Skip to main content
SpringerLink
Log in

Defining Outcomes for β-Cell Replacement Therapy

  • Chapter
  • First Online:
Transplantation of the Pancreas

  • 321 Accesses

Abstract

β-Cell replacement by means of whole pancreas or isolated islet transplantation are established approaches to the treatment of diabetes caused by severe β-cell deficiency, most often established type 1 diabetes with undetectable or very low levels of C-peptide. The primary goal for β-cell replacement is to provide on-target glycemic control in the absence of severe hypoglycemia events, which is generally associated with a clinically significant reduction or elimination of insulin requirements attributed to restoration of endogenous insulin secretion (measured by C-peptide) from the β-cell graft. Validation of glycemic control metrics derived from continuous glucose monitoring (CGM) allows for simultaneous assessment of average glycemia, glucose variability/glycemic lability, time-in-range for on-target glycemic control, and time-below-range for exposure to hypoglycemia, including clinically important, serious hypoglycemia. These CGM-based metrics should be used to both compare outcomes with various forms of β-cell replacement, and to compare cell-based therapies to approaches based on artificial pancreas technologies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CGM:

Continuous glucose monitoring

CIT:

Clinical Islet Transplantation Consortium

CITR:

Collaborative Islet Transplant Registry

CONGA4:

Continuous overlapping net glycemic action at 4 h

CSII:

Continuous subcutaneous insulin infusion

CV:

Coefficient of variation; GVP, glycemic variable percentage

HbA1c:

Glycated hemoglobin

IPTR:

International Pancreas Transplant Registry

LI:

Lability index

MMTT:

Mixed-meal tolerance test

SD:

Standard deviation

SMBG:

Self-monitoring blood glucose

TAR:

Time-above-range

TBR:

Time-below-range

TIR:

Time-in-range

References

  1. Larsen JL. Pancreas transplantation: indications and consequences. Endocr Rev. 2004;25(6):919–46.

    Article  PubMed  Google Scholar 

  2. Rickels MR, Robertson RP. Pancreatic islet transplantation in humans: recent progress and future directions. Endocr Rev. 2019;40(2):631–68.

    Article  PubMed  Google Scholar 

  3. Vantyghem MC, de Koning EJP, Pattou F, Rickels MR. Advances in beta-cell replacement therapy for the treatment of type 1 diabetes. Lancet. 2019;394(10205):1274–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Foster NC, Beck RW, Miller KM, Clements MA, Rickels MR, DiMeglio LA, et al. State of type 1 diabetes management and outcomes from the T1D exchange in 2016-2018. Diabetes Technol Ther. 2019;21(2):66–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Beck RW, Bergenstal RM, Laffel LM, Pickup JC. Advances in technology for management of type 1 diabetes. Lancet. 2019;394(10205):1265–73.

    Article  CAS  PubMed  Google Scholar 

  6. Agiostratidou G, Anhalt H, Ball D, Blonde L, Gourgari E, Harriman KN, et al. Standardizing clinically meaningful outcome measures beyond HbA1c for type 1 diabetes: a consensus report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care. 2017;40(12):1622–30.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care. 2019;42(8):1593–603.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Rickels MR, Stock PG, de Koning EJP, Piemonti L, Pratschke J, Alejandro R, et al. Defining outcomes for beta-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop. Transpl Int. 2018;31(4):343–52.

    Article  CAS  PubMed  Google Scholar 

  9. Rickels MR, Stock PG, de Koning EJP, Piemonti L, Pratschke J, Alejandro R, et al. Defining outcomes for beta-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA Opinion Leaders Workshop. Transplantation. 2018;102(9):1479–86.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bergenstal RM, Beck RW, Close KL, Grunberger G, Sacks DB, Kowalski A, et al. Glucose Management Indicator (GMI): a new term for estimating A1C from continuous glucose monitoring. Diabetes Care. 2018;41(11):2275–80.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms. Diabetes Care. 1995;18(4):517–22.

    Article  CAS  PubMed  Google Scholar 

  12. Gold AE, Macleod KM, Frier BM. Frequency of severe hypoglycemia in patients with type-1 diabetes with impaired awareness of hypoglycemia. Diabetes Care. 1994;17(7):697–703.

