First-degree relatives of type 2 diabetic patients have reduced expression of genes involved in fatty acid metabolism in skeletal muscle
The Journal of Clinical Endocrinology & Metabolism, 2012•academic.oup.com
Context: First-degree relatives of patients with type 2 diabetes (FH+) have been shown to
have decreased energy expenditure and decreased expression of mitochondrial genes in
skeletal muscle. In previous studies, it has been difficult to distinguish whether mitochondrial
dysfunction and differential regulation of genes are primary (genetic) or due to reduced
physical activity, obesity, or other correlated factors. Objective: The aim of this study was to
investigate whether mitochondrial dysfunction is a primary defect or results from an altered …
have decreased energy expenditure and decreased expression of mitochondrial genes in
skeletal muscle. In previous studies, it has been difficult to distinguish whether mitochondrial
dysfunction and differential regulation of genes are primary (genetic) or due to reduced
physical activity, obesity, or other correlated factors. Objective: The aim of this study was to
investigate whether mitochondrial dysfunction is a primary defect or results from an altered …
Context
First-degree relatives of patients with type 2 diabetes (FH+) have been shown to have decreased energy expenditure and decreased expression of mitochondrial genes in skeletal muscle. In previous studies, it has been difficult to distinguish whether mitochondrial dysfunction and differential regulation of genes are primary (genetic) or due to reduced physical activity, obesity, or other correlated factors.
Objective
The aim of this study was to investigate whether mitochondrial dysfunction is a primary defect or results from an altered metabolic state.
Design
We compared gene expression in skeletal muscle from 24 male subjects with FH and 26 without FH matched for age, glucose tolerance, VO2peak (peak oxygen uptake), and body mass index using microarrays. Additionally, type fiber composition, mitochondrial DNA content, and citrate synthase activity were measured. The results were followed up in an additional cohort with measurements of in vivo metabolism.
Results
FH+ vs. FH− subjects showed reduced expression of mitochondrial genes (P = 2.75 × 10−6), particularly genes involved in fatty acid metabolism (P = 4.08 × 10−7), despite similar mitochondrial DNA content. Strikingly, a 70% reduced expression of the monoamine oxidase A (MAOA) gene was found in FH+ vs. FH− individuals (P = 0.0009). Down-regulation of the genes involved in fat metabolism was associated with decreased in vivo fat oxidation and increased glucose oxidation examined in an additional cohort of elderly men.
Conclusions
These results suggest that genetically altered fatty acid metabolism predisposes to type 2 diabetes and propose a role for catecholamine-metabolizing enzymes like MAOA in the regulation of energy metabolism.
Oxford University Press