RESUMEN
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 × 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.
Asunto(s)
Diabetes Mellitus Tipo 2 , Familia , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos/genética , Músculo Esquelético/metabolismo , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Regulación hacia Abajo/genética , Regulación de la Expresión Génica , Genes/fisiología , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/fisiología , Músculo Esquelético/fisiologíaRESUMEN
AIMS: The purpose of this study was to evaluate the effects of exercise on cardio-respiratory fitness and insulin sensitivity in sedentary, overweight Arabian and Swedish women with type 2 diabetes. METHODS: Eighteen Arabian and 14 Swedish women participated in a supervised 6-month resistance training and aerobic program of moderate intensity. Insulin sensitivity and VO(2max) were measured at entry to the study and after 3 and 6 months training. RESULTS: After 6 months exercise, insulin sensitivity (M-value) increased (2.7+/-1.4 mg kg(-1) min(-1) vs. 3.4+/-2 mg kg(-1) min(-1), p<0.05) in all patients and accounted for by an increase in non-oxidative glucose metabolism (0.3+/-1.1 mg kg(-1) min(-1) vs. 1.5+/-1.5 mg kg(-1) min(-1), p<0.005) with no significant difference between the ethnic groups. Notably, significant improvement in HbA1c was only seen in the Swedish patients who achieved greater exercise intensity (73.3+/-4.8% vs. 63.3+/-5.2% of maximum heart rate, p<0.005). No changes were observed regarding VO(2max) or lipid profile in either group. CONCLUSIONS: Although a 6-month exercise intervention of moderate intensity in Arabian and Swedish patients with type 2 diabetes can improve insulin sensitivity it is hampered by the metabolic inflexibility of switching between oxidation of glucose or fat.
