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Horm Metab Res 2024; 56(04): 286-293
DOI: 10.1055/a-2256-6344
Original Article: Endocrine Research

The Adrenal Gland and Pancreatic Islets – A Beneficial Endocrine Alliance

Undine Schubert
1   Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
2   Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
,
Susann Lehmann
1   Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
2   Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
,
Janine Schmid
1   Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
2   Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
,
Henning Morawietz
1   Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3   Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Stefan R. Bornstein
1   Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
2   Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
4   School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom of Great Britain and Northern Ireland
5   Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
6   Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
7   German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
,
Barbara Ludwig
1   Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
2   Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
6   Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
7   German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
› Author Affiliations Funding Information Deutsche Forschungsgemeinschaft — http://dx.doi.org/10.13039/501100001659; CRC/TR 127
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Abstract

Intraportal islet transplantation in patients with type 1 diabetes enables restoration of glucose-regulated insulin secretion. However, several factors hamper a widespread application and long-term success: chronic hypoxia, an inappropriate microenvironment and suppression of regenerative and proliferative potential by high local levels of immunosuppressive agents. Therefore, the identification of alternative and superior transplant sites is of major scientific and clinical interest. Here, we aim to evaluate the adrenal as an alternative transplantation site. The adrenal features a particular microenvironment with extensive vascularization, anti-apoptotic and pro-proliferative, anti-inflammatory and immunosuppressive effects. To validate this novel transplantation site, an in vitro co-culture system of adrenal cells and pancreatic islets was established and viability, islet survival, functional potency and antioxidative defense capacity were evaluated. For in vivo validation, an immune-deficient diabetic mouse model for intra-adrenal islet transplantation was applied. The functional capacity of intra-adrenally grafted islets to reverse diabetes was compared to a standard islet transplant model and measures of engraftment such as vascular integration were evaluated. The presence of adrenal cells positively impacted on cell metabolism and oxidative stress. Following transplantation, we could demonstrate enhanced islet function in comparison to standard models with improved engraftment and superior re-vascularization. This experimental approach allows for novel insights into the interaction of endocrine systems and may open up novel strategies for islet transplantation augmented through the bystander effect of other endocrine cells or the active factors secreted by adrenal cells modulating the microenvironment.

Keywords

diabetes - transplantation  - diabetes - site - microenvironment


Publication History

Received: 26 January 2024

Accepted after revision: 02 February 2024

Article published online:
12 March 2024

© 2024. Thieme. All rights reserved.

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  • References

  • 1 Hering BJ, Ballou CM, Bellin MD. et al. Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry. Diabetologia 2023; 66: 163-173
    Google Scholar
  • 2 Chetboun M, Drumez E, Ballou C. et al. Association between primary graft function and 5-year outcomes of islet allogeneic transplantation in type 1 diabetes: a retrospective, multicentre, observational cohort study in 1210 patients from the Collaborative Islet Transplant Registry. Lancet Diabetes Endocrinol 2023; 11: 391-401
    Google Scholar
  • 3 Chetboun M, Masset C, Maanaoui M. et al. Primary graft function and 5 year insulin independence after pancreas and islet transplantation for type 1 diabetes: a retrospective parallel cohort study. Transpl Int 2023; 36: 11950
    Google Scholar
  • 4 Cantarelli E, Piemonti L. Alternative transplantation sites for pancreatic islet grafts. Curr Diab Rep 2011; 11: 364-374
    Google Scholar
  • 5 Orlando G, Piemonti L, Ricordi C. et al. Transplantation, bioengineering, and regeneration of the endocrine pancreas:. Volume 2. Elsevier; Amsterdam: 2019
    Google Scholar
  • 6 Schubert U, Schmid J, Lehmann S. et al. Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone. Proc Natl Acad Sci U S A 2013; 110: 2288-2293
    Google Scholar
  • 7 Ansurudeen I, Kopprasch S, Ehrhart-Bornstein M. et al. Vascular-adrenal niche - Endothelial cell-mediated sensitization of human adrenocortical cells to angiotensin II. Horm Metab Res 2006; 38: 476-480
    Google Scholar
  • 8 Albertin G, Rucinski M, Carraro G. et al. Adrenomedullin and vascular endothelium growth factor genes are overexpressed in the regenerating rat adrenal cortex, and AM and VEGF reciprocally enhance their mRNA expression in cultured rat adrenocortical cells. Int J Mol Med 2005; 16: 431-435
    Google Scholar
  • 9 Hinson JP, Kapas S. The role of endothelial cell products in the regulation of adrenocortical function: Actions of endothelin, nitric oxide, adrenomedullin and PAMP. Horm Metab Res 1998; 30: 334-340
    Google Scholar
  • 10 Ludwig B, Ziegler CG, Schally AV.. et al. Agonist of growth hormone-releasing hormone as a potential effector for survival and proliferation of pancreatic islets. Proc Natl Acad Sci U S A 2010; 107: 12623-12628
    Google Scholar
  • 11 Ricordi C, Gray DWR, Hering BJ. et al. Islet isolation assessment in man and large animals. Acta Diabetol Lat 1990; 27: 185-195
    Google Scholar
  • 12 Halliwell B, Whiteman M. Measuring reactive species and oxidative damage in vivo and in cell culture: How should you do it and what do the results mean?. Br J Pharmacol 2004; 142: 231-255
    Google Scholar
  • 13 Fleury C, Mignotte B, Vayssière JL. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 2002; 84: 131-141
    Google Scholar
  • 14 Paraskevas S, Maysinger D, Wang R. et al. Cell loss in isolated human islets occurs by apoptosis. Pancreas 2000; 20: 270-276
    Google Scholar
  • 15 Pizzino G, Irrera N, Cucinotta M. et al. Oxidative Stress: Harms and benefits for human health. Oxid Med Cell Longev 2017; 8416763
    Google Scholar
  • 16 Ryoo I, geun Kwak MK. Regulatory crosstalk between the oxidative stress-related transcription factor Nfe2l2/Nrf2 and mitochondria. Toxicol Appl Pharmacol 2018; 359: 24-33
    Google Scholar
  • 17 Bottino R, Balamurugan AN, Bertera S. et al. Preservation of human islet cell functional mass by anti-oxidative action of a novel SOD mimic compound. Diabetes 2002; 51: 2561-2567
    Google Scholar
  • 18 Bottino R, Balamurugan AN, Tse H. et al. Response of human islets to isolation stress and the effect of antioxidant treatment. Diabetes 2004; 53: 2559-2568
    Google Scholar
  • 19 Mandrup-Poulsen T. Apoptotic signal transduction pathways in diabetes. Biochem Pharmacol 2003; 66: 1433-1440
    Google Scholar
  • 20 Mandrup-Poulsen T. Beta cell death and protection. Ann N Y Acad Sci 2003; 1005: 32-42
    Google Scholar
  • 21 Mandrup-Poulsen T. β-cell apoptosis: Stimuli and signaling. Diabetes 2001; 50: S58-S63
    Google Scholar
  • 22 Armann B, Hanson MS, Hatch E. et al. Quantification of basal and stimulated ROS levels as predictors of islet potency and function. Am J Transplant 2007; 7: 38-47
    Google Scholar
  • 23 Rackham CL, Jones PM, King AJF. Maintenance of Islet Morphology Is Beneficial for Transplantation Outcome in Diabetic Mice. PLoS One 2013; 8: e57844
    Google Scholar
  • 24 Lebreton F, Bellofatto K, Wassmer CH. et al. Shielding islets with human amniotic epithelial cells enhances islet engraftment and revascularization in a murine diabetes model. Am J Transplant 2020; 20: 1551-1561
    Google Scholar
  • 25 Figueiredo H, Figueroa ALC, Garcia A. et al. Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes. Sci Transl Med 2019; 11: eaar6294
    Google Scholar
  • 26 Starling S. Targeting PTP1B in islet grafts. Nat Rev Endocrinol 2019; 15: 500
    Google Scholar
  • 27 Brissova M, Powers AC. Revascularization of transplanted islets: Can it be Improved?. Diabetes 2008; 57: 2269-2271
    Google Scholar