title: Islet amyloid formation is an important determinant for inducing islet inflammation in high-fat-fed human IAPP transgenic mice.
abstract: OBJECTIVE
  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
  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.
authors: VA Puget Sound Health Care System (151), 1660 S. Columbian Way, Seattle, WA, 98108, USA, meierdan@uw.edu.
authors: Daniel T
authors: DT
authors: Meier
authors: Mary
authors: M
authors: Morcos
authors: Thanya
authors: T
authors: Samarasekera
authors: Sakeneh
authors: S
authors: Zraika
authors: Rebecca L
authors: RL
authors: Hull
authors: Steven E
authors: SE
authors: Kahn
mesh_terms: D000682:Amyloid / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002135:Calcium-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects; D005215:Fasting / Q000097:blood; D005838:Genotype; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism
chemical_list: C094471:ADGRE1 protein, human; D000682:Amyloid; D001786:Blood Glucose; D002135:Calcium-Binding Proteins; D004041:Dietary Fats; D058228:Islet Amyloid Polypeptide; D008562:Membrane Glycoproteins; D009077:Mucins; D043562:Receptors, G-Protein-Coupled