Macrophage alterations in islets of obese mice linked to beta cell disruption in diabetes

Abstract

Aims/hypothesis Mild islet inflammation has been suggested as a contributing factor to beta cell failure in type 2 diabetes. Macrophage levels are elevated in the islets of humans and mice with type 2 diabetes, but their effects on beta cells are not understood. Our goal was to examine the gene expression changes in islet-associated macrophages in obesity models with opposing disposition to diabetes development and to assess their potential contribution to beta cell (mal)adaptation. Methods Islets were isolated from lean control mice, obese diabetes-prone db/db mice and obese diabetes-resistant ob/ob mice. Macrophages were sorted using flow cytometry. Islets were treated ex vivo with clodronate-containing liposomes to deplete macrophages. Gene expression was assessed by real-time RT-PCR. Results Macrophage levels were increased in islets from db/db mice but not in islets from ob/ob mice compared with lean control mice. Macrophages from db/db and ob/ob islets displayed distinct changes in gene expression compared with control islet macrophages, suggesting differential shifts in functional state. Macrophages from db/db islets displayed increased expression of interferon regulatory factor 5 (Irf5), IL-1 receptor antagonist (Il1rn) and mannose receptor C-type 1 (Mrc1), whereas macrophages from ob/ob islets showed elevated levels of transforming growth factor beta 1 (Tgfb1) and reduced IL-1β (Il1b). Clodronate-liposome treatment of islets depleted macrophages, as evidenced by reduced mRNA expression of Cd11b (also known as Itgam) and F4/80 (also known as Adgre1) compared with PBS-liposome-treated islets. The depletion of macrophages in db/db islets increased the expression of genes related to beta cell identity. The mRNA levels of islet-associated transcription factors (Mafa and Pdx1), glucose transporter (Glut2 [also known as Slc2a2]), ATP-sensitive K + channel (Kcnj11), incretin receptor (Gipr) and adaptive unfolded protein response (UPR) genes (Xbp1, Hspa5, Pdia4 and Fkbp11) were increased in db/ db islets after macrophage depletion, whereas the mRNA levels of the deleterious UPR effector, Ddit3, were reduced. In contrast, depletion of macrophages in islets of ob/ob mice did not affect beta cell identity gene expression. Conclusions/interpretation The findings of this study suggest that distinct alterations in islet macrophages of obese mice are critically important for the disruption of beta cell gene expression in diabetes.

Glyoxalase 1 knockdown induces age‐related β‐cell dysfunction and glucose intolerance in mice

“…Besides the histological staining for the macrophage marker F4/80, the mRNA expression levels of F4/80 ( Adgre1 ) and the other macrophage markers, CD68 and Itgax, are higher in the isolated islets from Glo1 KD mice compared with WT mice. Although these are extensively used as macrophage markers (Marchetti, 2016; Chan et al , 2019; He et al , 2019; Mukhuty et al , 2021), CD68 has been found to be increased in aged and β‐Gal + β‐cells (Aguayo‐Mazzucato et al , 2017, 2019; Ebrahimi et al , 2020). In line with this, CD68 gene expression increases with aging also in the islets of our control WT mice (Fig EV6B).…”

Chemical inducer of regucalcin attenuates lipopolysaccharide‐induced inflammatory responses in pancreatic MIN6 β‐cells and RAW264.7 macrophages

“…It was reported that macrophages infiltrate pancreatic islets in T2D patients and model animals, such as Goto‐Kakizaki rats, db / db mice, and high‐fat d‐fed mice [ 28 , 42 , 43 ]. Communication between macrophages and β‐cells in the inflammatory islet microenvironment is mediated by proinflammatory mediators.…”

Emerging Roles of Metallothioneins in Beta Cell Pathophysiology: Beyond and above Metal Homeostasis and Antioxidant Response

“…This is an attractive hypothesis that is compatible with the observed increase in islet macrophages in diabetic db/db mice, but not ob/ob compensating mice. Interestingly, macrophages from diabetic db/db islets also displayed a distinct proinflammatory gene expression pattern in comparison to those from ob/ob islets [165].…”