Potential Role of the GLUT4 Tether TUG in AMPK-mediated Glucose Uptake
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Type 2 diabetes is quickly growing into an epidemic. Often known for its hyperglycemic state, type 2 diabetes also leads to dyslipidemia, β-cell dysfunction, and increased inflammation. These characteristics make the diabetic prone to cardiovascular problems, greatly enhancing their risk for heart failure and myocardial infarction by negatively impacting the plasticity of cardiac metabolism. AMPK, an enzyme responsible for activating catabolic pathways during energetic need, has grown into a potential therapeutic target for the treatment of type 2 diabetes. One reason is its ability to decrease serum glucose levels via stimulation of GLUT4 translocation. However, the mechanisms for this are still relatively unknown. Here, we show through immunoprecipitations (IPs) that AMPK activation in HL-1 cardiomyocytes via AICAR and hypoxia treatments results in the dissociation of TUG from GLUT4, an interaction that has been shown to be important for insulin-mediated glucose uptake. The AMPK inhibitor Compound C was given before AICAR treatment and was shown to prevent TUG separation, suggesting AMPK plays an important role in stimulating the disconnection. AMPK motifs exist on TUG and we believe phosphorylation to be the signal for TUG to detach from GLUT4. IPs revealed AMPK and TUG interact, with AICAR and hypoxia treatments enhancing the interaction between P-AMPK and TUG. Our preliminary data suggests TUG phosphorylation is possible in HL-1 cardiomyocytes. If so, TUG would be a novel AMPK substrate. Regardless, the stimulation of TUG dissociation from the glucose transporter GLUT4 by AMPK activation is a novel interaction that provides a mechanism for AMPK-mediated glucose uptake in the heart. By circumventing insulin resistance and targeting a protein further downstream that is directly involved with glucose uptake, stimulating TUG dissociation from GLUT4 may one day be used as a treatment for diabetes.