Kristoffer Ström1,2, Ola Hansson1,3, Hemang M Parikh4,5, Targ Elgzyri1, Amra Alibegovic6, Natalie Hiscock7, Ola Ekström1, Karl-Fredrik Eriksson1, Allan Vaag6, Leif C Groop1,3. 1. Department of Clinical Sciences, Diabetes & Endocrinology, Lund University, University Hospital Malmö, SE-20502, Malmö, Sweden. 2. Swedish Winter Sports Research Centre, Mid Sweden University, SE-83125, Östersund, Sweden. 3. Finnish Institute of Molecular Medicine, FI-00014, University of Helsinki, Helsinki, Finland. 4. Health Informatics Institute, Morsani College of Medicine, University of South Florida, 3650 Spectrum Blvd, Tampa, FL, 33612, USA. parikhhemangm@gmail.com. 5. Department of Clinical Sciences, Diabetes & Endocrinology, Lund University, University Hospital Malmö, SE-20502, Malmö, Sweden. parikhhemangm@gmail.com. 6. Steno Diabetes Center, DK-2820, Gentofte, Denmark. 7. Unilever Discover R & D, Colworth Science Park, Sharnbrook, Bedfordshire, MK44 1LQ, UK.
Abstract
BACKGROUND: Insulin 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. METHODS: To 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). RESULTS: We 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. CONCLUSIONS: The 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.
BACKGROUND:Insulin 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. METHODS: To explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabeticmen to a surrogate measure of insulin sensitivity, i.e. homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: We 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-diabeticmen 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. CONCLUSIONS: The 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.
Authors: Claus Thamer; Jürgen Machann; Oliver Bachmann; Michael Haap; Dominik Dahl; Beate Wietek; Otto Tschritter; Andreas Niess; Klaus Brechtel; Andreas Fritsche; Claus Claussen; Stephan Jacob; Fritz Schick; Hans-Ulrich Häring; Michael Stumvoll Journal: J Clin Endocrinol Metab Date: 2003-04 Impact factor: 5.958
Authors: M Krssak; K Falk Petersen; A Dresner; L DiPietro; S M Vogel; D L Rothman; M Roden; G I Shulman Journal: Diabetologia Date: 1999-01 Impact factor: 10.122
Authors: S Lillioja; D M Mott; M Spraul; R Ferraro; J E Foley; E Ravussin; W C Knowler; P H Bennett; C Bogardus Journal: N Engl J Med Date: 1993-12-30 Impact factor: 91.245
Authors: G Perseghin; P Scifo; F De Cobelli; E Pagliato; A Battezzati; C Arcelloni; A Vanzulli; G Testolin; G Pozza; A Del Maschio; L Luzi Journal: Diabetes Date: 1999-08 Impact factor: 9.461