Succinate-induced glucose uptake in skeletal muscle - a new therapeutic target for diabetes?
Dr Ingrid Wernstedt Asterholm
University of Gothenburg
2 000 000 SEK - 2020
We aim to identify a new therapeutic target for type-1 and type-2 diabetes by elucidating the mechanism for succinate-induced glucose uptake in muscle. In diabetes, glucose uptake is reduced due to decreased insulin levels and/or insulin resistance. Many diabetic patients are thus in need of insulin, but insulin therapy has side effects. Therefore, complementary treatment options would be valuable, and our hope is that this project will lead to the development of such options.
Based on our results, we hypothesize that increased succinate release from working muscle mediates increased glucose uptake. Succinate is a metabolite that normally is found inside the cells, but can also be released into the blood stream when the cells experience e.g. insufficient energy and/or oxygen levels. Thereby, we propose that increased succinate release helps the muscle to meet its increased metabolic demand during physical exercise.
Furthermore, we propose that this glucose uptake mechanism can be targeted to treat diabetes. To test these hypotheses, we will use mice, human blood and muscle biopsies, and cultured cells. Relevance to diabetes and potential benefit to people living with diabetes: In diabetes, glucose uptake is reduced due to decreased insulin levels and/or insulin resistance. Many diabetic patients are thus in need of insulin, but insulin therapy has side effects. Therefore, the development of complementary treatments would be valuable for people living with diabetes.
In this basic research project, we will elucidate a potentially insulin-independent mechanism that stimulates glucose uptake in skeletal muscle. Moreover, we will test if this mechanism improves the glucose homeostasis in mouse models of type-1 and type-2 diabetes. We believe that a successful outcome of this project will lead to the development of new strategies for the management of diabetes that will reduce the need for insulin therapy and yet improve the metabolic control in diabetic patients.