title: Association of proinflammatory cytokines and islet resident leucocytes with islet dysfunction in type 2 diabetes.
abstract: OBJECTIVE
  Chronic inflammation in type 2 diabetes is proposed to affect islets as well as insulin target organs. However, the nature of islet inflammation and its effects on islet function in type 2 diabetes remain unclear. Moreover, the immune cell profiles of human islets in healthy and type 2 diabetic conditions are undefined. We aimed to investigate the correlation between proinflammatory cytokine expression, islet leucocyte composition and insulin secretion in type 2 diabetic human islets.
  
  
  METHODS
  Human islets from organ donors with or without type 2 diabetes were studied. First and second phases of glucose-stimulated insulin secretion were determined by perifusion. The expression of inflammatory markers was obtained by quantitative PCR. Immune cells within human islets were analysed by FACS.
  
  
  RESULTS
  Type 2 diabetic islets, especially those without first-phase insulin secretion, displayed higher CCL2 and TNFa expression than healthy islets. CD45(+) leucocytes were elevated in type 2 diabetic islets, to a greater extent in moderately functional type 2 diabetic islets compared with poorly functional ones, and corresponded with elevated ALOX12 but not with CCL2 or TNFa expression. T and B lymphocytes and CD11c(+) cells were detectable within both non-diabetic and type 2 diabetic islet leucocytes. Importantly, the proportion of B cells was significantly elevated within type 2 diabetic islets.
  
  
  CONCLUSIONS
  Elevated total islet leucocyte content and proinflammatory mediators correlated with islet dysfunction, suggesting that heterogeneous insulitis occurs during the development of islet dysfunction in type 2 diabetes. In addition, the altered B cell content highlights a potential role for the adaptive immune response in islet dysfunction.
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, 700 West Olney Road, Norfolk, VA, 23507-1696, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Butcher
authors.forename: Daniel
authors.initials: D
authors.lastname: Hallinger
authors.forename: Eden
authors.initials: E
authors.lastname: Garcia
authors.forename: Yui
authors.initials: Y
authors.lastname: Machida
authors.forename: Swarup
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Jerry
authors.initials: J
authors.lastname: Nadler
authors.forename: Elena V
authors.initials: EV
authors.lastname: Galkina
authors.forename: Yumi
authors.initials: Y
authors.lastname: Imai
mesh_terms: D015992:Body Mass Index; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D007328:Insulin; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha