Fig. 3: The role of Gα13 in interorgan biological processes in insulin resistance.
Hepatic Gα13 levels are downregulated in high-fat diet (HFD)-fed or genetically obese mice and patients with diabetes. In response to a decrease in Gα13, the inter-α-trypsin inhibitor heavy chain 1 (ITIH1) is O-GlcNAcylated by O-GlucNAc transferase (OGT) induced in hepatocytes and then excessively secreted into the bloodstream. ITIH1 is a binding partner of HA, one of the major extracellular matrix components. In mice deficient in Gα13 in hepatocytes, increased ITIH1 is deposited onto the hyaluronan surrounding skeletal muscle and white adipose tissue. Overproduction of ITIH1 from the liver after the loss of Gα13 causes systemic insulin resistance. Treatment with ST045849 (an inhibitor of O-GlcNAC transferase) or antibody neutralization of ITIH1 ameliorates systemic insulin resistance.
