An unmet need: Pancreatic beta cell replacement

Authors

  • F Mohamed Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa https://orcid.org/0000-0001-5602-3621
  • C Adams Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa https://orcid.org/0000-0003-3977-4620
  • B Mansfield Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa https://orcid.org/0000-0002-8042-7041

DOI:

https://doi.org/10.7196/SAMJ.2024.v114i3b.1249

Keywords:

Diabetes, Pancreatic transplant, Islet transplant

Abstract

Diabetes mellitus (DM) is a growing public health concern in South Africa (SA) and poses a substantial economic burden on healthcare globally. A century has passed since the discovery of insulin, and despite advances in diabetes management, exogenous insulin remains a primary treatment for type 1 DM, posing challenges of hyperglycaemia and hypoglycaemia. Pancreas transplantation should be considered a treatment for insulin-deficient DM, offering sustained euglycaemia and preventing complications associated with the disease. However, there has been a global decrease in the number of transplants performed. In SA, only a few pancreas transplants have been performed, primarily because of surgical risks and the need for immunosuppression. Islet transplantation is an alternative but faces limitations due to donor scarcity and immunosuppression requirements. This review explores recent progress in pancreas and islet transplants for DM, with the aim of providing insights into expanding treatment options for people with insulin-deficient DM.

Author Biography

  • F Mohamed, Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa

    Dr Mohamed is a consultant Endocrinologist and acting clinical Head of the Division of Endocrinology at Charlotte Maxeke Johannesburg Academic Hospital, in Johannesburg, South Africa. She is an associate Lecturer at the University of the Witwatersrand. Farzahna has completed her master’s in medicine with distinction and was awarded the WITS 2016 award for her MMED. She is currently completing her PhD at Wits and is a recipient of two National Grants. Farzahna has published widely, both nationally and internationally. She is also an integral member of the undergraduate and postgraduate teaching program at Wits. Dr Mohamed’s areas of clinical interest include pregnancy and diabetes mellitus as well as lipids, especially the management of patients with familial hypercholesterolaemia and she is involved in studies with novel medications for the treatment of these patients. Farzahna is passionate about teaching, but she is mostly dedicated to ensuring the best care for her patients and is an advocate for empowering Women in Science.

References

Ong KL, Stafford LK, McLaughlin SA, et al.; GBD 2021 Diabetes Collaborators. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the Global Burden of Disease Study 2021. Lancet 2023;402(10397):203-234. https://doi. org/10.1016/S0140-6736(23)01301-6

Ogle GD, James S, Dabelea D, et al. Global estimates of incidence of type 1 diabetes in children and adolescents: Results from the International Diabetes Federation Atlas, 10th edition. Diabetes Res Clin Pract 2022;183:109083. https://doi.org/10.1016/j.diabres.2021.109083

ElSayed NA, Aleppo G, Aroda VR, et al. 4. Comprehensive medical evaluation and assessment of comorbidities: Standards of care in diabetes – 2023. Diabetes Care 2023;46(Suppl 1):S49-S67. https:// doi.org/10.2337/dc23-S004

Erzse A, Stacey N, Chola L, Tugendhaft A, Freeman M, Hofman K. The direct medical cost of type 2 diabetes mellitus in South Africa: A cost of illness study. Glob Health Action 2019;12(1):1636611. https://doi.org/10.1080/16549716.2019.1636611

Brown SA, Kovatchev BP, Raghinaru D, et al. Six-month randomised, multicenter trial of closed- loop control in type 1 diabetes. N Engl J Med 2019;381(18):1707-1717. https://doi.org/10.1056/ NEJMoa1907863

ChoudharyP,KolassaR,KeuthageW,etal.Advancedhybridclosedlooptherapyversusconventional treatment in adults with type 1 diabetes (ADAPT): A randomised controlled study. Lancet Diabetes Endocrinol 2022;10(10):720-731. https://doi.org/10.1016/S2213-8587(22)00212-1

Mathieu C, Gillard P, Benhalima K. Insulin analogues in type 1 diabetes mellitus: Getting better all the time. Nat Rev Endocrinol 2017;13(7):385-399. https://doi.org/10.1038/nrendo.2017.39

Beck RW, Riddlesworth T, Ruedy K, et al. Effect of continuous glucose monitoring on glycemic control in adults with type 1 diabetes using insulin injections: The DIAMOND randomised clinical trial. JAMA 2017;317(4):371-378. https://doi.org/10.1001/jama.2016.19975

Mingrone G, Castagneto-Gissey L, Bornstein SR. New horizons: Emerging antidiabetic medications. J Clin Endocrinol Metab 2022;107(12):e4333-e4340. https://doi.org/10.1210/clinem/dgac499

Herold KC, Bundy BN, Long SA, et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med 2019;381(7):603-613. https://doi.org/10.1056/NEJMoa1902226

Bornstein SR, Ludwig B, Steenblock C. Progress in islet transplantation is more important than ever. Nat Rev Endocrinol 2022;18(7):389-390. https://doi.org/10.1038/s41574-022-00689-0

Holt RIG, DeVries JH, Hess-Fischl A, et al. The management of type 1 diabetes in adults: A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2021;64(12):2609-2652. https://doi.org/10.1007/s00125-021-05568-3

Marfil-Garza BA, Imes S, Verhoeff K, et al. Pancreatic islet transplantation in type 1 diabetes: 20-year experience from a single-centre cohort in Canada. Lancet Diabetes Endocrinol 2022;10(7):519-532. https://doi.org/10.1016/S2213-8587(22)00114-0

Fridell JA, Stratta RJ, Gruessner AC. Pancreas transplantation: Current challenges, considerations, and controversies. J Clin Endocrinol Metab 2023;108(3):614-623. https://doi.org/10.1210/clinem/dgac644 15. Tullius SG, Rabb H. Improving the supply and quality of deceased-donor organs for transplantation.

N Engl J Med 2018;378(20):1920-1929. https://doi.org/10.1056/NEJMra1507080

Gruessner AC, Gruessner RWG. The 2022 International Pancreas Transplant Registry Report – a

review. Transplant Proc 2022;54(7):1918-1943. https://doi.org/10.1016/j.transproceed.2022.03.059

Stratta RJ, Fridell JA, Gruessner AC, Odorico JS, Gruessner RWG. Pancreas transplantation: A decade of decline. Curr Opin Organ Transplant 2016;21(4):386-392. https://doi.org/10.1097/

MOT.0000000000000319

Organ Donor Foundation, South Africa. Statistics. 2021. https://odf.org.za/statistics/ (accessed

May 2023).

Fabian J, Maher H, Bentley A, et al. Favourable outcomes for the first 10 years of kidney and pancreas

transplantation at Wits Donald Gordon Medical Centre, Johannesburg, South Africa. S Afr Med J

;106(2):172-176. https://doi.org/10.7196/SAMJ.2016.v106i2.10190

Alhamad T, Malone AF, Brennan DC, et al. Transplant center volume and the risk of pancreas allograft

failure. Transplantation 2017;101(11):2757-2764. https://doi.org/10.1097/TP.0000000000001628

Boggi U, Baronti W, Amorese G, et al. Treating type 1 diabetes by pancreas transplant alone: A cohort study on actual long-term (10 years) efficacy and safety. Transplantation 2022;106(1):147-157. https://

doi.org/10.1097/TP.0000000000003627

Johansen KL, Chertow GM, Gilbertson DT, et al. US Renal Data System 2021 annual data report: Epidemiology of kidney disease in the United States. Am J Kidney Dis 2022;79(4 Suppl 1):A8-12. https://doi.org/10.1053/j.ajkd.2022.02.001

Rana A, Gruessner A, Agopian VG, et al. Survival benefit of solid-organ transplant in the United States. JAMA Surg 2015;150(3):252-259. https://doi.org/10.1001/jamasurg.2014.2038

Shingde R, Calisa V, Craig JC, et al. Relative survival and quality of life benefits of pancreas-kidney transplantation, deceased kidney transplantation and dialysis in type 1 diabetes mellitus – a probabilistic simulation model. Transpl Int 2020;33(11):1393-1404. https://doi.org/10.1111/tri.13679

Andacoglu OM, Himmler A, Geng X, et al. Comparison of glycemic control after pancreas transplantation for type 1 and type 2 diabetic recipients at a high-volume center. Clin Transplant 2019;33(8):e13656. https://doi.org/10.1111/ctr.13656

Hau H-M, Jahn N, Brunotte M, et al. Short and long-term metabolic outcomes in patients with type 1 and type 2 diabetes receiving a simultaneous pancreas kidney allograft. BMC Endocr Disord 2020;20(1):30. https://doi.org/10.1186/s12902-020-0506-9

Choudhary P, Rickels MR, Senior PA, et al. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care 2015;38(6):1016- 1029. https://doi.org/10.2337/dc15-0090

Tamburrini R, Odorico JS. Pancreas transplant versus islet transplant versus insulin pump therapy: In which patients and when? Curr Opin Organ Transplant 2021;26(2):176-183. https://doi.org/10.1097/ MOT.0000000000000857

Léonet J, Malaise J, Goffin E, et al. Solitary pancreas transplantation for life-threatening allergy to human insulin. Transpl Int 2006;19(6):474-477. https://doi.org/10.1111/j.1432-2277.2006.00282.x

Boggi U, Vistoli F, Marchetti P, Kandaswamy R, Berney T; World Consensus Group on Pancreas

Transplantation. First World Consensus Conference on Pancreas Transplantation: Part I – methods and

results of literature search. Am J Transplant 2021;21 Suppl 3:1-16. https://doi.org/10.1111/ajt.16738

Boggi U, Vistoli F, Andres A, et al. First World Consensus Conference on Pancreas Transplantation: Part II – recommendations. Am J Transplant 2021;21(Suppl 3):17-59. https://doi.org/10.1111/ajt.16750 32. Kukla A, Ventura-Aguiar P, Cooper M, et al. Transplant options for patients with diabetes and advanced kidney disease: A review. Am J Kidney Dis 2021;78(3):418-428. https://doi.org/10.1053/j.

ajkd.2021.02.339

Boggi U, Amorese G, Marchetti P, Mosca F. Segmental live donor pancreas transplantation: Review and critique of rationale, outcomes, and current recommendations. Clin Transplant 2011;25(1):4-12. https://doi.org/10.1111/j.1399-0012.2010.01381.x

Gruessner RWG, Sutherland DER, Kandaswamy R, Gruessner AC. Over 500 solitary pancreas transplants in nonuremic patients with brittle diabetes mellitus. Transplantation 2008;85(1):42-47. https://doi.org/10.1097/01.tp.0000296820.46978.3f

Esmeijer K, Hoogeveen EK, van den Boog PJM, et al. Superior long-term survival for simultaneous pancreas-kidney transplantation as renal replacement therapy: 30-year follow-up of a nationwide cohort. Diabetes Care 2020;43(2):321-328. https://doi.org/10.2337/dc19-1580

Ojo AO, Meier-Kriesche HU, Hanson JA, et al. The impact of simultaneous pancreas-kidney transplantation on long-term patient survival. Transplantation 2001;71(1):82-90. https://doi. org/10.1097/00007890-200101150-00014

Parajuli S, Mandelbrot DA. One more time, emphasizing the advantage of simultaneous pancreas and kidney transplantation for patients with type 1 diabetes and end-stage renal disease. Transpl Int 2020;33(11):1384-1386. https://doi.org/10.1111/tri.13686

Fiorina P, Venturini M, Folli F, et al. Natural history of kidney graft survival, hypertrophy, and vascular function in end-stage renal disease type 1 diabetic kidney-transplanted patients: Beneficial impact of pancreas and successful islet cotransplantation. Diabetes Care 2005;28(6):1303-1310. https://doi. org/10.2337/diacare.28.6.1303

Moosa MR. Impact of age, gender and race on patient and graft survival following renal transplantation – developing country experience. S Afr Med J 2003;93(9):689-695.

Amorese G, Lombardo C, Tudisco A, et al. Induction and immunosuppressive management of pancreas transplant recipients. Curr Pharm Des 2020;26(28):3425-3439. https://doi.org/10.2174/138 1612826666200430111620

Li Z, Xiang J, Liu J, Wang L. Race does not predict pancreas graft failure after pancreas transplantation in the modern era. Clin Transplant 2022;36(5):e14576. https://doi.org/10.1111/ctr.14576

Rogers J, Jay CL, Farney AC, et al. Simultaneous pancreas‐kidney transplantation in Caucasian versus African American patients: Does recipient race influence outcomes? Clin Transplant 2022;36(5):e14599. https://doi.org/10.1111/ctr.14599

Scharp DW, Lacy PE, Santiago JV, et al. Insulin independence after islet transplantation into type I diabetic patient. Diabetes 1990;39(4):515-518. https://doi.org/10.2337/diab.39.4.515

Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343(4):230-238. https://doi.org/10.1056/NEJM200007273430401

Collaborative Islet Transplant Registry. Scientific summary of the Collaborative Islet Transplant Registry (CITR) 2020 Eleventh Allograft Data Report. https://citregistry.org/content/reports- publications-presentations (accessed May 2023).

Shapiro AMJ, Pokrywczynska M, Ricordi C. Clinical pancreatic islet transplantation. Nat Rev Endocrinol 2017;13(5):268-277. https://doi.org/10.1038/nrendo.2016.178

Hering BJ, Clarke WR, Bridges ND, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care 2016;39(7):1230-1240. https://doi. org/10.2337/dc15-1988

Ryan EA, Bigam D, Shapiro AMJ. Current indications for pancreas or islet transplant. Diabetes Obes Metab 2006;8(1):1-7. https://doi.org/10.1111/j.1463-1326.2004.00460.x

Kin T, Shapiro AMJ. Surgical aspects of human islet isolation. Islets 2010;2(5):265-273. https://doi. org/10.4161/isl.2.5.13019

Kaddis JS, Danobeitia JS, Niland JC, Stiller T, Fernandez LA. Multicenter analysis of novel and established variables associated with successful human islet isolation outcomes. Am J Transplant 2010;10(3):646-656. https://doi.org/10.1111/j.1600-6143.2009.02962.x

Hanley SC, Paraskevas S, Rosenberg L. Donor and isolation variables predicting human islet isolation success. Transplantation 2008;85(7):950-955. https://doi.org/10.1097/TP.0b013e3181683df5

Nano R, Clissi B, Melzi R, et al. Islet isolation for allotransplantation: Variables associated with successful islet yield and graft function. Diabetologia 2005;48(5):906-912.

Kilimnik G, Zhao B, Jo J, et al. Altered islet composition and disproportionate loss of large islets in patients with type 2 diabetes. PLoS ONE 2011;6(11):e27445. https://doi.org/10.1371/journal.pone.0027445

Bellin MD, Barton FB, Heitman A, et al. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 2012;12(6):1576-1583. https://doi.org/10.1111/j.1600-6143.2011.03977.x

Senior PA, Kin T, Shapiro J, Koh A. Islet transplantation at the University of Alberta: Status update and review of progress over the last decade. Can J Diabetes 2012;36(1):32-37. https://doi.org/10.1016/j. jcjd.2012.01.002

Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care 2012;35(7):1436-1445. https://doi.org/10.2337/dc12-0063

Walker JT, Saunders DC, Brissova M, Powers AC. The human islet: Mini-organ with mega-impact. Endocr Rev 2021;42(5):605-657. https://doi.org/10.1210/endrev/bnab010

Foster ED, Bridges ND, Feurer ID, et al. Improved health-related quality of life in a phase 3 islet transplantation trial in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care 2018;41(5):1001-1008. https://doi.org/10.2337/dc17-1779

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(1):163-173. https://doi.org/10.1007/ s00125-022-05804-4

Forbes S. BETA-2 score at 28 days after islet allogeneic transplantation in type 1 diabetes for predicting 5-year outcomes. Lancet Diabetes Endocrinol 2023;11(6):376-377. https://doi.org/10.1016/S2213- 8587(23)00090-6

