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Abstract Disclosure: R. Laybutt: None. J. Chan: None. C. Liang: None. K. Lee: None. Background: Pancreatic beta cell dedifferentiation may be an important contributing factor to beta cell dysfunction in type 1 and type 2 diabetes, but the triggering stimuli are poorly understood. We previously demonstrated that islet macrophages are critically important for the disruption of beta cell identity gene expression in the db/db mouse model of type 2 diabetes. However, the effects of islet macrophages on beta cell identity in type 1 diabetes are not clear. Our goal was to examine the gene expression pattern of islet-associated macrophages in non-obese diabetic (NOD) mice and to assess their potential influence on beta cell identity and function. Methods: Islets were isolated from 12-week-old female prediabetic NOD mice and control BALB/c 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. Insulin and proinsulin secretion was assessed. Results: Macrophages from NOD islets showed a distinct gene expression pattern compared to BALB/c islet macrophages, suggesting a different functional state. Macrophages from NOD islets displayed a less inflammatory gene expression pattern with reduced interleukin 1 beta (IL1b) and tumor necrosis factor alpha (Tnfα) and elevated IL-1 receptor antagonist (Il1rn). Islet cells from NOD mice displayed reduced expression of genes related to beta cell identity. The mRNA levels of islet-associated transcription factors (Pdx1, NeuroD1 and Nkx6.1), glucose transporter (Glut2), the rate-limiting enzyme of the glycerol-phosphate shuttle, mitochondrial glycerol phosphate dehydrogenase 2 (Gpd2), ATP-sensitive potassium channel (kcnj11), incretin GIP and GLP-1 receptors (Gipr and glp1r) and adaptive unfolded protein response genes (Xbp1, Hspa5, Grp94 and Fkbp11) were reduced. Clodronate-liposome treatment of islets depleted macrophages, as evidenced by reduced mRNA expression of CD11b and F4/80. However, the depletion of macrophages in islets of NOD mice did not affect beta cell identity gene expression. Beta cell dysfunction in NOD islets was evidenced by increased proinsulin secretion. Proinsulin secretion remained elevated following macrophage depletion in NOD islets. Conclusion: These novel findings suggest that islet macrophages of prediabetic NOD mice are in a reduced inflammatory state. In contrast to previous findings from our group in a mouse model of type 2 diabetes, we found that depleting macrophages in islets from NOD mice did not improve beta cell dedifferentiation. Depleting islet macrophages may not be beneficial for restoring beta cell identity gene expression in type 1 diabetes. Presentation: 6/2/2024
Laybutt et al. (Tue,) studied this question.