title: Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes.
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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01375491.
authors.affiliation: Veteran's Affairs, San Diego Healthcare System, 3350 La Jolla Village Drive (111 G), San Diego, CA, 92161, USA. Karen.herbst@va.gov.
authors.forename: Karen
authors.initials: K
authors.lastname: Frankwich
authors.forename: Courtney
authors.initials: C
authors.lastname: Tibble
authors.forename: Moises
authors.initials: M
authors.lastname: Torres-Gonzalez
authors.forename: Mariah
authors.initials: M
authors.lastname: Bonner
authors.forename: Roy
authors.initials: R
authors.lastname: Lefkowitz
authors.forename: Matt
authors.initials: M
authors.lastname: Tyndall
authors.forename: Geert W
authors.initials: GW
authors.lastname: Schmid-Schönbein
authors.forename: Francisco
authors.initials: F
authors.lastname: Villarreal
authors.forename: Mike
authors.initials: M
authors.lastname: Heller
authors.forename: Karen
authors.initials: K
authors.lastname: Herbst