Insulin facilitates monocyte migration: a possible link to tissue inflammation in insulin-resistance.
Mononuclear cells (MNCs) are the primary cell type involved in the pro-inflammatory state of obesity-linked insulin-resistance, and atherosclerosis. Increased serum levels of MMP-9 are reported in insulin-resistant type 2 diabetic patients. Here we demonstrate insulin facilitating human monocytic THP-1 cell chemotaxis via prolonged Erk1/2-dependent induction of MMP-9. In vivo, significantly increased serum levels of MMP-9 were found in obesity-induced hyperinsulinemic C57BL/J6 mice, which were diminished by treatment with the anti-diabetic PPARgamma-ligand pioglitazone. In line with this, pioglitazone inhibited Erk1/2-phosphorylation and subsequent insulin-dependent MMP-9 synthesis in THP-1 cells. Thus, insulin increases MMP-9 gelatinolytic activity in monocytic cells, which results in accelerated chemotaxis. Hyperinsulinemia is associated with enhanced MMP-9 serum levels, potentially facilitating monocyte migration to and infiltration of adipose tissue and the arterial wall, thereby contributing to the increased cardiovascular risk in obese, hyperinsulinemic patients.
Kappert
Kai
K
Center for Cardiovascular Research, Institute of Pharmacology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Hessische Str. 3-4, D-10115 Berlin, Germany.
Meyborg
Heike
H
Clemenz
Markus
M
Graf
Kristof
K
Fleck
Eckart
E
Kintscher
Ulrich
U
Stawowy
Philipp
P
D000818:Animals; D002096:C-Peptide / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000201:enzymology / Q000276:immunology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000150:complications*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
D002096:C-Peptide; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D020780:Matrix Metalloproteinase 9; D000077205:Pioglitazone