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GLP-1 Therapy: The Role of IL-6 Signaling and Adipose Tissue Remodeling in Metabolic Response

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ClinicalTrials.gov Identifier: NCT04387201
Recruitment Status : Recruiting
First Posted : May 13, 2020
Last Update Posted : May 13, 2020
Sponsor:
Information provided by (Responsible Party):
Absalon D Gutierrez, The University of Texas Health Science Center, Houston

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Glucose Intolerance Overweight and Obesity Drug Effect Adiposity Drug: Dulaglutide Drug: Cyanocobalamin Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Randomized crossover clinical trial
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: GLP-1 Therapy: The Role of IL-6 Signaling and Adipose Tissue Remodeling in Metabolic Response
Estimated Study Start Date : May 15, 2020
Estimated Primary Completion Date : May 1, 2022
Estimated Study Completion Date : May 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dulaglutide, then Cyanocobalamin
Dulaglutide is experimental, cyanocobalamin is inactive placebo comparator
Drug: Dulaglutide
Dulaglutide 0.75 mg subcutaneous weekly for 2 weeks, followed by 1.5 mg subcutaneous weekly for 4 weeks
Other Name: Trulicity

Drug: Cyanocobalamin
Cyanocobalamin (vitamin B12) 1000 mcg subcutaneous weekly for 6 weeks
Other Name: Vitamin B12

Experimental: Cyanocobalamin, then Dulaglutide
Cyanocobalamin is inactive placebo comparator, dulaglutide is experimental
Drug: Dulaglutide
Dulaglutide 0.75 mg subcutaneous weekly for 2 weeks, followed by 1.5 mg subcutaneous weekly for 4 weeks
Other Name: Trulicity

Drug: Cyanocobalamin
Cyanocobalamin (vitamin B12) 1000 mcg subcutaneous weekly for 6 weeks
Other Name: Vitamin B12




Primary Outcome Measures :
  1. Interleukin-6 (IL-6) messenger ribonucleic acid (mRNA) (from adipose tissue) [ Time Frame: 6 weeks after start of each intervention ]
    cytokine

  2. Uncoupling protein 1 (UCP1) (from adipose tissue) [ Time Frame: 6 weeks after start of each intervention ]
    marker of beige/brown fat

  3. 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


Secondary Outcome Measures :
  1. PR domain containing 16 (PRDM16) (from adipose tissue) [ Time Frame: 6 weeks after start of each intervention ]
    marker of beige/brown fat

  2. 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

  3. Beta1-adrenoceptor (ADRB1) (from adipose tissue) [ Time Frame: 6 weeks after start of each intervention ]
    marker of beige/brown fat

  4. Beta2-adrenoceptor (ADRB2) (from adipose tissue) [ Time Frame: 6 weeks after start of each intervention ]
    marker of beige/brown fat

  5. Beta3-adrenoceptor (ADRB3) (from adipose tissue) [ Time Frame: 6 weeks after start of each intervention ]
    marker of beige/brown fat

  6. 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

  7. Interleukin-6 (IL-6) mRNA (from peripheral blood mononuclear cells) [ Time Frame: 6 weeks after start of each intervention ]
    cytokine

  8. IL-6 (from peripheral blood mononuclear cells) [ Time Frame: 6 weeks after start of each intervention ]
    cytokine

  9. 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

  10. IL-6 (from plasma) [ Time Frame: 6 weeks after start of each intervention ]
    cytokine

  11. Free fatty acids (from plasma) [ Time Frame: 6 weeks after start of each intervention ]
    signaling intermediary with interleukin-6, marker of insulin resistance

  12. Insulin (from plasma) [ Time Frame: 6 weeks after start of each intervention ]
    marker of insulin resistance

  13. Glucose (from plasma) [ Time Frame: 6 weeks after start of each intervention ]
    marker of insulin resistance

  14. Tumor necrosis factor - alpha (from plasma) [ Time Frame: 6 weeks after start of each intervention ]
    cytokine

  15. Interleukin-4 (from plasma) [ Time Frame: 6 weeks after start of each intervention ]
    cytokine

  16. Interleukin-10 (from plasma) [ Time Frame: 6 weeks after start of each intervention ]
    cytokine

  17. Interleukin-11 (from plasma) [ Time Frame: 6 weeks after start of each intervention ]
    cytokine

  18. Interleukin-13 (from plasma) [ Time Frame: 6 weeks after start of each intervention ]
    cytokine

  19. Glucagon-like peptide-1 (from plasma) [ Time Frame: 6 weeks after start of each intervention ]
    incretin

  20. 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

  21. 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

  22. Oroboros oxygen consumption [ Time Frame: 6 weeks after start of each intervention ]
    measure of oxygen consumption



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women, ages 18-50 years
  2. 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 glycated hemoglobin (HbA1C) ranging from 5.7% to 6.4%
  3. Body Mass index (BMI) ≤ 30 kg/m2
  4. Women of childbearing age must agree to use an acceptable method of pregnancy prevention (barrier methods, abstinence, or surgical sterilization) for the duration of the study
  5. Patients must have the following laboratory values: Hematocrit ≥ 34 vol%, estimated glomerular filtration rate ≥ 60 mL/min per 1.73 m2, aspartate aminotransferase (AST) < 2.5 times upper limit of normal (ULN), alanine aminotransferase (ALT) < 2.5 times ULN, alkaline phosphatase < 2.5 times ULN
  6. 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.
  7. If patients are receiving nonsteroidal anti-inflammatory drugs (NSAIDs) or antioxidant vitamins, these must be discontinued one week prior to study initiation and cannot be restarted during the study.

Exclusion Criteria:

  1. History of Type 1 or Type 2 diabetes mellitus
  2. Pregnant or breastfeeding women
  3. Medications: Beta blockers, corticosteroids, monoamine oxidase inhibitors, diabetes medications (including incretin mimetics and thiazolidinediones), thyroid medications, hormonal therapy, and/or immunosuppressive therapy over the last 2 months
  4. Current hypo- or hyperthyroidism
  5. Current tobacco use
  6. Active malignancy
  7. History of clinically significant cardiac, hepatic, or renal disease.
  8. History of any serious hypersensitivity reaction to study medications, any other incretin mimetic, any other formulation of supplemental vitamin B12, and/or cobalt
  9. Personal or family history of Leber hereditary optic nerve atrophy
  10. Prisoners or subjects who are involuntarily incarcerated
  11. Compulsorily detention for treatment of either a psychiatric or physical (e.g., infectious disease) illness
  12. Prior history of pancreatitis, medullary thyroid cancer, or multiple endocrine neoplasia type 2 (MEN 2)
  13. Serum vitamin B12 level above the upper limit of assay detection

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04387201


Contacts
Layout table for location contacts
Contact: Absalon D Gutierrez, MD 713-500-6641 absalon.d.gutierrez@uth.tmc.edu
Contact: Krystle Oliver, RN 713-704-4137 krystle.l.oliver@uth.tmc.edu

Locations
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United States, Texas
The University of Texas Health Science Center at Houston Recruiting
Houston, Texas, United States, 77030
Contact: Absalon D Gutierez, MD    713-500-6641    absalon.d.gutierrez@uth.tmc.edu   
Contact: Krystle Oliver, RN    713-704-4137    krystle.l.oliver@uth.tmc.edu   
Principal Investigator: Absalon D Gutierrez, MD         
Sub-Investigator: Alan Cohen, MD         
Sub-Investigator: Isis Gayed, MD         
Sub-Investigator: MinJae Lee, PhD         
Sub-Investigator: Mikhail Kolonin, PhD         
Sub-Investigator: Zhanguo Gao, PhD         
Sub-Investigator: Hongyu Wang, MD PhD         
Sponsors and Collaborators
The University of Texas Health Science Center, Houston
Investigators
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Principal Investigator: Absalon D Gutierrez, MD The University of Texas Health Science Center at Houston, Dept. of Medicine
  Study Documents (Full-Text)

Documents provided by Absalon D Gutierrez, The University of Texas Health Science Center, Houston:
Informed Consent Form  [PDF] April 27, 2020

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Responsible Party: Absalon D Gutierrez, Associate Professor of Medicine, The University of Texas Health Science Center, Houston
ClinicalTrials.gov Identifier: NCT04387201    
Other Study ID Numbers: HSC-MS-19-0787
First Posted: May 13, 2020    Key Record Dates
Last Update Posted: May 13, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
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.
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.

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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
Keywords provided by Absalon D Gutierrez, The University of Texas Health Science Center, Houston:
GLP-1
prediabetes
brown fat
adipose tissue
IL-6
Additional relevant MeSH terms:
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Glucose Intolerance
Overweight
Body Weight
Hyperglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Vitamin B 12
Hydroxocobalamin
Dulaglutide
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Vitamin B Complex
Hematinics
Hypoglycemic Agents