Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes.
OBJECTIVE
The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-alpha blockade with etanercept could reverse vascular and metabolic insulin resistance.


RESULTS
Twenty obese patients with type 2 diabetes were randomized to etanercept treatment (25 mg subcutaneously twice weekly for 4 weeks) or used as controls in an open parallel study. Forearm blood flow and glucose uptake were measured during intra-arterial infusions of serotonin, sodium nitroprusside and insulin co-infused with serotonin. Beta-cell function was assessed with oral and intra-venous glucose tolerance tests and whole-body insulin sensitivity by hyperinsulinemic euglycemic clamps. Plasma levels of C-reactive protein and interleukin-6 decreased significantly with etanercept (C-reactive protein from 9.9 +/- 3.1 to 4.8 +/- 1.4 mg l(-1), p = 0.04; interleukin-6 from 3.1 +/- 0.4 to 1.9 +/- 0.2 ng l(-1), p = 0.03). Vasodilatory responses to serotonin and sodium nitroprusside infusions remained unchanged. Insulin effect on vasodilatation and on whole-body and forearm glucose uptake remained unchanged as well. Beta-cell function tended to improve.


CONCLUSIONS
Although short-term etanercept treatment had a significant beneficial effect on systemic inflammatory markers, no improvement of vascular or metabolic insulin sensitivity was observed.
Dominguez
Helena
H
Cardiology Department, Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark. hd@heart.dk
Storgaard
Heidi
H
Rask-Madsen
Christian
C
Steffen Hermann
Thomas
T
Ihlemann
Nikolaj
N
Baunbjerg Nielsen
Dorthe
D
Spohr
Camilla
C
Kober
Lars
L
Vaag
Allan
A
Torp-Pedersen
Christian
C
D000328:Adult; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D000068800:Etanercept; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
D015415:Biomarkers; D002097:C-Reactive Protein; D000068800:Etanercept; D007074:Immunoglobulin G; D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors