The role of macrophages in early phases of type 2 diabetes mellitus
Date of Issue2018-11-19
Interdisciplinary Graduate School (IGS)
Inflammatory response is a hallmark process of type 2 diabetes mellitus (T2DM) development and progression. In overt hyperglycaemia, low-grade inflammation of the pancreatic islets is known to cause β-cell dysfunction paving way for the pathogenesis of T2DM. Macrophages are vital elements of the immune system that play a major role in both innate and adaptive immune responses. Increased macrophage infiltration in islets of Langerhans has been documented in humans and rodents with T2DM, thus exposing the islets to a pro-inflammatory milieu and thereby contributing to the disease. Though the detrimental role of islet macrophages in overt T2DM has been widely studied, the role of macrophages in islet cell remodelling during the (very) early stage of pre-diabetes, i.e. the compensatory phase, is hardly known. Elucidating the role of macrophages, and more so islet resident macrophages, along with their contribution to islet remodelling in early stages of T2DM can offer a window of opportunity to delay the progression of the disease. We established an animal model of pre-diabetes by exposing mice to a very short term high-fat diet (HFD) and utilized different established macrophage markers, to understand the dynamics of islet macrophages during this phase of pre-diabetes. We found a significant increase in islet macrophage cells within HFD fed mice at 21-days when compared to mice treated with the iso-calorie low-fat diet (LFD). To further determine whether macrophages play a direct role in islet dysfunction during the initial compensatory phase, we used diphtheria toxin receptor (DTR) mice to deplete macrophages during HFD feeding. Our results suggest that presence of macrophages may be important to promote compensatory islet hyperplasia (growth of islet size) at a much earlier stage of mouse T2DM pathogenesis. As macrophages seem to play a dual role in the pathogenesis of diabetes, with early anti-inflammatory role predominating while the later phase is marked by pro-inflammation and islet destruction, it is important to understand which phenotype/ or subtype modulation of macrophages (from pro-inflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype) will keep islets healthy and functioning. To this end, a recent report showed that a small molecule drug, I-BET151, which is a bromodomain and extra-terminal (BET) protein inhibitor, can perform dual function i.e. to modulate macrophages to adopt an anti-inflammatory phenotype and also aid in pancreatic β-cell regeneration and was then subsequently found to be particularly effective against type 1 diabetes mellitus (T1DM) development in non-obese diabetic (NOD) mice. As I-BET151 is emerging as a potential drug for diabetes treatment, we studied the effect of this drug on macrophage re-programming to M2-like phenotype and the effect of macrophage secreted factors on β-cell, in vitro. We found reduced gene expression of pro-inflammatory cytokines in macrophages treated with I-BET151. We also found that I-BET151 has a direct effect on β-cell gene expression levels than indirectly through I-BET151 treated macrophage secreted factors. Marked reduction in gene expression levels of T2DM-associated susceptibility genes were observed in the β-cells as a result of exposure to I-BET151 on murine β-cells. Our novel finding suggests that while I-BET151 may be effective for modulating macrophage phenotype and function, it may also have unintended consequences on the health of the β-cell. As literary evidences suggest that low dose of I-BET151 can elicit anti-inflammatory response in macrophages we also devised a poly(lactic-co-glycolic) acid (PLGA) based nanoparticle system for the controlled and sustained release of I-BET151 with the aim of modulating macrophage function without the side-effect of increasing β-cell dysfunction. We achieved 72% encapsulation efficiency of the compound and sustained release of low dose I-BET151 over a period of 48h. In summary, we show that islet macrophages increase in a mouse model that recapitulates human pre-diabetes and that this increase contributes to islet growth, function and thus compensation. It is also reported herein that attempts to modulate macrophage phenotype by BET protein inhibitors was not macrophage-specific and may also exert “undesirable consequences” on the β-cells. Therefore, drug development targeting BET protein must proceed with caution.