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(6):391-401. https://doi.org/10.1016/S2213-8587(23)00082-7

Fiorina P, Shapiro AMJ, Ricordi C, Secchi A. The clinical impact of islet transplantation. Am J Transplant 2008;8(10):1990-1997. https://doi.org/10.1111/j.1600-6143.2008.02353.x

Thompson DM, Meloche M, Ao Z, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 2011; 91(3):373-378. https://doi.org/10.1097/TP.0b013e31820437f3

Moassesfar S, Masharani U, Frassetto LA, et al. A comparative analysis of the safety, efficacy, and cost of islet versus pancreas transplantation in nonuremic patients with type 1 diabetes. Am J Transplant 2016;16(2):518-526. https://doi.org/10.1111/ajt.13536

Bellin MD, Dunn TB. Transplant strategies for type 1 diabetes: Whole pancreas, islet and porcine beta cell therapies. Diabetologia 2020;63(10):2049-2056. https://doi.org/10.1007/s00125-020-05184-7

Shapiro AMJ, Thompson D, Donner TW, et al. Insulin expression and C-peptide in type 1 diabetes

subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell

Rep Med 2021;2(12):100466. https://doi.org/10.1016/j.xcrm.2021.100466

Ludwig B, Ludwig S, Steffen A, et al. Favorable outcome of experimental islet xenotransplantation

without immunosuppression in a nonhuman primate model of diabetes. Proc Natl Acad Sci U S A

;114(44):11745-11750. https://doi.org/10.1073/pnas.1708420114

Bandeiras C, Hwa AJ, Cabral JMS, Ferreira FC, Finkelstein SN, Gabbay RA. Economics of beta-cell

replacement therapy. Curr Diab Rep 2019;19(9):75. https://doi.org/10.1007/s11892-019-1203-9

Aronson R, Galstyan G, Goldfracht M, Al Sifri S, Elliott L, Khunti K. Direct and indirect health economic impact of hypoglycaemia in a global population of patients with insulin-treated diabetes.

Diabetes Res Clin Pract 2018;138:35-43. https://doi.org/10.1016/j.diabres.2018.01.007

Soares AR, Coelho M, Tracey M, Carvalho D, Silva-Nunes J. Epidemiological, social and economic burden of severe hypoglycaemia in patients with diabetes mellitus in Portugal: A structured literature

review. Diabetes Ther 2023;14(2):265-291. https://doi.org/10.1007/s13300-022-01358-1

De Groot S, Enters-Weijnen CF, Geelhoed-Duijvestijn PH, Kanters TA. A cost of illness study of hypoglycaemic events in insulin-treated diabetes in the Netherlands. BMJ Open 2018;8:e019864.

https://doi.org/10.1136/bmjopen-2017-019864

Tzogiou C, Wieser S, Eichler K, et al. Incidence and costs of hypoglycemia in insulin-treated diabetes in Switzerland: A health-economic analysis. J Diabetes Complications 2023;37(6):108476. https://doi. org/10.1016/j.jdiacomp.2023.108476

Opperman AM, de Klerk M. A total cost perspective of type 1 and 2 diabetes mellitus in two South African medical schemes servicing the public healthcare sector. S Afr Med J 2021;111(7):635-641. https://doi.org/10.7196/SAMJ.2021.v111i7.15169

Bandeiras C, Cabral JMS, Gabbay RA, Finkelstein SN, Ferreira FC. Bringing stem cell-based therapies for type 1 diabetes to the clinic: Early insights from bioprocess economics and cost-effectiveness analysis. Biotechnol J 2019;14(8):e1800563. https://doi.org/10.1002/biot.201800563

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2024-04-24

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Supplement: Transplantation in SA

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1.
Mohamed F, Adams C, Mansfield B. An unmet need: Pancreatic beta cell replacement. S Afr Med J [Internet]. 2024 Apr. 24 [cited 2025 May 13];114(3b):e1249. Available from: https://samajournals.co.za/index.php/samj/article/view/1249