title: The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Kitt Falk
authors.initials: KF
authors.lastname: Petersen
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dufour
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
authors.forename: Stefan
authors.initials: S
authors.lastname: Bilz
authors.forename: Gina
authors.initials: G
authors.lastname: Solomon
authors.forename: Shin
authors.initials: S
authors.lastname: Yonemitsu
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.forename: Douglas
authors.initials: D
authors.lastname: Befroy
authors.forename: Laura
authors.initials: L
authors.lastname: Zemany
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
authors.forename: Xenophon
authors.initials: X
authors.lastname: Papademetris
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Rothman
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D016207:Cytokines / Q000097:blood; D005215:Fasting; D006003:Glycogen / Q000378:metabolism; D006728:Hormones / Q000097:blood; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D024821:Metabolic Syndrome / Q000453:epidemiology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*
chemical_list: D016207:Cytokines; D006728:Hormones; D006003:Glycogen