Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance.

ABSTRACT: Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations. 'Diversity Outbred in Australia (DOz)' is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscle's contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that associated with whole-body insulin sensitivity (Matsuda Index) including regulators of endocytosis and muscle proteostasis. To enrich for causality, we refined this network by focusing on negatively associated, genetically regulated proteins, resulting in a 76-protein fingerprint of insulin resistance.

SUBMITTER: Masson SWC 

PROVIDER: S-EPMC10371229 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature