GLP-1 Therapy: The Role of IL-6 Signaling and Adipose Tissue Remodeling in Metabolic Response
Study Details
Study Description
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 |
|---|---|---|
| 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.
Study Design
Arms and Interventions
| 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 Names:
Drug: Cyanocobalamin
Cyanocobalamin (vitamin B12) 1000 mcg subcutaneous weekly for 6 weeks
Other Names:
|
| 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 Names:
Drug: Cyanocobalamin
Cyanocobalamin (vitamin B12) 1000 mcg subcutaneous weekly for 6 weeks
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Interleukin-6 (IL-6) messenger ribonucleic acid (mRNA) (from adipose tissue) [6 weeks after start of each intervention]
cytokine
- Uncoupling protein 1 (UCP1) (from adipose tissue) [6 weeks after start of each intervention]
marker of beige/brown fat
- Signal transducer and activator of transcription 3 (STAT3) band intensity/Western blot (from adipose tissue) [6 weeks after start of each intervention]
signaling intermediary with interleukin-6
Secondary Outcome Measures
- PR domain containing 16 (PRDM16) (from adipose tissue) [6 weeks after start of each intervention]
marker of beige/brown fat
- Nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) iron-sulfur protein3 (NDUFS3) (from adipose tissue) [6 weeks after start of each intervention]
marker of beige/brown fat
- Beta1-adrenoceptor (ADRB1) (from adipose tissue) [6 weeks after start of each intervention]
marker of beige/brown fat
- Beta2-adrenoceptor (ADRB2) (from adipose tissue) [6 weeks after start of each intervention]
marker of beige/brown fat
- Beta3-adrenoceptor (ADRB3) (from adipose tissue) [6 weeks after start of each intervention]
marker of beige/brown fat
- Nuclear factor kappa B (NfKappaB) p65 band intensity/Western blot (from peripheral blood mononuclear cells) [6 weeks after start of each intervention]
signaling intermediary with interleukin-6
- Interleukin-6 (IL-6) mRNA (from peripheral blood mononuclear cells) [6 weeks after start of each intervention]
cytokine
- IL-6 (from peripheral blood mononuclear cells) [6 weeks after start of each intervention]
cytokine
- Suppressor of cytokine signaling 3 (SOCS3) band intensity/Western blot (from peripheral blood mononuclear cells) [6 weeks after start of each intervention]
signaling intermediary with interleukin-6
- IL-6 (from plasma) [6 weeks after start of each intervention]
cytokine
- Free fatty acids (from plasma) [6 weeks after start of each intervention]
signaling intermediary with interleukin-6, marker of insulin resistance
- Insulin (from plasma) [6 weeks after start of each intervention]
marker of insulin resistance
- Glucose (from plasma) [6 weeks after start of each intervention]
marker of insulin resistance
- Tumor necrosis factor - alpha (from plasma) [6 weeks after start of each intervention]
cytokine
- Interleukin-4 (from plasma) [6 weeks after start of each intervention]
cytokine
- Interleukin-10 (from plasma) [6 weeks after start of each intervention]
cytokine
- Interleukin-11 (from plasma) [6 weeks after start of each intervention]
cytokine
- Interleukin-13 (from plasma) [6 weeks after start of each intervention]
cytokine
- Glucagon-like peptide-1 (from plasma) [6 weeks after start of each intervention]
incretin
- Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [6 weeks after start of each intervention]
marker of insulin resistance, calculated from fasting plasma glucose and fasting plasma insulin values
- Standard Uptake Value (from positron emission tomography - computed tomography (PET-CT) reading) [6 weeks after start of each intervention]
radiologic marker of brown fat
- Oroboros oxygen consumption [6 weeks after start of each intervention]
measure of oxygen consumption
Eligibility Criteria
Criteria
Inclusion criteria:
-
Men and women, ages 18-50 years
-
Diagnosis of prediabetes or at risk for 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
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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
-
Patients must have the following laboratory values: Hematocrit ≥ 34 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), hormonal therapy, and/or immunosuppressive therapy over the last 2 months.
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Uncontrolled hypo- or hyperthyroidism
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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
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | The University of Texas Health Science Center at Houston | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- The University of Texas Health Science Center, Houston
Investigators
- Principal Investigator: Absalon D Gutierrez, MD, The University of Texas Health Science Center at Houston, Dept. of Medicine
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HSC-MS-19-0787