Acute and resolving inflammation differentially regulates beta cell function in mice via interactions between...

Area of Science:

• Immunology
• Endocrinology
• Metabolic Disease

Background:

• Islet-associated macrophages are known to regulate beta cell function during inflammation and tissue repair.
• Their role in metabolic adaptation and its failure, particularly in type 2 diabetes, is less understood.
• Understanding macrophage coordination with extra-pancreatic macrophages is crucial for metabolic health.

Purpose of the Study:

• To investigate the influence of islet-associated macrophages on insulin secretion during caloric overload and type 2 diabetes.
• To determine how islet macrophages coordinate with extra-pancreatic macrophages in metabolic regulation.
• To assess the role of macrophage remodeling in beta cell function and failure.

Main Methods:

• Conditional depletion and expansion of islet-associated macrophages in CD11b-DTR and wild-type mice, respectively.
• Assessment of glucose tolerance, insulin secretion, and gene expression.
• Flow cytometry analysis of immune cells in islets and peritoneal exudates.
• Evaluation in a type 2 diabetes model (db/db mice).

Main Results:

• Depletion of islet macrophages in high-fat diet-fed mice led to biphasic effects on beta cell function.
• Peritoneal macrophage populations were remodeled, influencing insulin secretion via IL-6 and GLP-1.
• Expansion of peritoneal macrophages impaired insulin secretion.
• Beta cell defects involved islet macrophages, COX1, and prostaglandin E2.
• Diabetic db/db mice showed augmented peritoneal macrophages, with defects reversed by COX1/prostaglandin E2 inhibition.

Conclusions:

• Islet and extra-pancreatic macrophages coordinate to regulate glucose homeostasis and insulin secretion.
• Peritoneal macrophage remodeling can promote beneficial inflammatory responses.
• Maladaptive inflammatory resolution by macrophages may contribute to type 2 diabetes beta cell failure.