Final Report

Insulin is a hormone, which reduces blood glucose ("blood sugar") concentration mainly by stimulating the transfer of glucose from blood into skeletal muscle, where glucose is stored as glycogen (a starch-like compound). Hence, muscle is important for the treatment of diabetes mellitus, a disease characterized by increased blood glucose due to shortage in insulin and/or shortage in the efficacy of available insulin.
The present project employed isolated specimens of rat muscle to better understand insulin action.
Part 1 of the project was to better understand the chain of biochemical events, via which insulin triggers glycogen storage in muscle cells. We were able to demonstrate that changes in cell volume are not related to insulin action or to the induction of glycogen storage in muscle, which is contrast to what is known for the liver. It is important to understand the signalling chain, via which insulin exerts its actions on muscle cells, because defects in this chain can cause diabetes, and because compounds that interact with this chain could be helpful for the treatment of diabetes.
Part 2 of the project dealed with TZDs, a novel class of compounds used for the treatment of diabetes. TZDs decrease blood glucose by improving insulin´s action on muscle. It is believed that this is - at least in part - due to their impact on fat tissue, which releases signals that finally act on skeletal muscle. It was the aim of our study to examine, if and in what way TZDs can directly act on skeletal muscle. We found that TZDs indeed exert marked direct effects on muscle metabolism, and we demonstrated an acute inhibitory effect on cellular respiration, a previously unknown aspect of TZD action. Furthermore, we demonstrated that the biochemical targets and mechanisms responsible for TZD-induced inhibition of respiration are completely different from those underlying their established effects on fat. Such elucidation of the cellular actions of TZDs is essential to optimize their therapeutic application and to avoid unwanted side effects.