A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin.
The epidemic increase in type 2 diabetes can be prevented only if markers of risk can be identified and used for early intervention. We examined the clinical phenotype of individuals characterized by normal or low IRS-1 protein expression in fat cells as well as the potential molecular mechanisms related to the adipose tissue. Twenty-five non-obese individuals with low or normal IRS-1 expression in subcutaneous abdominal fat cells were extensively characterized and the results compared with 71 carefully matched subjects with or without a known genetic predisposition for type 2 diabetes. In contrast to the commonly used risk marker, known heredity for diabetes, low cellular IRS-1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. Circulating levels of adiponectin were also significantly reduced. Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPARgamma, and lipoprotein lipase) in the group of individuals characterized by a low IRS-1 expression and insulin resistance. A low IRS-1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. Impaired adipocyte differentiation, including low gene expression and circulating levels of adiponectin, can provide a link between the cellular marker and the in vivo phenotype.
Jansson
Per-Anders
PA
The Lundberg Laboratory for Diabetes Research, Sahlgrenska Academy at Göteborg University, Sweden.
Pellmé
Fredrik
F
Hammarstedt
Ann
A
Sandqvist
Madeléne
M
Brekke
Hilde
H
Caidahl
Kenneth
K
Forsberg
Margeta
M
Volkmann
Reinhard
R
Carvalho
Eugénia
E
Funahashi
Tohru
T
Matsuzawa
Yuji
Y
Wiklund
Olle
O
Yang
Xiaolin
X
Taskinen
Marja-Riita
MR
Smith
Ulf
U
D052242:Adiponectin; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D001161:Arteriosclerosis / Q000175:diagnosis* / Q000000981:diagnostic imaging; D015415:Biomarkers / Q000032:analysis; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D014158:Transcription, Genetic; D014463:Ultrasonography
D052242:Adiponectin; D015415:Biomarkers; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011506:Proteins