Tbc1d4, also known as AS160 (Akt Substrate of 160 kDa), is a Rab GTPase-activating protein (RabGAP) that plays a crucial role in glucose homeostasis [2,3,4,5,6]. It is involved in regulating glucose transport into skeletal muscle and white adipose tissue, and is thus important in the development of insulin resistance and type 2 diabetes. Additionally, it participates in autophagic and endocytic pathways [1]. Genetic models, such as KO mouse models, have been instrumental in studying its functions.

In KO mouse models, hepatocyte-or adipocyte-specific tbc1d4 knockout led to elevated autophagic flux and endocytic degradation and tissue damage, establishing Tbc1d4 as a critical molecular brake in autophagic and endocytic pathways [1]. Conventional Tbc1d4-deficient (D4KO) mice fed a high-fat diet showed improved glucose and insulin tolerance after moderate endurance exercise training, indicating that chronic exercise can overcome the genetically induced insulin resistance caused by Tbc1d4 depletion [3]. In cardiac tissue, Tbc1d4-knockout abolished insulin-stimulated glucose uptake and led to increased myocardial damage after ischemia/reperfusion [5].

In summary, Tbc1d4 is essential for maintaining normal glucose homeostasis and regulating autophagic and endocytic pathways. The use of KO mouse models has provided key insights into its role in diseases such as insulin resistance, type 2 diabetes, and cardiovascular disease, highlighting its potential as a therapeutic target for these conditions.