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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Journal of Inflammation 1/2012

Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes

Zeitschrift:
Journal of Inflammation > Ausgabe 1/2012
Autoren:
Karen Frankwich, Courtney Tibble, Moises Torres-Gonzalez, Mariah Bonner, Roy Lefkowitz, Matt Tyndall, Geert W Schmid-Schönbein, Francisco Villarreal, Mike Heller, Karen Herbst
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-9255-9-35) contains supplementary material, which is available to authorized users.

Competing interests

GWSS holds interest in InhibeX, a company that has licensed MMP treatment from UCSD.

Authors’ contributions

KH, GWSS, FV conceptualized this study and developed the initial study structure. KH, KF, CT, and MB conducted subject visits, collected samples, and input data for analyses, statistics and writing the paper. RL, MT, and MH conducted MMP 2/9 activity data, conducted statistics and wrote methods for these data. MTG conducted muscle and MPO assays and wrote methods and results for these data. KF, KH, CT were involved in writing the paper including statistics and figure development. All authors read and approved the final manuscript.

Abstract

Background

Obesity is a state of subclinical inflammation resulting in loss of function of insulin receptors and decreased insulin sensitivity. Inhibition of the inflammatory enzymes, matrix metalloproteinases (MMPs), for 6 months in rodent models restores insulin receptor function and insulin sensitivity.

Methods

This 12-week double-blind, randomized, placebo (PL)-controlled proof-of-concept study was performed to determine if the MMP inhibitor (MMPI), doxycycline, decreased global markers of inflammation and enhanced muscle insulin sensitivity in obese people with type 2 diabetes (DM2). The study included non-DM2 controls (n = 15), and DM2 subjects randomized to PL (n = 13) or doxycycline 100 mg twice daily (MMPI; n = 11). All participants were evaluated on Day 1; MMPI and PL groups were also evaluated after 84 days of treatment.

Results

There was a significant decrease in inflammatory markers C-reactive protein (P < 0.05) and myeloperoxidase (P = 0.01) in the MMPI but not PL group. The MMPI also significantly increased skeletal muscle activated/total insulin signaling mediators: 3’phosphoinositide kinase-1 (PDK1) (p < 0.03), protein kinase B (PKB/Akt) (p < 0.004), and glycogen synthase kinase 3ß (GSK3ß) (p < 0.03).

Conclusions

This study demonstrated short term treatment of people with diabetes with an MMPI resulted in decreased inflammation and improved insulin sensitivity. Larger, longer studies are warranted to determine if doxycycline can improve glucose control in people with diabetes.

Trial Registration

Clinicaltrials.gov NCT01375491
Zusatzmaterial
Authors’ original file for figure 1
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Authors’ original file for figure 2
12950_2012_252_MOESM2_ESM.tiff
Authors’ original file for figure 3
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Literatur
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