Impaired insulin-mediated glucose uptake in skeletal muscle is believed to be the primary defect leading to the development of type 2 diabetes. Our research aims at finding means to improve peripheral glucose metabolism by manipulating thioredoxin and thioredoxin-interacting protein (TXNip).

Thioredoxin system is composed of the small oxidoreductase thioredoxin, thioredoxin reductase and NAPDH. This system is essential for life in mammals, as it regulates cellular redox status and maintains proteins in their reduced state. TXNip is a pro-apoptotic protein that binds to thioredoxin with high affinity, inhibiting its activity. TXNip-deficiency gives protection against diabetes by preventing beta-cell death and enhancing glucose uptake in fat and skeletal muscle cells, whereas TXNip overexpression has an inhibitory effect on glucose uptake. Blood glucose level and insulin have opposite roles in regulating the TXNip protein in the skeletal muscle. High glucose increases the expression of TXNip, which further increases the glucose level in blood by inhibiting glucose uptake. In contrast, insulin reduces TXNip expression. TXNip expression is found to be consistently higher in the muscles of patients with type 2 diabetes or prediabetic condition, characterized by insulin resistance and elevated blood glucose level.

We have developed rat L6 skeletal muscle cell lines where thioredoxin or TXNip have been stably overexpressed / silenced. According to our recent findings, overexpression of thioredoxin downregulates endogenous TXNip in L6 myoblasts, and we seek to elucidate the mechanisms by which thioredoxin is regulating TXNip expression. We are also characterizing how changes in thioredoxin / TXNip expression affect glucose uptake in differentiated L6 myotubes. We are in process of shedding some light on the mechanisms by which TXNip inhibits glucose uptake and improving glucose uptake through intracellular TXNip silencing. As any impairment in skeletal muscle glucose uptake disturbs the whole body glucose homeostasis, new means to interfere with the inhibitory effect of TXNip would have a major therapeutic potential in the prevention of type 2 diabetes.