Abstract
BackgroundInsulin resistance (IR) in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and also predicts type 2 diabetes. However, the underlying molecular mechanisms are still poorly understood.MethodsTo explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabetic men to a surrogate measure of insulin sensitivity, i.e. homeostatic model assessment of insulin resistance (HOMA-IR).ResultsWe identified 70 genes positively and 110 genes inversely correlated with insulin sensitivity in human skeletal muscle, identifying autophagy-related genes as positively correlated with insulin sensitivity. Replication in an independent study of 9 non-diabetic men resulted in 10 overlapping genes that strongly correlated with insulin sensitivity, including SIRT2, involved in lipid metabolism, and FBXW5 that regulates mammalian target-of-rapamycin (mTOR) and autophagy. The expressions of SIRT2 and FBXW5 were also positively correlated with the expression of key genes promoting the phenotype of an insulin sensitive myocyte e.g.PPARGC1A.ConclusionsThe muscle expression of 180 genes were correlated with insulin sensitivity. These data suggest that activation of genes involved in lipid metabolism, e.g.SIRT2, and genes regulating autophagy and mTOR signaling, e.g.FBXW5, are associated with increased insulin sensitivity in human skeletal muscle, reflecting a highly flexible nutrient sensing.
Highlights
Insulin resistance (IR) in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and predicts type 2 diabetes
Insulin sensitivity was estimated using the 1/homeostatic model assessment of insulin resistance (HOMA-IR) method calculated from oral glucose tolerance test (OGTT) values (Methods)
Genes involved in fatty acid metabolism (CPT1B and sirtuin 2 (SIRT2)) and in autophagy and mammalian target-of-rapamycin (mTOR) signaling (FBXW5), TSC complex subunit 2 (TSC2) and unc-51 like autophagy activating kinase 1 (ULK1) were found to be associated with insulin sensitivity and related traits
Summary
Insulin resistance (IR) in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and predicts type 2 diabetes. Insulin resistance (or low insulin sensitivity) in skeletal muscle is a key feature of the pre-diabetic state and a predictor of type 2 diabetes (T2D) [1, 2]. It is observed in individuals with hypertension, dyslipidemia, and cardiovascular diseases [3]. Enhancing autophagy in mice leads to an anti-ageing phenotype, including leanness and increased insulin sensitivity [16]
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