Examination of the Anti-inflammatory and Insulin Sensitizing Properties of Doxycycline in Humans (DOXY)

Blockade of Receptor Cleavage in Diabetes Mellitus With an MMP Inhibitor

Obesity is a heightened state of inflammation in which production of cytokines and matrix metalloproteinases (MMPs) result in loss of function of insulin receptors and insulin resistance. Doxycycline (DOX) is a potent MMP inhibitor. We hypothesize that DOX will enhance insulin sensitivity and decreases inflammation in obese participants with type 2 diabetes (DM2).

Study Overview

• Status: Completed
• Conditions: Obesity; Type 2 Diabetes
• Intervention / Treatment: Drug: Doxycycline; Other: Placebo

Detailed Description

Design and Setting: 84 day (D84), double-blind, randomized, placebo (PL)-controlled clinical trial conducted in an academic tertiary care center.

Patients: Non-DM2 Controls (n=15); participants with DM2 receiving PL (n=13) or DOX (n=11).

Interventions: All participants were evaluated at day 1 (D1); those with DM2 were also evaluated at D84 after DOX 100mg twice daily or PL.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • University of California San Diego Clinical trials Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ambulatory, medically stable, able to give informed consent, and comply with the protocol.
• Obesity with BMI >30 kg/m2.
• DM2 for less than 10 years.
• 7.5% < HA1C < 10%
• Taking insulin and/or oral medications (biguanide, sulfonlylurea, etc.)

Exclusion Criteria:

• Mental states that would preclude complete understanding of the protocol and compliance.
• Chronic illness such as renal failure (with creatinine clearance <80 ml/min for Specific Aim 2).
• Women of child-bearing age because of the potential hazard to the fetus (doxycycline may cause permanent discoloration of the teeth and deposition in bone inhibiting growth) and because doxycycline may render oral contraceptives less effective.
• Nursing mothers.
• Allergy to tetracyclines.
• Subjects taking the following drugs: penicillin or it's derivatives, anticoagulant therapy, antacids containing aluminum, calcium, or magnesium, iron-containing preparations, bismuth subsalicylate, barbiturates, carbamazepine, phenytoin or methoxyflurane, thiazolidinediones (TZD)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doxycycline; Participants with DM2 receiving doxycycline 100mg BID	Drug: Doxycycline; generic doxycycline 100mg twice daily; Other Names: Vibramycin
Placebo Comparator: Placebo; Pills prepared identical to doxycycline.	Other: Placebo; Placebo comparator to doxycycline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MMP Activity	MMP activity is measured using a charge-changing peptide substrate for MMP-2 and MMP-9.	Baseline (Day 1)
MMP Activity	MMP activity is measured using a charge-changing peptide substrate for MMP-2 and MMP-9. Only the Doxycycline and Placebo arms are reported because the control group was not evaluated at Day 84.	Day 84

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CRP	Measure of global inflammation.	Baseline (Day 1)
CRP	Measure of global inflammation. Only the Doxycycline and Placebo arms are reported because the control group was not evaluated at Day 84.	Day 84

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Research Resources (NCRR); Ruth L. Kirschstein National Research Service Award
• Investigators: Principal Investigator: Karen L Herbst, PhD, MD, UCSD

Publications and helpful links

General Publications

• DeLano FA, Schmid-Schonbein GW. Proteinase activity and receptor cleavage: mechanism for insulin resistance in the spontaneously hypertensive rat. Hypertension. 2008 Aug;52(2):415-23. doi: 10.1161/HYPERTENSIONAHA.107.104356. Epub 2008 Jul 7.
• Frankwich K, Tibble C, Torres-Gonzalez M, Bonner M, Lefkowitz R, Tyndall M, Schmid-Schonbein GW, Villarreal F, Heller M, Herbst K. Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes. J Inflamm (Lond). 2012 Oct 1;9(1):35. doi: 10.1186/1476-9255-9-35.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): June 1, 2011

Study Registration Dates

• First Submitted: May 25, 2011
• First Submitted That Met QC Criteria: June 16, 2011
• First Posted (Estimate): June 17, 2011

Study Record Updates

• Last Update Posted (Actual): January 13, 2020
• Last Update Submitted That Met QC Criteria: January 8, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: obesity; inflammation; insulin resistance; doxycycline
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Doxycycline
• Other Study ID Numbers: 090395; 5M01RR000827 (U.S. NIH Grant/Contract); P30DK063491 (U.S. NIH Grant/Contract)