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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

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Abstract

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.

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Acknowledgements

We thank Professor P. Browett for his encouragement, Dr. S Amirapu for histological assistance and Associate Professor M Merrilees for critically appraising the manuscript. We gratefully acknowledge receipt of rare pancreatic sections, from the DiViD Study Group and the Network for Pancreatic Organ Donors with Diabetes (nPOD; RRID: SCR_014641), a collaborative type 1 diabetes research project sponsored by JDRF (nPOD: 5-SRA-2018-557-Q-R) and The Leona M. & Harry B. Helmsley Charitable Trust (Grant #2018PG-T1D053). Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org/for-partners/npod-partners/. We thank Professors Sarah Richardson and Noel Morgan from the University of Exeter, for providing pancreatic sections from the Exeter Archival Diabetes Biobank (http://foulis.vub.ac.be/).

Funding

This research was supported by grants to SR from the Maurice Phyllis Paykel Trust and the New Zealand Society for the Study of Diabetes. KD-J received the Novo Nordisk Foundation Grant through the PEVNET Study Group, funded by the European Union’s Seventh Framework Programme (FP7/2007-2013) under agreement Number 26441 PEVNET. KD-J is the principal investigator of the DiViD Study, which was funded by South Eastern Norway Regional Health Authority.

A brief report based on some aspects of this study was presented at the 11th Annual Scientific Meeting of nPOD, Hollywood, FL, USA, February 2019 and the Annual Scientific Meeting of the New Zealand Society for the Study of Diabetes, Napier, New Zealand, May 2019.

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Authors and Affiliations

  1. Department of Molecular Medicine and Pathology, Faculty of Medical and Health Science, University of Auckland, Auckland, 1023, New Zealand

    Shiva Reddy, Charlton Martin, Kevin Xueying Sun, Owen Martin & Aamenah Al-Ani

  2. Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway

    Lars Krogvold

  3. Faculty of Dentistry, University of Oslo, Oslo, Norway

    Lars Krogvold & Knut Dahl-Jørgensen

  4. Faculty of Medicine, University of Oslo, Oslo, Norway

    Knut Dahl-Jørgensen

Authors
  1. Shiva Reddy
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  2. Lars Krogvold
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  3. Charlton Martin
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  4. Kevin Xueying Sun
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  5. Owen Martin
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  6. Aamenah Al-Ani
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  7. Knut Dahl-Jørgensen
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Contributions

SR conceived and designed the experimental studies, carried out a considerable portion of them, acquired and analysed the data, wrote and revised the manuscript critically for publication and led and directed the study. KS, KD-J and LK made a significant contribution to the conception of the study and its design and data interpretation. They also assisted in critically reading and offering valuable advice in revising the manuscript for intellectual content. KS also carried out statistical analysis and prepared all bar graphs. OM and AA assisted in designing the study, performed part of the experimental work, acquired multiple microscopic images from several samples. In addition, following discussions with SR, CM compiled all figures with microscopic images and contributed to the study design and revision of the manuscript. All authors have given their final approval of the version to be published. SR is the guarantor of the work.

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Correspondence to Shiva Reddy.

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The authors declare that they have no conflict of interest.

Informed consent

Informed consent for donation and analysis of pancreatic biopsies from DiViD donors were obtained by the DiViD Study Group from the Norwegian Government’s Regional Ethics Committee.

Ethical approval

Ethical approval for conducting this study was granted by the New Zealand Ministry of Health and Disability Ethics Committee (approval number NTX/11/EXP/092/AM02). Approval for biopsy procurement from new-onset type 1 diabetes donors was granted by the Norwegian Government’s Regional Ethics Committee following informed consent. Ethical approval for the analysis of pancreatic sections from deceased nPOD donors was granted to nPOD. Ethical approval for analysis of sections from postmortem pancreas for EADB (http://foulis.vub.ac.be/) was granted by the West of Scotland Research Committee 4 (WoSREC4; 15/WS/0258) to Professors S Richardson and N Morgan, University of Exeter. Therefore, all procedures performed in studies involving human tissue donors were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Reddy, S., Krogvold, L., Martin, C. et al. 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 384, 655–674 (2021). https://doi.org/10.1007/s00441-020-03340-4

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