Presentations

Abstract

Introduction:

96 million Americans suffer from prediabetes, but it is currently unclear what factors drive the transition from prediabetes to type 2 diabetes. This study aims to determine whether dysregulated CSF1Rhi monocytes/macrophages drive the progression to diabetes and if their removal and endogenous replacement with fresh macrophages resolves disease. Therefore, we hypothesize that depletion of activated CSF1R+ tissue macrophages using a monoclonal antibody against CSF1R and replacement with freshly differentiated macrophages will alleviate inflammation in tissues and ameliorate diabetes- associated disease in prediabetic rhesus macaques.

Methods:

We identified 6 aged Indian rhesus macaques with heightened fasting blood glucose as well as higher area-under-the-curve in an intravenous glucose tolerance test (IVGTT), indicating prediabetes. Three animals were treated with a rhesus IgG1 recombinantanti-CSF1R antibody administered i.v. (15 mg/kg) once every two weeks for 6 weeks. An IgG1 control was administered to the remaining 3 animals. Clinical parameters such as blood pressure, plasma levels of total cholesterol, glucose, insulin, adiponectin, colony stimulating factor 1 (CSF1), IL1β, monocyte chemoattractant protein 1 (MCP-1) were monitored throughout treatment and up to 8 weeks after the 3rd injection. A 27-color spectral flow cytometry panel was used to monitor changes in immune cell populations throughout the study.

Results:

Treatment with anti-CSF1R resulted in decreased total cholesterol, increased adiponectin, increased CSF1, decreased fasting insulin levels and increased IL1β levels in the blood throughout the study. Flow cytometry experiments confirmed the depletion of CD16+ monocytes (known to be CSF1R+) in treated animals.

Conclusion:

Treatment with anti-CSF1R resulted in improvement in multiple clinical parameters associated with the progression to type-2 diabetes mellitus.