Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance.
In the present study, we explore the role of decreased renal function and a genetic polymorphism on the recently discovered protein resistin, apparently able to inhibit hepatic insulin action in mice. We also investigate possible links with inflammation and the insulin resistance present in patients with chronic kidney disease (CKD). This is a post hoc, cross-sectional study comparing 239 prevalent CKD patients with varying degrees of renal function impairment with an age- and gender-matched randomly selected control group of 25 individuals. Glomerular filtration rate (GFR) was estimated by the mean of urea and creatinine clearance (24-h urine samples) (n=204) or by iohexol clearance (n=60). Plasma analysis of blood lipids, insulin, glucose, inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, vascular cellular adhesion molecule, intercellular adhesion molecule) and resistin (kit from LINCO Research, St Charles, MS) was performed using commercially available assays or routine methods. Insulin resistance was estimated by quantitative insulin-sensitivity check index (QUICKI) and homeostasis model assessment for insulin resistance (HOMA-IR) and body composition by dual-energy X-ray absorptiometry. Genotyping of a C/G promoter single nucleotide polymorphism (n=168) at position -180 of the resistin gene was performed by PyroSequencing. Serum levels of resistin were markedly elevated in the CKD patients with both advanced (39.9+/-1.3 ng/ml) and mild to moderate (23.2+/-1.0 ng/ml) renal function impairment, as compared to controls (8.5+/-0.7 ng/ml; P<0.001). In a multiple linear regression model in patients (adjusted r(2)=0.60), only GFR (beta=3.4; P<0.0001), lean body mass (beta=2.2; P<0.001) and the inflammatory markers were independently associated with circulating resistin levels. There was a weak but significant impact of -180 C/G genotype on plasma levels of resistin (median 43.0+/-2.4 ng/ml in CC, 37.5+/-2.0 ng/ml in CG, and 41.1+/-4.9 ng/ml in GG; P<0.05). Univariate analysis of non-diabetic patients and controls showed that serum resistin was associated with markers of glucose metabolism. However, in a multiple regression model, resistin, as well as all the measured markers of inflammation, was only associated with insulin resistance if GFR was not taken into account. Circulating resistin levels are strongly associated with both GFR and inflammatory biomarkers in CKD. As the significant relationship between plasma resistin levels and insulin resistance was lost following the correction for GFR, resistin is not a likely mediator of insulin resistance in patients with CKD. Renal function is an important factor to take into account in clinical studies relating insulin sensitivity to inflammatory biomarkers in CKD as well as in patients with diabetes mellitus, who often have an impaired renal function.
Axelsson
J
J
Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden.
Bergsten
A
A
Qureshi
A R
AR
Heimbürger
O
O
Bárány
P
P
Lönnqvist
F
F
Lindholm
B
B
Nordfors
L
L
Alvestrand
A
A
Stenvinkel
P
P
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001823:Body Composition; D015992:Body Mass Index; D016022:Case-Control Studies; D002908:Chronic Disease; D003404:Creatinine / Q000652:urine; D003430:Cross-Sectional Studies; D005260:Female; D005919:Glomerular Filtration Rate; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance; D007472:Iohexol / Q000032:analysis; D007668:Kidney / Q000503:physiopathology; D007674:Kidney Diseases / Q000097:blood* / Q000503:physiopathology* / Q000652:urine; D016014:Linear Models; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D052243:Resistin / Q000097:blood* / Q000235:genetics / Q000502:physiology
D015415:Biomarkers; D008055:Lipids; D052243:Resistin; D007472:Iohexol; D003404:Creatinine; D005947:Glucose