    Article  CAS  PubMed  Google Scholar 

  13. International Hypoglycaemia Study G. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2017;40(1):155–7.

    Article  Google Scholar 

  14. Senior PA, Bellin MD, Alejandro R, Yankey JW, Clarke WR, Qidwai JC, et al. Consistency of quantitative scores of hypoglycemia severity and glycemic lability and comparison with continuous glucose monitoring system measures in long-standing type 1 diabetes. Diabetes Technol Ther. 2015;17(4):235–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ryan EA, Shandro T, Green K, Paty BW, Senior PA, Bigam D, et al. Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes. 2004;53(4):955–62.

    Article  CAS  PubMed  Google Scholar 

  16. Whitelaw BC, Choudhary P, Hopkins D. Evaluating rate of change as an index of glycemic variability, using continuous glucose monitoring data. Diabetes Technol Ther. 2011;13(6):631–6.

    Article  CAS  PubMed  Google Scholar 

  17. Rodbard D. Hypo- and hyperglycemia in relation to the mean, standard deviation, coefficient of variation, and nature of the glucose distribution. Diabetes Technol Ther. 2012;14(10):868–76.

    Article  CAS  PubMed  Google Scholar 

  18. Peyser TA, Balo AK, Buckingham BA, Hirsch IB, Garcia A. Glycemic variability percentage: a novel method for assessing glycemic variability from continuous glucose monitor data. Diabetes Technol Ther. 2018;20(1):6–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hill NR, Oliver NS, Choudhary P, Levy JC, Hindmarsh P, Matthews DR. Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups. Diabetes Technol Ther. 2011;13(9):921–8.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Froud T, Faradji RN, Gorn L, Monroy K, Paz C, Baidal DA, et al. Dapsone-induced artifactual a1c reduction in islet transplant recipients. Transplantation. 2007;83(6):824–5.

    Article  PubMed  Google Scholar 

  21. Riddlesworth TD, Beck RW, Gal RL, Connor CG, Bergenstal RM, Lee S, et al. Optimal sampling duration for continuous glucose monitoring to determine long-term glycemic control. Diabetes Technol Ther. 2018;20(4):314–6.

    Article  CAS  PubMed  Google Scholar 

  22. Aleppo G, Ruedy KJ, Riddlesworth TD, Kruger DF, Peters AL, Hirsch I, et al. REPLACE-BG: a randomized trial comparing continuous glucose monitoring with and without routine blood glucose monitoring in adults with well-controlled type 1 diabetes. Diabetes Care. 2017;40(4):538–45.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Beck RW, Bergenstal RM, Cheng P, Kollman C, Carlson AL, Johnson ML, et al. The relationships between time in range, hyperglycemia metrics, and HbA1c. J Diabetes Sci Technol. 2019;13(4):614–26.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Henriksen MM, Andersen HU, Thorsteinsson B, Pedersen-Bjergaard U. Hypoglycemic exposure and risk of asymptomatic hypoglycemia in type 1 diabetes assessed by continuous glucose monitoring. J Clin Endocrinol Metab. 2018;103(6):2329–35.

    Article  PubMed  Google Scholar 

  25. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and The Endocrine Society. J Clin Endocrinol Metab. 2013;98(5):1845–59.

    Article  CAS  PubMed  Google Scholar 

  26. Rickels MR. Hypoglycemia-associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes. Ann N Y Acad Sci. 2019;1454(1):68–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gruessner AC, Gruessner RW. Pancreas transplantation of US and non-US cases from 2005 to 2014 as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud. 2016;13(1):35–58.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. 2012;35(7):1436–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bellin MD, Gelrud A, Arreaza-Rubin G, Dunn TB, Humar A, Morgan KA, et al. Total pancreatectomy with islet autotransplantation: summary of an NIDDK workshop. Ann Surg. 2015;261(1):21–9.

    Article  PubMed  Google Scholar 

  30. Ryan EA, Lakey JRT, Paty BW, Bigam D, Senior PA, Shapiro AMJ. beta-Score - an assessment of beta-cell function after islet transplantation. Diabetes Care. 2005;28(2):343–7.

    Article  PubMed  Google Scholar 

  31. Vantyghem MC, Raverdy V, Balavoine AS, Defrance F, Caiazzo R, Arnalsteen L, et al. Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (beta-score greater than 7) is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (beta-score greater than 3). J Clin Endocrinol Metab. 2012;97(11):E2078–E83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Forbes S, Oram RA, Smith A, Lam A, Olateju T, Imes S, et al. Validation of the BETA-2 score: an improved tool to estimate beta cell function after clinical islet transplantation using a single fasting blood sample. Am J Transplant. 2016;16(9):2704–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Faradji RN, Monroy K, Messinger S, Pileggi A, Froud T, Baidal DA, et al. Simple measures to monitor beta-cell mass and assess islet graft dysfunction. Am J Transplant. 2007;7(2):303–8.

