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Updated: May 15, 2025

Leprdb Mouse Model of Type 2 Diabetes: Pancreatic Islet Isolation and Live-cell 2-Photon Imaging Of Intact Islets
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Leprdb Mouse Model of Type 2 Diabetes: Pancreatic Islet Isolation and Live-cell 2-Photon Imaging Of Intact Islets

Published on: May 11, 2015

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FFAR4-mediated IL-6 release from islet macrophages promotes insulin secretion and is compromised in type-2 diabetes

Xinyi Chen1, Jingchen Shao1, Isabell Brandenburger1

  • 1Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany.

Nature Communications
|April 10, 2025
PubMed

Insights

Islet macrophages activate FFAR4 to release IL-6, promoting glucose-stimulated insulin secretion (GSIS). This pathway is impaired in obesity and type 2 diabetes, suggesting FFAR4 reactivation as a therapeutic target.

Area of Science:

  • Immunology
  • Metabolic Disease
  • Endocrinology

Background:

  • The role of islet macrophages in regulating insulin secretion remains largely unknown.
  • Existing knowledge suggests macrophages influence glucose-stimulated insulin secretion (GSIS) in lean states, but the precise mechanisms are unclear.

Purpose of the Study:

  • To elucidate the mechanism by which islet macrophages regulate GSIS.
  • To investigate the role of FFAR4 and IL-6 in islet macrophage function.
  • To determine if this mechanism is altered in obesity and type 2 diabetes.

Main Methods:

  • Investigated FFAR4 activation on islet macrophages and its downstream effects.
  • Measured interleukin-6 (IL-6) release and its impact on beta-cell function.
  • Compared these mechanisms in lean mice, obese mice, and human islets from individuals with obesity and type 2 diabetes.

Main Results:

  • FFAR4 activation on islet macrophages stimulates IL-6 release, which enhances beta-cell function and GSIS in lean male mice.
  • This FFAR4-mediated IL-6 pathway is impaired in islets from individuals with obesity and obese type 2 diabetic mice.
  • Reduced FFAR4 signaling in macrophages of obese mice leads to diminished IL-6 release, but IL-6 treatment remains effective in improving GSIS.

Conclusions:

  • A defect in FFAR4-mediated islet macrophage activation contributes to impaired GSIS in type 2 diabetes.
  • Reactivating islet macrophage FFAR4 or promoting IL-6 release could be a therapeutic strategy for type 2 diabetes.

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