Title of project

From correlation to causation: Illuminating the role of mTORC1 signaling in muscle insulin action in man

Abstract

During insulin stimulation up to 80% of all glucose is disposed in skeletal muscle. Thus, skeletal muscle is integral in maintaining euglycemia. Accordingly, muscle insulin resistance is a central pathology within type II diabetes. Despite this, there are currently no available pharmacological treatments that specifically targets muscle insulin resistance to alleviate hyperglycemia in type II diabetes. The main reason underlying this is that skeletal muscle insulin resistance is, despite rigorous research, still incompletely understood. Notably, we recently observed a robust and surprising a positive correlation between mTORC1-signaling and insulin-stimulated muscle glucose uptake, which we have confirmed in insulin resistant subjects in preliminary data. Thus, now we want to take correlation to causation by utilizing the mTORC1 inhibitor rapamycin in humans to illuminate the impact of mTORC1 signaling on insulin action.

During two experimental days with and without rapamycin, we will utilize invasive methodologies such as femoral arteriovenous catheterization and muscle biopsy sampling during a ‘gold standard’ hyperinsulinemic clamp to obtain a deep glucometabolic in vivo phenotyping, which will allow us to quantify the impact of mTORC1 signaling on insulin action. Furthermore, we believe that by combining our deep in vivo phenotyping and functional measurements with state-of-the-art muscle phosphoproteomics, we will be able to identify pivotal molecular junctions that possess the potential to become future therapeutic targets to combat muscle insulin resistance in type II diabetes. Finally, through a collaboration, we are currently gathering a cohort of lean, healthy obese and subjects with type II diabetes. Through in vivo clamp data with muscle biopsies before and after insulin stimulation, this will allow us to separate the impact of type II diabetes from that of obesity alone and provide independent, clinically relevant confirmation of the importance of mTORC1-signaling in muscle insulin resistance in type II diabetes.

Thus, through a sophisticated, invasive setup combined with advanced methodologies, we believe that this study has a large potential of providing novel data on muscle insulin resistance in type II diabetes. Furthermore, the combination of in vivo functional measures of insulin action and state-of-the-art muscle phosphoproteomics, will allow us illuminate new potential molecular drug targets to combat insulin resistance in type II diabetes.