Association of MMP-8 with obesity, smoking and insulin resistance

• Published in: European journal of clinical investigation Vol. 46; no. 9; pp. 757 - 765
• Main Authors: Lauhio, Anneli, Färkkilä, Esa, Pietiläinen, Kirsi H., Åström, Pirjo, Winkelmann, Alina, Tervahartiala, Taina, Pirilä, Emma, Rissanen, Aila, Kaprio, Jaakko, Sorsa, Timo A., Salo, Tuula
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.09.2016
• Subjects: Adult; Antigens, CD - metabolism; Case-Control Studies; Dipeptides - pharmacology; Doxycycline - pharmacology; Female; Humans; Hydroxamic Acids; In Vitro Techniques; Indoles - pharmacology; Insulin Resistance; Male; Matrix Metalloproteinase 13 - blood; Matrix Metalloproteinase 8 - blood; Matrix Metalloproteinase 8 - drug effects; Matrix Metalloproteinase 8 - metabolism; Matrix Metalloproteinase 9 - blood; Matrix Metalloproteinase Inhibitors - pharmacology; Medicin och hälsovetenskap; MMP-8; MMP-8 inhibitor; obesity; Obesity - blood; Overweight - blood; Receptor, Insulin - metabolism; smoking; Smoking - blood; therapy target; Tissue Inhibitor of Metalloproteinase-1 - blood; Twins, Dizygotic; Twins, Monozygotic; Young Adult; therapy target; MMP-8 inhibitor; Insulin resistance; MMP-8; obesity; smoking
• ISSN: 0014-2972; 1365-2362; 1365-2362
• DOI: 10.1111/eci.12649

Background Obesity has been recognized as a state of subclinical inflammation resulting in a loss of insulin receptors and decreased insulin sensitivity. We here studied in vivo the role of circulating matrix metalloproteinase‐8 (MMP‐8) among young healthy twin adults. Also, in vitro analysis of the cleavage of human insulin receptor (INSR) by MMP‐8 was investigated as well its inhibition by doxycycline and other MMP‐8 inhibitor, Ilomastat/GM6001, which are broad‐spectrum MMP inhibitors. Materials and methods We analysed serum MMP‐8 levels by a time‐resolved immunofluorometric assay in obese (n = 34), overweight (n = 76) and normal weight (n = 130) twin individuals. The effect of MMP‐8 on INSR and the effects of synthetic MMP‐8 inhibitors, doxycycline and Ilomastat/GM6001, were studied by SDS‐PAGE. Results We found that in obese individuals relative to normal weight individuals, the serum MMP‐8 levels and MMP‐8/TIMP‐1 ratio were significantly increased (P = 0·0031 and P = 0·031, respectively). Among normal weight and obese individuals, also smoking significantly increases serum MMP‐8 and MMP‐8/TIMP‐1 ratio. In vitro, we found that INSR was degraded by MMP‐8 and this was inhibited by doxycycline and Ilomastat/GM6001. Conclusions Obesity associated with elevated circulating MMP‐8 found among young adults may contribute to progression of insulin resistance by cleaving INSR. This INSR cleavage by MMP‐8 can be inhibited by synthetic MMP‐8 inhibitors such as doxycycline. In addition to obesity, also smoking independently explained increased MMP‐8 levels. Our results suggest that MMP‐8 is an essential mediator in systemic subclinical inflammatory response in obesity, and a potential drug target.