Muscle glucose absorption driven by insulin is an important step in glycemic regulation. This process is dependent on the redistribution of glucose transporters to the surface membrane, which is regulated by proteins like TBC1D1 and TBC1D4. As a result, a TBC1D4 loss-of-function mutation in human skeletal muscle is related to an elevated risk of type 2 diabetes, and TBC1D1 variation carriers have a severe obesity phenotype.
An unbiased proteomics technique was used to identify interactors of the endogenous TBC1D4 protein in human skeletal muscle. Researchers identified 76 proteins as potential TBC1D4 interactors. Insulin affected the binding of 12 of these interactors, including proteins involved in glucose metabolism (e.g., 14-3-3 proteins and -actinin-4 [ACTN4]). In both human and mouse skeletal muscle, TBC1D1 co-occurred with TBC1D4 and vice versa. Insulin or exercise did not affect this relationship in young, healthy, lean people. Similarly, exercise or insulin did not affect the TBC1D1-TBC1D4 complex’s phosphorylation.
In contrast, they discovered an altered interaction and impaired insulin-stimulated phosphoregulation of the TBC1D1-TBC1D4 complex in the muscle of obese type 2 diabetes patients. Overall, they presented a library of TBC1D4 interactors in human and mouse skeletal muscle that may operate as possible regulators of TBC1D4 activity and insulin-stimulated glucose uptake in human skeletal muscle.