Association of Proinflammatory Cytokines and Islet Resident Leucocytes With Islet Dysfunction in Type 2 Diabetes

Diabetologia. 2014 Mar;57(3):491-501. doi: 10.1007/s00125-013-3116-5. Epub 2014 Jan 16.

Abstract

Aims/hypothesis: 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/interpretation: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Mass Index
  • Cells, Cultured
  • Chemokine CCL2 / metabolism*
  • Diabetes Mellitus, Type 2 / immunology
  • Diabetes Mellitus, Type 2 / metabolism*
  • Flow Cytometry
  • Gene Expression Regulation
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / metabolism
  • Leukocytes / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • CCL2 protein, human
  • Chemokine CCL2
  • Insulin
  • TNF protein, human
  • Tumor Necrosis Factor-alpha