Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2016

Il-1 signalling in macrophages is required for normal glucose homeostasis in the obese state (#133)

Phillippa T Whitworth 1 , Trevor J Biden 1
  1. The Garvan Institute of Medical Research, Sydney, NSW, Australia

Type 2 diabetes is associated with chronic systemic inflammation and elevated levels of circulating lipids. Increases in both resident and recruited macrophages to both white adipose tissue (WAT) and pancreatic islets have been seen in all models of type 2 diabetes. Interleukin-1beta (Il-1b) has been implicated as a major contributor to macrophage recruitment, beta cell damage and secretory dysfunction. However, our understanding of underlying mechanisms, the roles that macrophages play, and the timing of when those impacts occur, are still relatively unknown. 

A myeloid specific knockout mouse of MyD88, a key protein in IL-1b signalling, was generated by crossing MyD88-floxed with LycM-cre mice which were placed on high fat diet (HFD). MyD88KO mice exhibit basal hyperinsulinemia, irrespective of diet. MyD88KO mice are glucose intolerant at 8wk HFD, with a corresponding increase in insulin levels compared to controls. By 12wk HFD this glucose intolerance has disappeared, with continued insulin hypersecretion. Islets taken at both 8wks and 12wks HFD also show significantly increased secretion at basal levels and 8wk islets also have increased secretion at 20mM glucose. MyD88KO mice also gain extra weight, within 2 weeks of fat feeding, compared to controls, with a corresponding increase in epididymal WAT mass and liver triglyceride levels. Peritoneal macrophages from 12wk HFD control mice, co-cultured with min6 cells, inhibited GSIS, but this was not affected by 12wk HFD MyD88KO macrophages.

Therefore, Il-1b signalling in macrophages plays a key role in regulating glucose homeostasis in the obese mouse. Mice without macrophage Il-1 signalling are hyperinsulinemic which is consistent with an increase in whole body weight, increased fat deposition in the epididymal fat pad, and increased liver triglyceride levels. While these macrophages may appear beneficial to beta cells in an ex vivo setting, they are in fact detrimental when observed in vivo in the obese state.