Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis.
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.
Semple
Robert K
RK
Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. rks16@cam.ac.uk
Sleigh
Alison
A
Murgatroyd
Peter R
PR
Adams
Claire A
CA
Bluck
Les
L
Jackson
Sarah
S
Vottero
Alessandra
A
Kanabar
Dipak
D
Charlton-Menys
Valentine
V
Durrington
Paul
P
Soos
Maria A
MA
Carpenter
T Adrian
TA
Lomas
David J
DJ
Cochran
Elaine K
EK
Gorden
Phillip
P
O'Rahilly
Stephen
S
Savage
David B
DB
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
D005230:Fatty Acids, Nonesterified; D008079:Lipoproteins, VLDL; D011972:Receptor, Insulin; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt