Protective effects of carbohydrate restriction on the liver of insulin resistant mice with a deficiency in TBC1D4

Background and aims: The Rab-GTPase activating protein (RabGAP) TBC1D4 (AS160) plays a crucial role in glucose homeostasis by facilitating glucose uptake from the blood into skeletal muscle and adipose tissue. In Arctic populations, a muscle-specific nonsense mutation (p.Arg684Ter) in the Tbc1d4 gene has been associated with postprandial hyperglycemia, hyperinsulinemia and a substantially elevated Type 2 Diabetes Mellitus (T2D) risk. This variant is hypothesized to represent an evolutionary adaptation to the traditional lifestyle of indigenous populations, which is characterized by a diet high in protein and low in carbohydrate content (Arctic diet). A previous study has shown that Greenlanders with T2D have a more favourable outcome on liver complications caused by diabetes, compared to a reference population. The aim of our study is to gain a better understanding of the role of the liver in Tbc1d4-deficency and the interactions between insulin-responsive tissues. To this end, we assess liver function in Tbc1d4-deficient mice after a dietary intervention with either an Arctic or a Western diet high in saturated fats and carbohydrates.