Expression of immunoreactive inducible nitric oxide synthase in pancreatic islet cells from newly diagnosed and long-term type 1 diabetic donors is heterogeneous and not disease-associated

Cell Tissue Res. 2021 Jun;384(3):655-674. doi: 10.1007/s00441-020-03340-4. Epub 2021 Jan 11.


Exposure of isolated human islets to proinflammatory cytokines leads to up-regulation of inducible nitric oxide synthase (iNOS), raised NO, and beta cell toxicity. These findings have led to increasing interest in the clinical utility of iNOS blockade to mitigate beta cell destruction in human type 1 diabetes (T1D). However, recent studies show that iNOS-derived NO may also confer beta cell protection. To investigate this dichotomy, we compared islet cell distributions and intensity of iNOS immunostaining in pancreatic sections, co-stained for insulin and glucagon, from new-onset T1D donors (group 1), with non-diabetic autoantibody-negative (group 2), non-diabetic autoantibody-positive (group 3) and long-term diabetic donors (group 4). The cellular origins of iNOS, its frequency and graded intensities in islets and number in peri-islet, intra-islet and exocrine regions were determined. All donors showed iNOS positivity, irrespective of disease and presence of beta cells, had variable labelling intensities, without significant differences in the frequency of iNOS-positive islets among study groups. iNOS was co-localised in selective beta, alpha and other endocrine cells, and in beta cell-negative islets of diabetic donors. The number of peri- and intra-islet iNOS cells was low, being significantly higher in the peri-islet area. Exocrine iNOS cells also remained low, but were much lower in group 1. We demonstrate that iNOS expression in islet cells is variable, heterogeneous and independent of co-existing beta cells. Its distribution and staining intensities in islets and extra-islet areas do not correlate with T1D or its duration. Interventions to inactivate the enzyme to alleviate disease are currently not justified.

Keywords: Distribution; Inducible nitric oxide synthase; Islet cells; Nitric oxide; Type 1 diabetes.

MeSH terms

  • Adolescent
  • Adult
  • Cells, Cultured
  • Diabetes Mellitus, Type 1* / immunology
  • Diabetes Mellitus, Type 1* / pathology
  • Female
  • Humans
  • Islets of Langerhans* / immunology
  • Islets of Langerhans* / pathology
  • Male
  • Nitric Oxide / immunology
  • Nitric Oxide Synthase Type II / immunology*
  • Young Adult


  • Nitric Oxide
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II