TMF1- A novel mediator of the Insulin regulated glucose homeostasis and normal glycemic level

Significance 

Striking a balance between the appearance of glucose in the blood and its uptake into cells and use by the body’s tissues is how the body maintains normal glucose homeostasis. GLUT4 is an insulin-sensitive glucose transporter; in muscle and adipose tissues, which are major sites for insulin-regulated postprandial glucose disposal, it is the most abundant glucose transporter. GLUT4 effects glucose uptake at the plasma membrane and its translocation to this site is driven by insulin. It is important to decipher the regulatory components and steps that mediate and control this complex translocation process. The TATA Element Modulatory Factor (TMF1) is a protein that was initially identified as a transcription regulator that can bind to the TATA element in the human immunodeficiency virus genome. It has however been found to have multiple cellular interactors and cellular functions. Studies have shown that TMF1 can associate with vesicles through several mediators, and has been implicated in vesicle trafficking and fusion.

In a new study by Israeli scientists from the Bar-Ilan University: Roni Rahimi, Israel Malek, Tali Lerrer-Goldshtein, Yoav Elkis, Irit Shoval, Avi Jacob, Dr. Sally Shpungin and Professor Uri Nir examined the regulatory role of TMF1 in the GLUT4 mediated, insulin-directed glucose uptake. Their results showed that TMF1 is essential for the translocation of GLUT4-carrying vesicles from a perinuclear compartment to the cytosol and to the plasma membrane. The original research article is now published in the FASEB Journal.

The research team observed that insulin upregulated TMF1 in myoblasts and the formation of insulin responsive, glucose transporter GLUT4-containing vesicles required TMF1. Thus, the absence of TMF1 led to an alteration in the subcellular localization of GLUT4 in myoblastic cells. This caused GLUT4-carrying vesicles to be non-responsive to insulin stimulation and impaired GLUT4 trafficking throughout the cytoplasm and to the cell plasma membrane.

In addition to the upregulation of TMF1, the authors also found that insulin stimulated the co-distribution of TMF1 with GLUT4 containing vesicles. The absence of TMF1 resulted in an elevation in GLUT4 levels and also increased the basal level of the insulin receptor in unstimulated TMF1 deficient cells. The absence of TMF1 reduced glucose uptake in myoblastic cells. This was noticed when TMF1-deficient cells displayed an impaired response to insulin and their glucose uptake was only slightly increased after being subjected to insulin treatment for 30 or 60 minutes, comparing to normal myoblastic cell that showed significantly higher glucose uptake.

Just as TMF1 deficient cells had impaired glucose uptake, TMF1 deficient mice were also observed to be hyperglycemic as reflected by the mice impaired sustenance of blood glucose level under starvation, and abnormal blood glucose clearance after glucose overload. TMF1 deficient mice were also noticed to be leaner than their normal littermates.

Through this study, the authors have identified a new physiological role of TMF1, which combines some of the earlier known functions of this multifunctional protein. They have demonstrated that TMF1 is upregulated by insulin and is required for the homeostasis of glucose. They also showed that TMF1 mediated the formation of glucose transporter GLUT4-containing vesicles that were responsive to insulin, and the trafficking of these vesicles to the plasma membrane of insulin-stimulated cells, where GLUT4 can perform insulin-regulated glucose uptake.

In summary, the findings of Professor Uri Nir and his colleagues show that TMF1 is a novel effector of insulin-regulated glucose homeostasis, and malfunction of this protein may contribute to the onset of a diabetes-like disorder. Development of new therapies that manipulate the TMF signaling might offer novel diabetes treatment.

Reference

Rahimi R, Malek I, Lerrer-Goldshtein T, Elkis Y, Shoval I, Jacob A, Shpungin S, Nir U. TMF1 is upregulated by insulin and is required for a sustained glucose homeostasis. FASEB J. 2021;35(2):e21295.

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