- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04387201
GLP-1 Therapy: The Role of IL-6 Signaling and Adipose Tissue Remodeling in Metabolic Response
December 1, 2023 updated by: Absalon D Gutierrez, The University of Texas Health Science Center, Houston
This project investigates the anti-obesity mechanisms of glucagon-like peptide-1 (GLP-1) analogs, which are used in the treatment of human obesity and diabetes mellitus.
The investigators will test if GLP-1 induces secretion of interleukin-6 (IL-6), a cytokine that may collaborate with GLP-1 analogs to induce the formation of brown fat, which has anti-diabetic properties.
The results will guide future obesity and diabetes mellitus therapies.
Study Overview
Status
Active, not recruiting
Intervention / Treatment
Detailed Description
Incretins, the analogs of glucagon-like peptide-1 (GLP-1), improve glucose control in type 2 diabetes mellitus and counteract obesity through mechanisms that are not completely understood.
The investigators' preliminary data show that, in prediabetic human subjects and mice, GLP-1 analog therapy induces an increase in plasma interleukin-6 (IL-6), a cytokine activating signal transducer and activator of transcription 3 (STAT3) signaling, which induces brown (beige) adipocyte differentiation in adipose tissue (AT).
The investigators discovered that plasma IL-6 induction occurs through GLP-1 receptor (GLP-1R) stimulation in leukocytes.
Interestingly, studies in rodents indicate that GLP-1 / GLP-1R signaling also induces AT beiging.
Based on these observations, the investigators hypothesize that incretins induce AT browning in part via transient IL-6 / IL-6 receptor (IL-6R) / STAT3 signaling.
The primary objective is to further elucidate the role of IL-6 and GLP-1 signaling in mediating beneficial metabolic effects of incretin therapy.
Studies will be paralleled in a human clinical trial, a human cell culture model, and a mouse diet-induced obesity model.
GLP-1 analog therapy combined with an IL-6 blocking antibody will be used.
Specific Aim 1 is to (A) investigate IL-6 induction / downstream STAT3 signaling and AT browning upon incretin therapy in prediabetic human subjects; and (B) validate mice as a model to study incretin-induced IL-6 signaling as a mediator of AT browning.
Specific Aim 2 is to (A) investigate if GLP-1 analog effects on beige adipogenesis depend on IL-6 signaling in human adipocyte progenitors; and (B) investigate if GLP-1 analog effects on beige adipogenesis depend on IL-6 signaling in mice.
It is expected that 1) GLP-1 analog signaling via GLP-1R induces IL-6 secretion by leukocytes, and 2) GLP-1 analog therapy induces adipose tissue browning via both direct GLP-1 / GLP-1R signaling and indirect incretin-induced IL-6 / IL-6R / STAT3 signaling.
The results of this novel study will give critical insights on the anti-obesity mechanisms of GLP-1 analogs and serve as the basis for developing more targeted therapies for diabetes and obesity.
Understanding the anti-diabetic IL-6 effects will also be important for interpreting the results of IL-6 blockade, a therapeutic approach for patients with diabetes and other inflammatory conditions, which may need to be re-considered.
Study Type
Interventional
Enrollment (Actual)
23
Phase
- Phase 4
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Absalon D Gutierrez, MD
- Phone Number: 713-500-6641
- Email: absalon.d.gutierrez@uth.tmc.edu
Study Contact Backup
- Name: Sarah Smith, RN
- Phone Number: 713-704-4137
- Email: Sarah.E.Smith@uth.tmc.edu
Study Locations
-
-
Texas
-
Houston, Texas, United States, 77030
- The University of Texas Health Science Center at Houston
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 50 years (Adult)
Accepts Healthy Volunteers
No
Description
Inclusion criteria:
- Men and women, ages 18-50 years
- Diagnosis of Prediabetes - defined as either impaired fasting glucose (fasting glucose of 100-125 mg/dL), impaired glucose tolerance (2-hour postprandial blood glucose of 140-199 mg/dL after 75-gram oral glucose challenge), and/or a hemoglobin A1C ranging from 5.5% to 6.4%.
