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

التفاصيل البيبلوغرافية
العنوان: Macrophage alterations in islets of obese mice linked to beta cell disruption in diabetes
المؤلفون: Emma L. Maxwell, D. Ross Laybutt, Kailun Lee, Jeng Yie Chan, Cassandra Liang
المصدر: Diabetologia. 62:993-999
بيانات النشر: Springer Science and Business Media LLC, 2019.
سنة النشر: 2019
مصطلحات موضوعية: 0301 basic medicine, endocrine system, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Mice, Obese, Incretin, 030209 endocrinology & metabolism, Real-Time Polymerase Chain Reaction, Islets of Langerhans, Mice, 03 medical and health sciences, 0302 clinical medicine, Insulin-Secreting Cells, Internal medicine, Internal Medicine, medicine, Animals, Humans, Endoplasmic Reticulum Chaperone BiP, geography, geography.geographical_feature_category, biology, Chemistry, Macrophages, Transforming growth factor beta, Flow Cytometry, Islet, Interleukin 1 Receptor Antagonist Protein, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Integrin alpha M, Interferon Regulatory Factors, Liposomes, Unfolded Protein Response, biology.protein, PDX1, Beta cell, Mannose receptor, IRF5
الوصف: 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. 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. 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. 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.
تدمد: 1432-0428
0012-186X
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af27124a992c990d3c130ff7f4be7e5e
https://doi.org/10.1007/s00125-019-4844-y
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....af27124a992c990d3c130ff7f4be7e5e
قاعدة البيانات: OpenAIRE
الوصف
تدمد:14320428
0012186X