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

Overweight and Obesity Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04387201
• Other study ID #: HSC-MS-19-0787
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: May 15, 2020
• Est. completion date: October 6, 2024

Study information

• Verified date: December 2023
• Source: The University of Texas Health Science Center, Houston
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 23
• Est. completion date: October 6, 2024
• Est. primary completion date: October 6, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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 hemoglobin A1C ranging from 5.5% to 6.4%.

3. BMI = 35 kg/m2

4. 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

5. 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

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 NSAIDs or antioxidant vitamins, these must be discontinued one week prior to study initiation and cannot be restarted during the study.

8. If patient takes thyroid medications, these must be dosed to control hypo- or hyperthyroidism.

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), and/or immunosuppressive therapy over the last 2 months.

4. Uncontrolled 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

Related Conditions & MeSH terms

• Adiposity
• Drug Effect
• Glucose Intolerance
• Overweight
• Overweight and Obesity

Intervention

Drug:
• Cyanocobalamin
Cyanocobalamin (vitamin B12) 1000 mcg subcutaneous weekly for 6 weeks.
• Dulaglutide
Dulaglutide 0.75 mg subcutaneous weekly for 2 weeks, followed by 1.5 mg subcutaneous weekly for 4 weeks

Locations

Country	Name	City	State
United States	The University of Texas Health Science Center at Houston	Houston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
The University of Texas Health Science Center, Houston

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Interleukin-6 (IL-6) messenger ribonucleic acid (mRNA) (from adipose tissue)	cytokine	6 weeks after start of each intervention
Primary	Uncoupling protein 1 (UCP1) (from adipose tissue)	marker of beige/brown fat	6 weeks after start of each intervention
Primary	Signal transducer and activator of transcription 3 (STAT3) band intensity/Western blot (from adipose tissue)	signaling intermediary with interleukin-6	6 weeks after start of each intervention
Secondary	PR domain containing 16 (PRDM16) (from adipose tissue)	marker of beige/brown fat	6 weeks after start of each intervention
Secondary	Nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) iron-sulfur protein3 (NDUFS3) (from adipose tissue)	marker of beige/brown fat	6 weeks after start of each intervention
Secondary	Beta1-adrenoceptor (ADRB1) (from adipose tissue)	marker of beige/brown fat	6 weeks after start of each intervention
Secondary	Beta2-adrenoceptor (ADRB2) (from adipose tissue)	marker of beige/brown fat	6 weeks after start of each intervention
Secondary	Beta3-adrenoceptor (ADRB3) (from adipose tissue)	marker of beige/brown fat	6 weeks after start of each intervention
Secondary	Nuclear factor kappa B (NfKappaB) p65 band intensity/Western blot (from peripheral blood mononuclear cells)	signaling intermediary with interleukin-6	6 weeks after start of each intervention
Secondary	Interleukin-6 (IL-6) mRNA (from peripheral blood mononuclear cells)	cytokine	6 weeks after start of each intervention
Secondary	IL-6 (from peripheral blood mononuclear cells)	cytokine	6 weeks after start of each intervention
Secondary	Suppressor of cytokine signaling 3 (SOCS3) band intensity/Western blot (from peripheral blood mononuclear cells)	signaling intermediary with interleukin-6	6 weeks after start of each intervention
Secondary	IL-6 (from plasma)	cytokine	6 weeks after start of each intervention
Secondary	Free fatty acids (from plasma)	signaling intermediary with interleukin-6, marker of insulin resistance	6 weeks after start of each intervention
Secondary	Insulin (from plasma)	marker of insulin resistance	6 weeks after start of each intervention
Secondary	Glucose (from plasma)	marker of insulin resistance	6 weeks after start of each intervention
Secondary	Tumor necrosis factor - alpha (from plasma)	cytokine	6 weeks after start of each intervention
Secondary	Interleukin-4 (from plasma)	cytokine	6 weeks after start of each intervention
Secondary	Interleukin-10 (from plasma)	cytokine	6 weeks after start of each intervention
Secondary	Interleukin-11 (from plasma)	cytokine	6 weeks after start of each intervention
Secondary	Interleukin-13 (from plasma)	cytokine	6 weeks after start of each intervention
Secondary	Glucagon-like peptide-1 (from plasma)	incretin	6 weeks after start of each intervention
Secondary	Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)	marker of insulin resistance, calculated from fasting plasma glucose and fasting plasma insulin values	6 weeks after start of each intervention
Secondary	Standard Uptake Value (from positron emission tomography - computed tomography (PET-CT) reading)	radiologic marker of brown fat	6 weeks after start of each intervention
Secondary	Oroboros oxygen consumption	measure of oxygen consumption	6 weeks after start of each intervention