Islet macrophages are associated with islet vascular remodeling and compensatory hyperinsulinemia during diabetes

Abstract

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.

Islet-Resident Dendritic Cells and Macrophages in Type 1 Diabetes: In Search of Bigfoot’s Print

“…Upon reappearance of DCs and macrophages, lymphocytes reappeared (57). Ex vivo depletion resulted in a reduced release of pro-inflammatory cytokines such as IL-6, IP-10, and G-CSF (58). Interestingly, T-cells from macrophagedepleted NOD mice were unable to induce diabetes upon transfer into NOD.scid mice (59)(60)(61).…”

Targeting macrophage polarization for therapy of diabesity–the feasibility of early improvement of insulin sensitivity and insulin resistance-a comprehensive systematic review

“…Actually in case of macrophages removed mice displayed less than β cells proliferation rate, reduced insulin secretion as well as altered glucose tolerance as compared to controls. 46 This enhancing of β cells proliferation by islets macrophages is brought about by platelet derived growth factor receptor (PDGFR) signaling path. 47 On obesity becoming chronic, ultimately insulin secretion does not compensate regarding enhanced insulin needs, ending in hyperglycemia as well as T2D.The β cells failing correlates with local inflammation of the Islets as well as synthesis of inflammation effectors(IL-1β, TNF-α ,CCL2).…”

Metabolic Syndrome and Viral Pathogenesis: Lessons from Influenza and Coronaviruses

“…Type 2 diabetes mellitus develops when the body is unable to respond to insulin (14). The etiology of T2DM is often associated with obesity because chronic inflamma-FIG 1 Obesity and T2DM impair host immunity and enhance the severity of influenza virus infection.…”

“…Insulin resistance develops in pancreatic ␤ cells and contributes to the increase in proinflammatory cytokines that results in systemic inflammation. Additionally, infiltrating macrophages have been implicated in the late stage of T2DM because interleukin 1␤ (IL-1␤) expression in islets facilitates the accumulation of proinflammatory macrophages in ␤ cells (14). This leads to ␤-cell failure, which is the triggering factor for the transition from an insulin-resistant state to the development of T2DM (14).…”

“…Additionally, infiltrating macrophages have been implicated in the late stage of T2DM because interleukin 1␤ (IL-1␤) expression in islets facilitates the accumulation of proinflammatory macrophages in ␤ cells (14). This leads to ␤-cell failure, which is the triggering factor for the transition from an insulin-resistant state to the development of T2DM (14). Few studies have investigated whether the T2DM milieu has an impact on viral infection.…”