Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect?
In view of the fact that insulin resistance is associated with atherogenesis and that troglitazone, an insulin sensitizer, has anti-inflammatory effects, which may be potentially antiatherogenic in the long term, we have now investigated whether insulin has potential anti-inflammatory effects. We infused 2.0 to 2.5 IU/h in 5% dextrose (100 mL/h) iv into 10 obese subjects for 4 h followed by 5% dextrose alone for 2 h. The rate of insulin infusion was varied to maintain glucose concentrations as close to the baseline as possible. Blood samples were obtained before and at 2, 4, and 6 h. Subjects were also infused with 5% dextrose without insulin and with saline on separate occasions. Intranuclear nuclear factor kappaB (NFkappaB) in mononuclear cells fell at 2 and further at 4 h, reverting toward the baseline at 6 h (P < 0.05). IkappaB increased significantly at 2 h, increasing further at 4 h and remaining elevated at 6 h (P < 0.001). Reactive oxygen species (ROS) generation by mononuclear cells fell significantly at 2 h and fell further at 4 h; it partially reverted to baseline at 6 h (P < 0.005). p47(phox) subunit, the key protein of nicotinamide adenine dinucleotide phosphate oxidase also fell at 2 h and 4 h, reverting toward the baseline at 6 h (P < 0.05). In addition, soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) fell significantly following insulin infusion. Glucose or saline infusions without insulin caused no alteration in NFkappaB, IkappaB, ROS generation, p47(phox) subunit, sICAM-1, MCP-1, or PAI-1. We conclude that insulin has a potent acute anti-inflammatory effect including a reduction in intranuclear NFkappaB, an increase in IkappaB, and decreases in ROS generation, p47(phox) subunit, plasma soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1. This acute anti-inflammatory effect, if demonstrated in the long term, may have implications for atherosclerosis and its complications.
Dandona
P
P
Division of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo and Kaleida Health, Buffalo, New York 14209, USA.
Aljada
A
A
Mohanty
P
P
Ghanim
H
H
Hamouda
W
W
Assian
E
E
Ahmad
S
S
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D018932:Chemokine CCL2 / Q000097:blood; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000097:blood*; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000097:blood; D009765:Obesity / Q000097:blood*; D010750:Phosphoproteins / Q000097:blood; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D017382:Reactive Oxygen Species / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D018932:Chemokine CCL2; D020672:I-kappa B Proteins; D007328:Insulin; D016328:NF-kappa B; D010750:Phosphoproteins; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; D018799:Intercellular Adhesion Molecule-1; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1