SAT-161 Macrophage Alterations in Islets of Obese Mice Linked to Beta Cell Compensation or Beta Cell Dedifferentiation in Diabetes

Abstract

Background: Pancreatic beta cell dedifferentiation may be an important contributing factor to beta cell failure in type 2 diabetes, but the triggering stimuli are poorly understood. Macrophage levels are elevated in the islets of humans and mice with type 2 diabetes, but their effect on beta cell identity is not clear. 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, obese diabetes-prone db/db 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 to controls. Macrophages from db/db and ob/ob islets displayed distinct changes in gene expression, suggesting differential shifts in functional state. Macrophages from db/db islets maintained pro-inflammatory gene expression, whereas macrophages from ob/ob islets shifted towards an anti-inflammatory gene expression pattern with elevated levels of transforming growth factor beta 1 (Tgfb1) and reduced interleukin 1 beta (IL1b). Clodronate-liposome treatment of islets depleted macrophages, as evidenced by reduced mRNA expression of CD11b and F4/80. The depletion of macrophages in db/db islets increased the expression of beta cell identity genes. The mRNA levels of islet-associated transcription factors (Mafa and Pdx1), glucose transporter (Glut2), ATP-sensitive potassium channel (kcnj11), incretin receptor (Gipr) and adaptive unfolded protein response 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. Furthermore, macrophage depletion in db/db islets reduced the expression of genes involved in inflammatory (IL1b, Fas and Nfkbia) and oxidative stress [catalase (Cat) and heme oxygenase-1 (Hmox1)]. In contrast, depletion of macrophages in islets of ob/ob mice did not affect beta cell identity gene expression. Conclusion: These novel findings suggest that distinct alterations in islet macrophages of obese mice are critically important for the maintenance of beta cell compensation or the loss of beta cell identity in diabetes. Depleting islet macrophages could be beneficial for reducing beta cell stress and preserving beta cell identity in type 2 diabetes.