NCT04387201

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

• Status: Completed
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 23 (actual)
• Sponsor: The University of Texas Health Science Center, Houston · Academic / Other
• Sex: All
• Age: 18 Years – 50 Years
• Healthy volunteers: Not accepted

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.

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.

Conditions

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

Interventions

Type	Name	Description
DRUG	Cyanocobalamin	Cyanocobalamin (vitamin B12) 1000 mcg subcutaneous weekly for 6 weeks.
DRUG	Dulaglutide	Dulaglutide 0.75 mg subcutaneous weekly for 2 weeks, followed by 1.5 mg subcutaneous weekly for 4 weeks

Timeline

• Start date: 2020-05-15
• Primary completion: 2023-10-06
• Completion: 2023-10-06
• First posted: 2020-05-13
• Last updated: 2024-12-05
• Results posted: 2024-12-05

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study