Inaugural Article: The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome

Harvard University, Cambridge, Massachusetts, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2007; 104(31):12587-94. DOI: 10.1073/pnas.0705408104
Source: PubMed


We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by approximately 60% in young, lean, insulin-resistant subjects compared with a similar cohort of age-weight-body mass index-activity-matched, insulin-sensitive, control subjects. In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects. These changes were associated with a 60% increase in plasma triglyceride concentrations and an approximately 20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-alpha, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume. These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-alpha, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome.

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    • "Thus, the vasodilatory and antioxidant effects of insulin are depressed in case of insulin deficiency and IR conditions. IR plays a major patho-physiological role in type 2 diabetes and is tightly associated with major public health problems including obesity, hypertension, coronary artery disease, dyslipidemias, and a cluster of metabolic and cardiovascular abnormalities that define the metabolic syndrome [3] [4]. The increase of childhood obesity has determined the increased incidence and prevalence of IR and its cardiovascular complications [5]. "
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    ABSTRACT: Insulin resistance (IR) impairs cellular response to insulin due to a dysfunction in glucose metabolism, associated with an increased cardiovascular risk. The aim of our study was to investigate the relationship among homeostasis model assessment index (HOMA index), endothelial function and vascular morphology in order to better stratify cardiovascular risk in children and adolescents. A total of 150 children and adolescents (55 pre-pubertal, mean age 10.4±3.1years) were enrolled. Anthropometric [body mass index (BMI), waist circumference (WC)], laboratory [blood lipids, inflammatory markers, insulinemia, glycemia], HOMA index and ultrasound parameters [flow-mediated dilatation (FMD), common carotid intima-media thickness (cIMT) and antero-posterior diameter of infra-renal abdominal aorta (APAO)] were assessed. cIMT was positively related to age (r=0.274, p<0.01), BMI (r=0.318, p<0.01), WC (r=0.315, p<0.01) and triglycerides (r=0.230, p<0.01). APAO measurements showed a linear positive correlation with age (r=0.435, p<0.01), BMI (r=0.505, p<0.01), WC (r=0.487, p<0.01), triglycerides (r=0.280, p<0.01), C-reactive protein (r=0.209, p<0.05), fasting insulin (r=0.378, p<0.01) and HOMA index (r=0.345, p<0.01). FMD was inversely related to age (r=-0.251, p<0.01), rough BMI (r=-0.318, p<0.01), WC (r=-0.340, p<0.01), fasting insulin (r=-0.281, p<0.01) and HOMA index (r=-0.282, p<0.01). Multiple regression analysis found no influence of HOMA index on APAO and cIMT. HOMA index was an independent predictor for brachial artery FMD worsening after the statistical adjustment. HOMA index increase induced a worsening in endothelial function since childhood.
    Full-text · Article · Apr 2014 · International journal of cardiology
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    • "According to NCEP ATP III, a lifestyle change, including increased physical activity, reduces the incidence of cardiovascular disease. Other studies involving cardiovascular disease patients also showed the effectiveness of physical activity on MS and insulin resistance.36) "
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    ABSTRACT: This study aimed to investigate the relationship between leisure time physical activities (LTPA) and metabolic syndrome (MS). Five thousand seven hundred and thirty two adults 40 years old or older were enrolled in the study from April 2009 to December 2010. National Cholesterol Education Program's Adult Treatment Panel III was used for the criteria of MS, and Minnesota Leisure Time Physical Activity Questionnaire was used to measure LTPA. After adjusted covariates (age, hypertension, smoking, drinking, education level, household income level, work time physical activities, and menopause for females), the relationship between LTPA and MS was analyzed using logistic regression analysis. The prevalence of MS was 22.8% in men, and 14.1% in women. Average LTPA was 1,498 kcal/wk in men, and 1,308 kcal/wk in women. After adjustment for covariates, the odds ratios of middle and low LTPA compared with high LTPA were 1.06 (0.87-1.34), 1.54 (1.08-1.75), for women, this same association was not seen in men. The prevalence of MS was 22.8% in men and 14.1% in women, and their LTPA burned 1,498 and 1,308 kcal/wk, respectively. When the odds ratio of MS for the high LTPA group was set at 1.0, the odds ratio of MS was 1.06 (0.87-1.34) in the middle LTPA group and 1.54 (1.08-1.75) in the low LTPA group in women, which showed that the MS risk increased when the LTPA was lower. This same association was not seen in men. LTPA was independently associated with metabolic syndrome, but only for women.
    Full-text · Article · Mar 2014 · Korean Journal of Family Medicine
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    • "The accretion of hepatic DAG content could be a result of prolonged, intensified FFAs release from insulin resistant white adipose tissue [17]. The latter, in tandem with decreased mitochondrial í µí»½-oxidation rate and increased hepatic de novo lipogenesis, is likely to be the factor contributing to overaccumulation of DAG in hepatocytes [18]. "
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    ABSTRACT: Nowadays diabetes is one of the most common metabolic diseases. Sphingolipids, which are vitally important constituents of intracellular signal transduction pathways, may be among the most pathogenic lipid moieties intermingled in the origin and development of diabetes. It is now well established that inhibition of de novo ceramide synthesis with myriocin exerts positive effects on lipid metabolism and glucose homeostasis in type 2 diabetes mellitus animal models. However, its influence on type I diabetes still remains unknown. Therefore, the scope of this paper is to fulfill that particular gap in our knowledge.
    Full-text · Article · Feb 2014
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