Islet amyloid formation is an important determinant for inducing islet inflammation in high-fat-fed human IAPP transgenic mice
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- 作者：Daniel T. Meier (1) (2)
Mary Morcos (1) (2)
Thanya Samarasekera (1) (2)
Sakeneh Zraika (1) (2)
Rebecca L. Hull (1) (2)
Steven E. Kahn (1) (2) - 关键词：Chemokine ; Cytokine ; In vivo ; Insulin secretion ; Macrophage ; NLRP3 inflammasome
- 刊名：Diabetologia
- 出版年：2014
- 出版时间：September 2014
- 年：2014
- 卷：57
- 期：9
- 页码：1884-1888
- 全文大小：807 KB
- 参考文献：1. Hull RL, Westermark GT, Westermark P, Kahn SE (2004) Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab 89:3629-643 CrossRef
2. Donath MY, Boni-Schnetzler M, Ellingsgaard H, Halban PA, Ehses JA (2010) Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends Endocrinol Metab 21:261-67 CrossRef
3. Jurgens CA, Toukatly MN, Fligner CL et al (2011) Beta-cell loss and beta-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am J Pathol 178:2632-640 CrossRef
4. Larsen CM, Faulenbach M, Vaag A et al (2007) Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 356:1517-526 CrossRef
5. Westwell-Roper C, Dai DL, Soukhatcheva G et al (2011) IL-1 blockade attenuates islet amyloid polypeptide-induced proinflammatory cytokine release and pancreatic islet graft dysfunction. J Immunol 187:2755-765 CrossRef
6. Masters SL, Dunne A, Subramanian SL et al (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol 11:897-04 CrossRef
7. Westwell-Roper CY, Ehses JA, Verchere CB (2013) Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1β production and beta cell dysfunction. Diabetes 63:1698-711
8. Hull RL, Andrikopoulos S, Verchere CB et al (2003) Increased dietary fat promotes islet amyloid formation and beta-cell secretory dysfunction in a transgenic mouse model of islet amyloid. Diabetes 52:372-79 CrossRef
9. Zraika S, Hull RL, Udayasankar J et al (2007) Identification of the amyloid-degrading enzyme neprilysin in mouse islets and potential role in islet amyloidogenesis. Diabetes 56:304-10 CrossRef - 作者单位：Daniel T. Meier (1) (2)
Mary Morcos (1) (2)
Thanya Samarasekera (1) (2)
Sakeneh Zraika (1) (2)
Rebecca L. Hull (1) (2)
Steven E. Kahn (1) (2)
1. VA Puget Sound Health Care System (151), 1660 S. Columbian Way, Seattle, WA, 98108, USA
2. Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA - ISSN：1432-0428
文摘
Aims/hypothesis Amyloid deposition and inflammation are characteristic of islet pathology in type 2 diabetes. The aim of this study was to determine whether islet amyloid formation is required for the development of islet inflammation in vivo. Methods Human islet amyloid polypeptide transgenic mice and non-transgenic littermates (the latter incapable of forming islet amyloid) were fed a low-fat (10%) or high-fat (60%) diet for 12?months; high-fat feeding induces islet amyloid formation in transgenic mice. At the conclusion of the study, glycaemia, beta cell function, islet amyloid deposition, markers of islet inflammation and islet macrophage infiltration were measured. Results Fasting plasma glucose levels did not differ by diet or genotype. Insulin release in response to i.v. glucose was significantly greater in both high vs low fat groups, and significantly lower in both transgenic compared with non-transgenic groups. Only high-fat-fed transgenic mice developed islet amyloid and showed a trend towards reduced beta cell area. Compared with islets from low-fat-fed transgenic or high-fat-fed non-transgenic mice, islets of high-fat-fed transgenic mice displayed a significant increase in the expression of genes encoding chemokines (Ccl2, Cxcl1), macrophage/dendritic cell markers (Emr1, Itgax), NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome components (Nlrp3, Pycard, Casp1) and proinflammatory cytokines (Il1b, Tnf, Il6), as well as increased F4/80 staining, consistent with increased islet inflammation and macrophage infiltration. Conclusions/interpretation Our results indicate that islet amyloid formation is required for the induction of islet inflammation in this long-term high-fat-diet model, and thus could promote beta cell dysfunction in type 2 diabetes via islet inflammation.