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Open Access Research

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

Karen Frankwich2, Courtney Tibble2, Moises Torres-Gonzalez2, Mariah Bonner15, Roy Lefkowitz34, Matt Tyndall3, Geert W Schmid-Schönbein3, Francisco Villarreal2, Mike Heller3 and Karen Herbst12*

Author Affiliations

1 Veteran’s Affairs, San Diego Healthcare System, 3350 La Jolla Village Drive (111 G), San Diego, CA, 92161, USA

2 Department of Medicine, Division of Endocrinology & Metabolism, University of California, 9500 Gilman Drive, #0673 La Jolla, San Diego, CA, 92093, USA

3 Department of Bioengineering, University of California, 9500 Gilman Drive, #0412 La Jolla, San Diego, CA, 92093, USA

4 Department of Pharmacology, University of California, 9500 Gilman Drive, #0636 La Jolla, San Diego, CA, 92093, USA

5 Veteran’s Medical Research Foundation, 3350 La Jolla Village Drive (111 G), San Diego, CA, 92161, USA

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Journal of Inflammation 2012, 9:35  doi:10.1186/1476-9255-9-35

Published: 1 October 2012

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

Keywords:
Diabetes; Doxycycline; Insulin sensitivity; Matrix metalloproteinases; Myeloperoxidase