    Article  CAS  PubMed  Google Scholar 

  34. Uitbeijerse BS, Nijhoff MF, Sont JK, de Koning EJP. Fasting parameters for estimation of stimulated beta cell function in islet transplant recipients with or without basal insulin treatment. Am J Transplant. 2020;21:297.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lachin JM, McGee P, Palmer JP, Group DER. Impact of C-peptide preservation on metabolic and clinical outcomes in the Diabetes Control and Complications Trial. Diabetes. 2014;63(2):739–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jeyam A, Colhoun H, McGurnaghan S, Blackbourn L, McDonald TJ, Palmer CNA, et al. Clinical impact of residual C-peptide secretion in type 1 diabetes on glycemia and microvascular complications. Diabetes Care. 2020;44:390.

    Article  PubMed  Google Scholar 

  37. Steffes MW, Sibley S, Jackson M, Thomas W. beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care. 2003;26(3):832–6.

    Article  PubMed  Google Scholar 

  38. Rickels MR, Evans-Molina C, Bahnson HT, Ylescupidez A, Nadeau KJ, Hao W, et al. High residual C-peptide likely contributes to glycemic control in type 1 diabetes. J Clin Invest. 2020;130(4):1850–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brooks AM, Oram R, Home P, Steen N, Shaw JAM. Demonstration of an intrinsic relationship between endogenous C-peptide concentration and determinants of glycemic control in type 1 diabetes following islet transplantation. Diabetes Care. 2015;38(1):105–12.

    Article  CAS  PubMed  Google Scholar 

  40. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment - insulin resistance and beta-cell function from fasting plasma-glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9.

    Article  CAS  PubMed  Google Scholar 

  41. Crutchlow MF, Robinson B, Pappachen B, Wimmer N, Cucchiara AJ, Cohen D, et al. Validation of steady-state insulin sensitivity indices in chronic kidney disease. Diabetes Care. 2007;30(7):1813–8.

    Article  CAS  PubMed  Google Scholar 

  42. Rickels MR, Mueller R, Teff KL, Naji A. beta-Cell secretory capacity and demand in recipients of islet, pancreas, and kidney transplants. J Clin Endocrinol Metab. 2010;95(3):1238–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rickels MR, Liu C, Shlansky-Goldberg RD, Soleimanpour SA, Vivek K, Kamoun M, et al. Improvement in beta-cell secretory capacity after human islet transplantation according to the CIT07 protocol. Diabetes. 2013;62(8):2890–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cottrell DA. Normalization of insulin sensitivity and glucose homeostasis in type I diabetic pancreas transplant recipients: a 48-month cross-sectional study - a clinical research center study. J Clin Endocrinol Metab. 1996;81(10):3513–9.

    CAS  PubMed  Google Scholar 

  45. Rickels MR, Kong SM, Fuller C, Dalton-Bakes C, Ferguson JF, Reilly MP, et al. Insulin sensitivity index in type 1 diabetes and following human islet transplantation: comparison of the minimal model to euglycemic clamp measures. Am J Physiol Endocrinol Metab. 2014;306(10):E1217–E24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. McEachron KR, Yang Y, Hodges JS, Beilman GJ, Kirchner VA, Pruett TL, et al. Performance of modified Igls criteria to evaluate islet autograft function after total pancreatectomy with islet autotransplantation - a retrospective study. Transpl Int. 2020;34:87.

    Article  PubMed  Google Scholar 

  47. Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care. 2016;39(7):1230–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Markmann JF, Rickels MR, Eggerman TL, Bridges ND, Lafontant DE, Qidwai J, et al. Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes. Am J Transplant. 2020;21:1477.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Lind M, Svensson AM, Kosiborod M, Gudbjornsdottir S, Pivodic A, Wedel H, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014;371(21):1972–82.

    Article  PubMed  Google Scholar 

  50. Stadler M, Peric S, Strohner-Kaestenbauer H, Kramar R, Kaestenbauer T, Reitner A, et al. Mortality and incidence of renal replacement therapy in people with type 1 diabetes mellitus-a three decade long prospective observational study in the Lainz T1DM Cohort. J Clin Endocrinol Metab. 2014;99(12):4523–30.