- BMI ≤ 35 kg/m2
- Women of childbearing age must agree to use an acceptable method of pregnancy prevention (barrier methods, abstinence, oral contraception, vaginal rings, long-acting reversible contraceptives, or surgical sterilization) for the duration of the study
- Patients must have the following laboratory values: Hematocrit ≥ 33 vol%, estimated glomerular filtration rate ≥ 60 mL/min per 1.73 m2, AST (SGOT) < 2.5 times ULN, ALT (SGPT) < 2.5 times ULN, alkaline phosphatase < 2.5 times ULN
- If patients are receiving antihypertensive medications (other than beta blockers) and/or lipid-lowering medications, they must remain on stable doses for the duration of the study.
- If patients are receiving NSAIDs or antioxidant vitamins, these must be discontinued one week prior to study initiation and cannot be restarted during the study.
- If patient takes thyroid medications, these must be dosed to control hypo- or hyperthyroidism.
Exclusion Criteria:
- History of Type 1 or Type 2 diabetes mellitus
- Pregnant or breastfeeding women
- Medications: Beta blockers, corticosteroids, monoamine oxidase inhibitors, diabetes medications (including incretin mimetics and thiazolidinediones), and/or immunosuppressive therapy over the last 2 months.
- Uncontrolled hypo- or hyperthyroidism
- Current tobacco use
- Active malignancy
- History of clinically significant cardiac, hepatic, or renal disease.
- History of any serious hypersensitivity reaction to study medications, any other incretin mimetic, any other formulation of supplemental vitamin B12, and/or cobalt
- Personal or family history of Leber hereditary optic nerve atrophy
- Prisoners or subjects who are involuntarily incarcerated
- Compulsorily detention for treatment of either a psychiatric or physical (e.g., infectious disease) illness
- Prior history of pancreatitis, medullary thyroid cancer, or multiple endocrine neoplasia type 2 (MEN 2)
- Serum vitamin B12 level above the upper limit of assay detection
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Non-Randomized
- Interventional Model: Crossover Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Cyanocobalamin
Placebo comparator
|
Cyanocobalamin (vitamin B12) 1000 mcg subcutaneous weekly for 6 weeks.
Other Names:
|
Experimental: Dulaglutide
Experimental arm
|
Dulaglutide 0.75 mg subcutaneous weekly for 2 weeks, followed by 1.5 mg subcutaneous weekly for 4 weeks
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Interleukin-6 (IL-6) messenger ribonucleic acid (mRNA) (from adipose tissue)
Time Frame: 6 weeks after start of each intervention
|
cytokine
|
6 weeks after start of each intervention
|
Uncoupling protein 1 (UCP1) (from adipose tissue)
Time Frame: 6 weeks after start of each intervention
|
marker of beige/brown fat
|
6 weeks after start of each intervention
|
Signal transducer and activator of transcription 3 (STAT3) band intensity/Western blot (from adipose tissue)
Time Frame: 6 weeks after start of each intervention
|
signaling intermediary with interleukin-6
|
6 weeks after start of each intervention
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
PR domain containing 16 (PRDM16) (from adipose tissue)
Time Frame: 6 weeks after start of each intervention
|
marker of beige/brown fat
|
6 weeks after start of each intervention
|
Nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) iron-sulfur protein3 (NDUFS3) (from adipose tissue)
Time Frame: 6 weeks after start of each intervention
|
marker of beige/brown fat
|
6 weeks after start of each intervention
|
Beta1-adrenoceptor (ADRB1) (from adipose tissue)
Time Frame: 6 weeks after start of each intervention
|
marker of beige/brown fat
|
6 weeks after start of each intervention
|
Beta2-adrenoceptor (ADRB2) (from adipose tissue)
Time Frame: 6 weeks after start of each intervention
|
marker of beige/brown fat
|
6 weeks after start of each intervention
|
Beta3-adrenoceptor (ADRB3) (from adipose tissue)
Time Frame: 6 weeks after start of each intervention
|
marker of beige/brown fat
|
6 weeks after start of each intervention
|
Nuclear factor kappa B (NfKappaB) p65 band intensity/Western blot (from peripheral blood mononuclear cells)
Time Frame: 6 weeks after start of each intervention
|
signaling intermediary with interleukin-6
|
6 weeks after start of each intervention
|
Interleukin-6 (IL-6) mRNA (from peripheral blood mononuclear cells)
