Insulin resistance (IR), a defect in insulin-stimulated glucose uptake in muscle and fat cells, is one of the first metabolic defects to arise in a constellation of human diseases including type 2 diabetes (T2D) and cardiovascular disease. Both genetic and environmental factors regulate insulin sensitivity, although how these mechanisms act, both in isolation and interaction, remains unclear. Complex relationships between IR and other risk factors such as hyperinsulinemia obscure which defect most directly contributes to disease. The mouse provides an ideal model system for disentangling complex phenotypes and the genetic programming of health, although current methods for measuring insulin sensitivity in mice are unsuitable for the large scale of study required.
We developed a novel in vivo method for assessing tissue-specific glucose uptake to overcome this challenge. The dual tracer test of insulin responsiveness quantifies insulin action in individual mice by serial measurement of basal and insulin-stimulated glucose uptake using two differentially radiolabelled 2-deoxyglucose tracers. Results are concordant with those from established single tracer protocols. We leveraged this assay to interrogate tissue-specific insulin responses in 11 inbred mouse strains across two diets, and the spectrum of metabolic dysfunction that resulted. Strains exhibited significant variation in their susceptibility to precise aspects of the metabolic syndrome following high fat high sugar (HFHS) feeding. Strikingly, despite observing considerable heterogeneity in muscle insulin sensitivity across strains fed chow diet, we did not observe a relationship with fasting insulin. The relationship between hyperinsulinemia and IR was only unearthed following HFHS feeding. Strain-specific protection from diet-induced IR was most evident in skeletal muscle and, unlike adipose tissue, explained defects in systemic glucose disposal. These findings implicate skeletal muscle IR as a primary driver of T2D evident prior to the onset of hyperinsulinemia and emphasise the role of gene-by-environment interactions in modifying susceptibility to metabolic disease.