    Article  CAS  PubMed  Google Scholar 

  51. Rickels MR, Peleckis AJ, Markmann E, Dalton-Bakes C, Kong SM, Teff KL, et al. Long-term improvement in glucose control and counterregulation by islet transplantation for type 1 diabetes. J Clin Endocrinol Metab. 2016;101(11):4421–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shah VN, DuBose SN, Li Z, Beck RW, Peters AL, Weinstock RS, et al. Continuous glucose monitoring profiles in healthy nondiabetic participants: a multicenter prospective study. J Clin Endocrinol Metab. 2019;104(10):4356–64.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Wilmot EG, Choudhary P, Leelarathna L, Baxter M. Glycaemic variability: the under-recognized therapeutic target in type 1 diabetes care. Diabetes Obes Metab. 2019;21(12):2599–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jalbert M, Zheng F, Wojtusciszyn A, Forbes F, Bonnet S, Skaare K, et al. Glycemic variability indices can be used to diagnose islet transplantation success in type 1 diabetic patients. Acta Diabetol. 2020;57(3):335–45.

    Article  PubMed  Google Scholar 

  55. Vantyghem MC, Quintin D, Caiazzo R, Leroy C, Raverdy V, Cassim F, et al. Improvement of electrophysiological neuropathy after islet transplantation for type 1 diabetes: a 5-year prospective study. Diabetes Care. 2014;37(6):e141–2.

    Article  PubMed  Google Scholar 

  56. Holmes-Walker DJ, Gunton JE, Hawthorne W, Payk M, Anderson P, Donath S, et al. Islet transplantation provides superior glycemic control with less hypoglycemia compared with continuous subcutaneous insulin infusion or multiple daily insulin injections. Transplantation. 2017;101(6):1268–75.

    Article  CAS  PubMed  Google Scholar 

  57. Mittal S, Franklin RH, Policola C, Sharples E, Friend PJ, Gough SC. Early postoperative continuous glucose monitoring in pancreas transplant recipients. Transpl Int. 2015;28(5):604–9.

    Article  CAS  PubMed  Google Scholar 

  58. Dadlani V, Kaur RJ, Stegall M, Xyda SE, Kumari K, Bonner K, et al. Continuous glucose monitoring to assess glycemic control in the first 6 weeks after pancreas transplantation. Clin Transpl. 2019;33(10):e13719.

    Article  Google Scholar 

  59. Mittal S, Nagendran M, Franklin RH, Sharples EJ, Friend PJ, Gough SC. Postoperative impaired glucose tolerance is an early predictor of pancreas graft failure. Diabetologia. 2014;57(10):2076–80.

    Article  CAS  PubMed  Google Scholar 

  60. Maahs DM, Buckingham BA, Castle JR, Cinar A, Damiano ER, Dassau E, et al. Outcome measures for artificial pancreas clinical trials: a consensus report. Diabetes Care. 2016;39(7):1175–9.

    Article  PubMed  PubMed Central  Google Scholar 

  61. van Duinkerken E, Snoek FJ, de Wit M. The cognitive and psychological effects of living with type 1 diabetes: a narrative review. Diabet Med. 2020;37(4):555–63.

    Article  PubMed  Google Scholar 

  62. Foster ED, Bridges ND, Feurer ID, Eggerman TL, Hunsicker LG, Alejandro R, 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):1001–8.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lablanche S, Vantyghem MC, Kessler L, Wojtusciszyn A, Borot S, Thivolet C, et al. Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(7):527–37.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

MRR is supported in part by Public Health Services Research Grant R01 DK091331.

Author information

Authors and Affiliations

  1. Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases, Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Michael R. Rickels

Authors
  1. Michael R. Rickels
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael R. Rickels .

Editor information

Editors and Affiliations

  1. Department of Surgery, State University of New York (SUNY), Downstate Health Sciences University, Brooklyn, NY, USA

    Rainer W. G. Gruessner

  2. Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY, USA

    Angelika C. Gruessner

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Rickels, M.R. (2023). Defining Outcomes for β-Cell Replacement Therapy. In: Gruessner, R.W.G., Gruessner, A.C. (eds) Transplantation of the Pancreas. Springer, Cham. https://doi.org/10.1007/978-3-031-20999-4_65

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-20999-4_65

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-20998-7

  • Online ISBN: 978-3-031-20999-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation