Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism

María Isabel Hernández-Alvarez, Angels Díaz-Ramos, María Berdasco, Jeff Cobb, Evarist Planet, Diane Cooper, Agnieszka Pazderska, Krzystof Wanic, Declan O'Hanlon, Antonio Gomez, Laura R de la Ballina, Manel Esteller, Manuel Palacin, Donal J O'Gorman, John J Nolan, Antonio Zorzano

41 Citationer (Scopus)

Abstract

The molecular mechanisms responsible for the pathophysiological traits of type 2 diabetes are incompletely understood. Here we have performed transcriptomic analysis in skeletal muscle, and plasma metabolomics from subjects with classical and early-onset forms of type 2 diabetes (T2D). Focused studies were also performed in tissues from ob/ob and db/db mice. We document that T2D, both early and late onset, are characterized by reduced muscle expression of genes involved in branched-chain amino acids (BCAA) metabolism. Weighted Co-expression Networks Analysis provided support to idea that the BCAA genes are relevant in the pathophysiology of type 2 diabetes, and that mitochondrial BCAA management is impaired in skeletal muscle from T2D patients. In diabetic mice model we detected alterations in skeletal muscle proteins involved in BCAA metabolism but not in obese mice. Metabolomic analysis revealed increased levels of branched-chain keto acids (BCKA), and BCAA in plasma of T2D patients, which may result from the disruption of muscle BCAA management. Our data support the view that inhibition of genes involved in BCAA handling in skeletal muscle takes place as part of the pathophysiology of type 2 diabetes, and this occurs both in early-onset and in classical type 2 diabetes.

OriginalsprogEngelsk
TidsskriftScientific Reports
Vol/bind7
Udgave nummer1
Sider (fra-til)13850
ISSN2045-2322
DOI
StatusUdgivet - 23 okt. 2017

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