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

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

doi:10.1186/1476-9255-9-35

Abstract

BackgroundObesity 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.MethodsThis 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.ResultsThere 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).ConclusionsThis 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 RegistrationClinicaltrials.gov NCT01375491

Highlights

Obesity is a state of subclinical inflammation resulting in loss of function of insulin receptors and decreased insulin sensitivity
In animal models of diabetes and hypertension, excessive proteolytic Matrix metalloproteinase (MMP) activity cleaves the extracellular domain of the insulin receptor, as well as other receptors, resulting in loss of function, including a reduction in insulin sensitivity. [8,9] Blockade of proteases by an MMP inhibitor (MMPI) improved MMP levels and activity but blood glucose levels by 33% in mice
MMP-2 and MMP-9 decreased after exercise-induced weight loss [10,11] but in a separate study, MMP-2 and MMP-3 levels did not decline after bariatric surgery

Summary

Introduction

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. Expression levels and activity of matrix metalloproteinases (MMPs), a family of extracellular endopeptidases, are significantly elevated in rodent. In animal models of diabetes and hypertension, excessive proteolytic MMP activity cleaves the extracellular domain of the insulin receptor, as well as other receptors, resulting in loss of function, including a reduction in insulin sensitivity. [7] Clinical outcome studies are warranted to determine whether MMP inhibition reduces inflammation and improves insulin sensitivity in obese diabetic patients. Golub et al demonstrated inhibition of MMP activity in rodent models of DM2 by MMPIs of which doxycycline was the most potent. [14,17]

Methods

Results

Discussion

Conclusion