A promoter genotype and oxidative stress potentially link resistin to human insulin resistance.
Insulin resistance is a component of type 2 diabetes and often precedes pancreatic beta-cell failure. Contributing factors include obesity and a central pattern of fat accumulation with a strong genetic component. The adipocyte secreted hormone resistin has been proposed as a link between the adipocyte and insulin resistance by inhibition of insulin-stimulated glucose uptake and/or blocking adipocyte differentiation. Here we report that the G/G genotype of a single nucleotide polymorphism (SNP) in the promoter of the human resistin gene, -180C>G, had significantly increased basal promoter activity in adipocytes. These data were recapitulated in vivo, where G/G homozygotes had significantly higher resistin mRNA levels in human abdominal subcutaneous fat. A significant interaction was also found between the -180C>G SNP, a marker of oxidative stress (NAD[P]H quinone oxidoreductase mRNA) and homeostasis model assessment of insulin resistance. In addition, resistin mRNA was positively and independently correlated with insulin resistance and hepatic fat as measured by liver X-ray attenuation. These data implicate resistin in the pathophysiology of the human insulin resistance syndrome, an effect mediated by the -180C>G promoter SNP and potentially cellular oxidative stress.
Smith
Steve R
SR
Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. smithsr@pbrc.edu
Bai
Fulu
F
Charbonneau
Chantal
C
Janderová
Lenka
L
Argyropoulos
George
G
D000273:Adipose Tissue / Q000033:anatomy & histology / Q000502:physiology; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D006729:Hormones, Ectopic / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008954:Models, Biological; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D009765:Obesity / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D052243:Resistin
D017931:DNA Primers; D005819:Genetic Markers; D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; C499624:RETN protein, human; C486574:RETNLB protein, human; D012333:RNA, Messenger; D052243:Resistin; D016660:NAD(P)H Dehydrogenase (Quinone)