When we eat a meal, the pancreas secretes insulin to signal that energy is plenty and should be harvested. High insulin means that energy stores should not be used but replenished. If a person has type 2 diabetes, this system is not functioning properly. We talk about the two hallmarks of type 2 diabetes, i.e. (1) decreased insulin secretion from the pancreas and (2) decreased insulin sensitivity of target tissues like fat, muscle and the liver. This leads to abnormally high blood glucose levels, which is the definition of diabetes. The largest user of glucose in the body is by far skeletal muscle. When we get older our muscles are getting less and less sensitive to insulin, but this can be counteracted by physical exercise. Today we have ways to pharmacologically stimulate the pancreas to enhance insulin secretion, but unfortunately after many years of research, still no drug to enhance insulin sensitivity specifically targeting skeletal muscle. Reasons for this lack of success could be many, but differences in muscle function and metabolism between humans and model organisms commonly used in research is probably contributing. The aim of this project is to use novel methods to finally identify pharmacological targets to specifically increase muscle insulin sensitivity.

We will test two different approaches. In aim I, we will take advantage of naturally occurring rare mutations that may change muscle insulin sensitivity in humans. By sequencing the DNA of ~10.000 individuals, we have already identified one such candidate in the MSS51 gene. A mutation carried by 139 individuals. This gene is only activated in skeletal muscle and has previously been linked to diabetes in rodent studies. We will now invite mutation carriers and measure their insulin sensitivity. Muscle stem cells will be isolated from biopsies to study how insulin sensitivity may be influenced by MSS51. With this study we will be able to test if MSS51 is associated with diabetes also in humans. In aim II we will investigate if a biological mechanism called splicing may be used to develop a completely new type of drugs to increase muscle insulin sensitivity. Taken together, this project will explore new approaches to elucidate the underlying mechanisms of insulin sensitivity in humans with the goal of identifying novel pharmacological targets to improve muscle health.