title: Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis.
abstract: Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. rks16@cam.ac.uk
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.forename: Alison
authors.initials: A
authors.lastname: Sleigh
authors.forename: Peter R
authors.initials: PR
authors.lastname: Murgatroyd
authors.forename: Claire A
authors.initials: CA
authors.lastname: Adams
authors.forename: Les
authors.initials: L
authors.lastname: Bluck
authors.forename: Sarah
authors.initials: S
authors.lastname: Jackson
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vottero
authors.forename: Dipak
authors.initials: D
authors.lastname: Kanabar
authors.forename: Valentine
authors.initials: V
authors.lastname: Charlton-Menys
authors.forename: Paul
authors.initials: P
authors.lastname: Durrington
authors.forename: Maria A
authors.initials: MA
authors.lastname: Soos
authors.forename: T Adrian
authors.initials: TA
authors.lastname: Carpenter
authors.forename: David J
authors.initials: DJ
authors.lastname: Lomas
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Cochran
authors.forename: Phillip
authors.initials: P
authors.lastname: Gorden
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
mesh_terms: D000293:Adolescent; D000328:Adult; D050171:Dyslipidemias / Q000209:etiology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000209:etiology*; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D005230:Fatty Acids, Nonesterified; D008079:Lipoproteins, VLDL; D011972:Receptor, Insulin; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt