The Adrenal Gland and Pancreatic Islets – A Beneficial Endocrine
                    Alliance

Undine Schubert; Susann Lehmann; Janine Schmid; Henning Morawietz; Stefan R. Bornstein; Barbara Ludwig

doi:10.1055/a-2256-6344

Hormone and Metabolic Research, Table of Contents

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

¹Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Paul 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

¹Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Paul 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

¹Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Paul 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

¹Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

³Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

,

Stefan R. Bornstein

¹Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Paul 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

⁴School 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

⁵Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

⁶Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany

⁷German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany

,

Barbara Ludwig

¹Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Paul 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

⁶Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany

⁷German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany

› Author Affiliations

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

Full Text

References

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
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
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
4 Cantarelli E, Piemonti L. Alternative transplantation sites for pancreatic islet grafts. Curr Diab Rep 2011; 11: 364-374
5 Orlando G, Piemonti L, Ricordi C. et al. Transplantation, bioengineering, and regeneration of the endocrine pancreas:. Volume 2. Elsevier; Amsterdam: 2019
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
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
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
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
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
11 Ricordi C, Gray DWR, Hering BJ. et al. Islet isolation assessment in man and large animals. Acta Diabetol Lat 1990; 27: 185-195
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
13 Fleury C, Mignotte B, Vayssière JL. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 2002; 84: 131-141
14 Paraskevas S, Maysinger D, Wang R. et al. Cell loss in isolated human islets occurs by apoptosis. Pancreas 2000; 20: 270-276
15 Pizzino G, Irrera N, Cucinotta M. et al. Oxidative Stress: Harms and benefits for human health. Oxid Med Cell Longev 2017; 8416763
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
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
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
19 Mandrup-Poulsen T. Apoptotic signal transduction pathways in diabetes. Biochem Pharmacol 2003; 66: 1433-1440
20 Mandrup-Poulsen T. Beta cell death and protection. Ann N Y Acad Sci 2003; 1005: 32-42
21 Mandrup-Poulsen T. β-cell apoptosis: Stimuli and signaling. Diabetes 2001; 50: S58-S63
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
23 Rackham CL, Jones PM, King AJF. Maintenance of Islet Morphology Is Beneficial for Transplantation Outcome in Diabetic Mice. PLoS One 2013; 8: e57844
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
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
26 Starling S. Targeting PTP1B in islet grafts. Nat Rev Endocrinol 2019; 15: 500
27 Brissova M, Powers AC. Revascularization of transplanted islets: Can it be Improved?. Diabetes 2008; 57: 2269-2271