First-Degree Relatives of Type 2 Diabetic Patients Have Reduced Expression of Genes Involved in Fatty Acid Metabolism in Skeletal Muscle.

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T1 - First-Degree Relatives of Type 2 Diabetic Patients Have Reduced Expression of Genes Involved in Fatty Acid Metabolism in Skeletal Muscle.

AU - Elgzyri, Targ

AU - Parikh, Hemang

AU - Zhou, Yuedan

AU - Dekker Nitert, Marloes

AU - Rönn, Tina

AU - Segerström, Å B

AU - Ling, Charlotte

AU - Franks, Paul

AU - Wollmer, Per

AU - Eriksson, Karl-Fredrik

AU - Groop, Leif

AU - Hansson, Ola

PY - 2012

Y1 - 2012

N2 - 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, VO(2peak) (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 x 10(-6)), particularly genes involved in fatty acid metabolism (P = 4.08 x 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.

AB - 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, VO(2peak) (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 x 10(-6)), particularly genes involved in fatty acid metabolism (P = 4.08 x 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.

U2 - 10.1210/jc.2011-3037

DO - 10.1210/jc.2011-3037

M3 - Article

VL - 97

SP - E1332-E1337

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

SN - 1945-7197

IS - 7

ER -