Inducible nitric oxide synthase (iNOS) in pancreatic islets of nonobese diabetic mice: identification of iNOS- expressing cells and relationships to cytokines expressed in the islets

Endocrinology. 1996 May;137(5):2093-9. doi: 10.1210/endo.137.5.8612552.


Inflammatory cytokines and nitric oxide (NO) are candidate mediators of pancreatic islet beta-cell destruction in insulin-dependent diabetes mellitus. In this study, we used a semiquantitative PCR assay to measure levels of messenger RNA (mRNA) expression of the inflammatory cytokines, interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha, and interferon-gamma (IFN gamma), and of the inducible form of NO synthase (iNOS) in mononuclear leukocytes isolated from pancreatic islets of autoimmune diabetes-prone nonobese diabetic (NOD) female mice. We found that mRNA levels of iNOS, IL-1 alpha, and IFN gamma in islet mononuclear leukocytes increased from 5 weeks of age to onset of diabetes ( > 13 weeks of age). To determine whether increased iNOS, IL-1 alpha, and IFN gamma mRNA expressions were related to diabetes development, we compared mRNA levels of these molecules in mononuclear leukocytes from islets of 12 week-old diabetes-prone NOD female mice and three groups of 12-week-old mice with low diabetes risk: NOD female mice injected with complete Freund's adjuvant at 4 weeks of age, NOD male mice, and BALB/c female mice that do not develop diabetes. We found that iNOS, IL-1 alpha, and IFN gamma mRNA levels were higher in mononuclear leukocytes from islets of diabetes-prone NOD female mice than in those from mice correlated with IL-1 alpha and IFN gamma mRNA levels. By using specific antibodies and immunohistochemical methods, we localized iNOS in macrophages as well as in beta-cells of islets from diabetes-prone NOD female mice. These findings suggest that IL-1 alpha and IFN gamma may promote islet beta-cell destruction at least in part by up-regulating iNOS expression an No production by both macrophages and beta-cells in the islets of autoimmune diabetes-prone NOD mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cytokines / genetics*
  • Diabetes Mellitus, Type 1 / enzymology*
  • Female
  • Gene Expression*
  • Humans
  • Interferon-gamma / genetics
  • Interleukin-1 / genetics
  • Islets of Langerhans / enzymology*
  • Islets of Langerhans / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Macrophages / enzymology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Molecular Sequence Data
  • Nitric Oxide Synthase / biosynthesis*
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / genetics


  • Cytokines
  • Interleukin-1
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Nitric Oxide Synthase