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Lee, H.Y.* ; Gattu, A.K.* ; Camporez, J.P.* ; Kanda, S.* ; Guigni, B.* ; Kahn, M.* ; Zhang, D.* ; Galbo, T.* ; Birkenfeld, A.L.* ; Jornayvaz, F.R.* ; Jurczak, M.J.* ; Choi, C.S.* ; Yan, Z.* ; Williams, R.S.* ; Shulman, G.I.* ; Samuel, V.T.*

Muscle-specific activation of Ca(2+)/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice.

Diabetologia 57, 1232-1241 (2014)
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AIMS/HYPOTHESIS: Aerobic exercise increases muscle glucose and improves insulin action through numerous pathways, including activation of Ca(2+)/calmodulin-dependent protein kinases (CAMKs) and peroxisome proliferator γ coactivator 1α (PGC-1α). While overexpression of PGC-1α increases muscle mitochondrial content and oxidative type I fibres, it does not improve insulin action. Activation of CAMK4 also increases the content of type I muscle fibres, PGC-1α level and mitochondrial content. However, it remains unknown whether CAMK4 activation improves insulin action on glucose metabolism in vivo. METHODS: The effects of CAMK4 activation on skeletal muscle insulin action were quantified using transgenic mice with a truncated and constitutively active form of CAMK4 (CAMK4([Symbol: see text])) in skeletal muscle. Tissue-specific insulin sensitivity was assessed in vivo using a hyperinsulinaemic-euglycaemic clamp and isotopic measurements of glucose metabolism. RESULTS: The rate of insulin-stimulated whole-body glucose uptake was increased by ∼25% in CAMK4([Symbol: see text]) mice. This was largely attributed to an increase of ∼60% in insulin-stimulated glucose uptake in the quadriceps, the largest hindlimb muscle. These changes were associated with improvements in insulin signalling, as reflected by increased phosphorylation of Akt and its substrates and an increase in the level of GLUT4 protein. In addition, there were extramuscular effects: CAMK4([Symbol: see text]) mice had improved hepatic and adipose insulin action. These pleiotropic effects were associated with increased levels of PGC-1α-related myokines in CAMK4([Symbol: see text]) skeletal muscle. CONCLUSIONS/INTERPRETATION: Activation of CAMK4 enhances mitochondrial biogenesis in skeletal muscle while also coordinating improvements in whole-body insulin-mediated glucose.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Journal Diabetologia
Quellenangaben Volume: 57, Issue: 6, Pages: 1232-1241 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Berlin ; Heidelberg [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute for Pancreatic Beta Cell Research (IPI)