GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study

Area of Science:

• Endocrinology and Metabolism
• Immunology
• Exercise Physiology

Background:

• Interleukin-6 (IL-6) is a cytokine influencing metabolism.
• In mice, IL-6 enhances beta cell function and glucose homeostasis by upregulating glucagon-like peptide 1 (GLP-1).
• Exercise-induced IL-6 release in muscle potentiates GLP-1 increase in mice.

Purpose of the Study:

• To investigate if exercise-induced IL-6 affects GLP-1 levels similarly in humans.
• To determine the role of IL-6 in regulating GLP-1 response to exercise and meals in humans.

Main Methods:

• A multicentre, double-blind clinical trial involving patients with type 2 diabetes or obesity.
• Participants were randomized to receive tocilizumab (IL-6 receptor antagonist), sitagliptin (DPP-4 inhibitor), or placebo.
• Primary endpoints assessed active GLP-1 response to acute exercise and GLP-1 area under the curve (AUC) during meal tolerance tests before and after a 12-week training intervention.

Main Results:

• Tocilizumab treatment led to a 26% decrease in active GLP-1 levels during acute exercise compared to placebo.
• Sitagliptin significantly increased active GLP-1 levels by 53% during exercise and approximately doubled GLP-1 AUC after the training intervention.
• GLP-1 AUC showed a non-significant 13% decrease after tocilizumab treatment cessation.

Conclusions:

• IL-6 is implicated in the regulation of GLP-1 in humans.
• IL-6 receptor blockade reversibly lowered active GLP-1 levels in response to meals and exercise.
• The effects of IL-6 receptor blockade on GLP-1 were transient and ceased after treatment discontinuation.