Increased Insulin Resistance in Male Hepatic Androgen Receptor Knockout Mice Fed High Fructose Diet

Abstract

Introduction Insulin resistance is a common hepatic dysfunction amongst individuals suffering from diabetes or obesity and affects 10‐25% of the general population1. The intracellular signaling pathway is reliant on every step being executed correctly. It is evident that excess dietary fats and sugars will result in obesity and likely diabetes. This cellular machinery can be altered when there is a build‐up of lipids which impact molecular insulin signaling. Our objective is to determine if chronic intake of fructose by male liver androgen receptor knockout (Liv‐ARKO) mice will show cascade alteration resulting in increased resistance to insulin when compared to male Liv‐ARKO mice on a control diet. We hypothesized that LivARKO mice on HFrD would show impaired insulin action when compared to control and chow diet mice. Methods We placed male Liv‐ARKO mice on high fructose (HFrD), Control (Research Diets Inc), and Chow diets. We performed insulin tolerance tests (ITT), glucose tolerance tests (GTT), and pyruvate tolerance tests (PTT) after 1‐2 months of being on diets. The mice were later sacrificed, and their tissues were extracted for further tests. To assess differences in insulin action that may arise from increased fructose some mice were given a dose of 0.5 U/kg insulin before being sacrificed to further investigate insulin signaling proteins. BCA protein assays were done to ensure that protein concentration in each sample was standardized. Western blots were performed using tissue from liver to measure molecular insulin action, via p‐AKT presence. Results Male mice on control diet for 2‐months showed improved glucose tolerance and enhanced pyruvate tolerance when compared to male mice on control diet for 1 month. Mice on 2‐month control diet showed impaired insulin sensitivity compared to mice on the same diet for 1 month. Male LivARKO mice displayed no insulin stimulated p‐AKT when on a chow diet. Levels of p‐AKT were the same in basal and insulin male LivARKO mice fed a chow diet. Male LivARKO mice fed a control diet displayed a 4‐fold increase in levels of p‐AKT when stimulated by insulin compared to mice not given insulin (basal). Moreover, male LivARKO mice fed a HFrD displayed no insulin stimulated p‐AKT. Foxo1 levels were not altered by insulin stimulation in male LivARKO mice fed a chow, control, or HFrD. However, it should be noted that control and HFrD both increased Foxo1 levels compared to chow diet. Conclusion Our results suggest that hepatic insulin action or the ability for insulin to initiate glucose uptake in liver is decreased in male LivARKO mice on HFrD. Further investigation of Research Diets Inc. data is necessary to determine why the control diet and HFrD lead to the results discovered.