Time Frame: 6 weeks after start of each intervention
|
cytokine
|
6 weeks after start of each intervention
|
IL-6 (from peripheral blood mononuclear cells)
Time Frame: 6 weeks after start of each intervention
|
cytokine
|
6 weeks after start of each intervention
|
Suppressor of cytokine signaling 3 (SOCS3) band intensity/Western blot (from peripheral blood mononuclear cells)
Time Frame: 6 weeks after start of each intervention
|
signaling intermediary with interleukin-6
|
6 weeks after start of each intervention
|
IL-6 (from plasma)
Time Frame: 6 weeks after start of each intervention
|
cytokine
|
6 weeks after start of each intervention
|
Free fatty acids (from plasma)
Time Frame: 6 weeks after start of each intervention
|
signaling intermediary with interleukin-6, marker of insulin resistance
|
6 weeks after start of each intervention
|
Insulin (from plasma)
Time Frame: 6 weeks after start of each intervention
|
marker of insulin resistance
|
6 weeks after start of each intervention
|
Glucose (from plasma)
Time Frame: 6 weeks after start of each intervention
|
marker of insulin resistance
|
6 weeks after start of each intervention
|
Tumor necrosis factor - alpha (from plasma)
Time Frame: 6 weeks after start of each intervention
|
cytokine
|
6 weeks after start of each intervention
|
Interleukin-4 (from plasma)
Time Frame: 6 weeks after start of each intervention
|
cytokine
|
6 weeks after start of each intervention
|
Interleukin-10 (from plasma)
Time Frame: 6 weeks after start of each intervention
|
cytokine
|
6 weeks after start of each intervention
|
Interleukin-11 (from plasma)
Time Frame: 6 weeks after start of each intervention
|
cytokine
|
6 weeks after start of each intervention
|
Interleukin-13 (from plasma)
Time Frame: 6 weeks after start of each intervention
|
cytokine
|
6 weeks after start of each intervention
|
Glucagon-like peptide-1 (from plasma)
Time Frame: 6 weeks after start of each intervention
|
incretin
|
6 weeks after start of each intervention
|
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Time Frame: 6 weeks after start of each intervention
|
marker of insulin resistance, calculated from fasting plasma glucose and fasting plasma insulin values
|
6 weeks after start of each intervention
|
Standard Uptake Value (from positron emission tomography - computed tomography (PET-CT) reading)
Time Frame: 6 weeks after start of each intervention
|
radiologic marker of brown fat
|
6 weeks after start of each intervention
|
Oroboros oxygen consumption
Time Frame: 6 weeks after start of each intervention
|
measure of oxygen consumption
|
6 weeks after start of each intervention
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Investigators
- Principal Investigator: Absalon D Gutierrez, MD, The University of Texas Health Science Center at Houston, Dept. of Medicine
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
May 15, 2020
Primary Completion (Actual)
October 6, 2023
Study Completion (Estimated)
October 6, 2024
Study Registration Dates
First Submitted
May 6, 2020
First Submitted That Met QC Criteria
May 11, 2020
First Posted (Actual)
May 13, 2020
Study Record Updates
Last Update Posted (Actual)
December 4, 2023
Last Update Submitted That Met QC Criteria
December 1, 2023
Last Verified
December 1, 2023
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- HSC-MS-19-0787
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
YES
IPD Plan Description
We will share all participant data (which will be deidentified) regarding our plasma samples, subcutaneous adipose tissue samples, and peripheral blood mononuclear cells.
A study protocol and statistical analysis plan will be available as specified per policy of clinicaltrials.gov.
IPD Sharing Time Frame
Data will become available one year after the primary completion date of the clinical trial, or 6 months post-publication, or 18 months after award end date - whichever comes first.
Data will then be available indefinitely.
IPD Sharing Access Criteria
Anyone can access the data via clinicaltrials.gov.
If applicable, data will also be shared via the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Information Network.
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
product manufactured in and exported from the U.S.
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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