversal by ITIH1 neutralization.

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