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. 2012 Oct 1;9(1):35.
doi: 10.1186/1476-9255-9-35.

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

Karen Frankwich  1 , Courtney Tibble, Moises Torres-Gonzalez, Mariah Bonner, Roy Lefkowitz, Matt Tyndall, Geert W Schmid-Schönbein, Francisco Villarreal, Mike Heller, Karen Herbst
Affiliations

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

Karen Frankwich et al. J Inflamm (Lond). .

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.

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Figures

Figure 1
Figure 1
MPO and CRP levels for the Control, PL, and MMPI groups. MPO and CRP levels for the Control group at D1, and the PL and MMPI groups at D1 and D84. † P < 0.05 versus Control group. # < 0.05 versus D1 of the MMPI group.
Figure 2
Figure 2
Activation of muscle insulin signaling mediators in PL and MMPI groups. MMPI but not PL improves insulin signaling in muscle. Left side panels, A, B and C are digital representations of western immunoblots of key mediators in the insulin signaling pathway (PDK1, Akt, GSK3β. Amounts of phosphorylated and total PDK-1 (A), Akt (B) and GSK3-β (C) in MMPI and PL participants were analyzed at D1 (labeled B on blots) and D84 (labeled A on blots). Specimens for this analysis were obtained from muscle biopsies of seven consecutive age-matched PL and MMPI subjects. In the right side panel, the data is presented as fold change from D1 to D84 in the percentage of phosphorylated (activated) to total molecules in the PL and MMPI groups.
Figure 3
Figure 3
MMP 2/9 activity in the Control, PL, and MMPI groups. MMP 2/9 activity in the Control group (D1) and PL and MMPI groups (D1 and D84). Activity was measured after mixing plasma with a charge-changing peptide substrate for MMP-2 and MMP-9 followed by electrophoresis (see Methods). *P = 0.001 versus the control group.
See this image and copyright information in PMC

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