Increased Insulin Resistance in 10‐month compared to 5‐month Old Male Hepatic Androgen Receptor Knockout Mice

Abstract

Insulin resistance is an important component of type 2 diabetes and metabolic syndrome. The liver plays an essential component in the metabolism of insulin and androgen signaling. Sex differences exist in type 2 diabetes with men having a higher prevelance than women. In our study we placed male liver androgen receptor knock‐out mice (Liv‐ARKO) on chow diets to determine if Liv‐ARKO had an effect on insulin resistance on younger age (5 month) compared to older age (10 month). In this study, male Liv‐ARKO mice were kept on chow diets for either 5 months or 10 months and then sacrificed. Some mice were given a dose of 0.5 U/kg insulin before sacrificing to investigate the effects of age on insulin signaling. Western blots were used to determine protein expression in tissue from the liver, skeletal muscle, white adipose tissue. BCA assays were used to standardize the protein concentration in each sample. Upon activation of the insulin signaling pathway, the insulin receptor substrate (IRS) proteins, initiates activation of the phosphatidylinositol 3‐kinase (PI3k) pathways, resulting in stimulation of protein kinases such as Akt. As seen in a previous study1 approximately 5 month old (22 week old) hepatic‐AR‐knockout chow mice showed that when stimulated with insulin there was an increase in PI3k activity. This study did not take it a step further to show what was going on with p‐AKT. It was hypothesized that p‐AKT is lowered in both 5 and 10 month old mice compared to mice not given insulin. Additionally, after 10 months, total AKT was increased. Insulin stimulated p‐Foxo was lowered at 5 months but at 10 months p‐Foxo was increased. Our results suggest that Liver Androgen Receptor is causing decreased insulin action at the level of p‐AKT in both young (5 month) and old (10 month) mice. If insulin is not stimulating p‐AKT, the body may try to make more total AKT to try to compensate; hence the increase in total AKT seen in the 10 month mice. Further investigation should also be performed on the gender differences in these results.