ESPE Abstracts (2019) 92 FC1.1

Insulin Resistance Leads to Mitochondrial Dysfunction in Hepatocyte

Hong Chen, Yanlan Fang, Li Liang, Chunlin Wang


The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China


Background: Insulin resistance in obesity and type 2 diabetes is associated with abnormalities in mitochondrial oxidative phosphorylation in skeletal muscle. Whether mitochondrial function changes in hepatocytes with hereditary insulin resistance is not clear. Type A Insulin Resistance Syndrome (TAIRS) is a rare disorder characterized by severe insulin resistance, a condition in which the body's tissues and organs do not respond properly to the hormone insulin. TAIRS is often caused by mutations in the INSR gene, leading to insulin receptor dysfunction.

Objective and Methods: To define the causal relationship between hereditary insulin resistance and mitochondrial dysfunction, we used Crispr/cas9 technology to precisely edit the INSR gene in hepatocellular carcinoma (HepG2) cells to construct a hereditary model of insulin resistance. Mitochondrial metabolism, oxidative respiratory chain and reactive oxygen species (ROS) levels were compared in wild type (INSR-WT) and mutant (INSR-MUT) HepG2 cell lines.

Results: Compared with the INSR-WT group, INSR gene mutation resulted in incomplete activation of downstream PI3K-Akt and MAPK-Erk signaling pathways and decreased cell glucose uptake. Mitochondrial function was changed in the INSR-MUT group, and oxidative respiratory chain-related proteins (such as ND5, ATP8 and Cox2) were significantly increased, and ATP production was reduced. Mitochondrial ROS increase, exacerbating insulin resistance.

Conclusions: Insulin resistance caused by INSR gene mutation can lead to mitochondrial dysfunction in hepatocyte, abnormal oxidative respiratory chain and reduced energy production. In addition, increased ROS may aggravate insulin resistance.

Keywords: Insulin resistance, INSR, Mitochondrial Dysfunction, Gene

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