β-Cells respond to peripheral insulin resistance by first increasing circulating insulin during diabetes. Islet remodeling supports this compensation, but its drivers remain poorly understood. Infiltrating macrophages have been implicated in late-stage type 2 diabetes, but relatively little is known on islet resident macrophages, especially during compensatory hyperinsulinemia. We hypothesized that islet resident macrophages would contribute to islet vascular remodeling and hyperinsulinemia during diabetes, the failure of which results in a rapid progression to frank diabetes. We used chemical (clodronate), genetics (CD169-diphtheria toxin receptor mice), or antibody-mediated (colony-stimulating factor 1 receptor α) macrophage ablation methods in diabetic (db/db) and diet-induced models of compensatory hyperinsulinemia to investigate the role of macrophages in islet remodeling. We transplanted islets devoid of macrophages into naïve diabetic mice and assessed the impact on islet vascularization. With the use of the above methods, we showed that macrophage depletion significantly and consistently compromised islet remodeling in terms of size, vascular density, and insulin secretion capacity. Depletion of islet macrophages reduced VEGF-A secretion in both human and mouse islets ex vivo, and this functionally translated to delayed revascularization upon transplantation in vivo. We revealed that islet resident macrophages were associated with islet remodeling and increased insulin secretion during diabetes. This suggests utility in harnessing islet macrophages during this phase to promote islet vascularization, remodeling, and insulin secretion.
β-cells respond to peripheral insulin resistance by increasing circulating insulin in early type-2 diabetes (T2D). Islet remodeling supports this compensation but the drivers of this process remain poorly understood. Infiltrating macrophages have been implicated in late stage T2D but relatively little is known on islet resident macrophages, especially in early T2D. We hypothesize that islet resident macrophages contribute to islet vascular remodeling and hyperinsulinemia, the failure of which results in a rapid progression to T2D. Using genetic and dietinduced models of compensatory hyperinsulinemia we show that its depletion significantly compromises islet remodeling in terms of size, vascular density and insulin secretion capacity. Depletion of islet macrophages reduces VEGF-A secretion from both human and mouse islets ex vivo and the impact of reduced Highlights• The compensatory hyperinsulinemic phase of type-2 diabetes is accompanied with significant pancreatic islet remodeling.• Bona fide islet resident macrophages are increased during the diabetic compensation phase by largely in situ proliferation.• Ablating macrophages severely compromises the islet remodeling process and exacerbates glycemic control in vivo.• Mouse and human islet macrophages contribute VEGF-A to the islet environment.• Specific removal of islet macrophages delays islet vascularization in compensatory hyperinsulinemic mice.
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. vi 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 proinflammation 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 reprogramming 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 expressio...
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