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Diabetologia

, Volume 62, Issue 1, pp 28–32 | Cite as

Capturing residual beta cell function in type 1 diabetes

  • Flemming Pociot
Commentary

Abstract

Since the 1970s, C-peptide has been used as a surrogate marker for monitoring the progression of type 1 and type 2 diabetes and to determine the effects of interventions designed to preserve or improve residual beta cell function. C-peptide measurement is a well-established surrogate of residual beta cell activity and of clinical significance as it is associated with HbA1c, risk for microvascular complications and the incidence of hyperglycaemia in longitudinal studies. Measurement of C-peptide after a mixed meal tolerance test is considered the gold standard of measuring beta cell function in type 1 diabetes, but the method is laborious and inconvenient. In this issue of Diabetologia, Wentworth et al ( https://doi.org/10.1007/s00125-018-4722-z) report an algorithm for estimating C-peptide (CPEST) based on six routine clinical measures. These do not include stimulated C-peptide measurement and outperform other prevailing algorithms for estimating residual beta cell function. Going forward it is very likely that this new algorithm will serve as a simple measure of beta cell function in routine practice and as a more acceptable primary outcome measure in future trials of disease-modifying therapies.

Keywords

Beta cell function C-peptide Glucagon stimulation test MMTT Modelling Type 1 diabetes 

Abbreviations

CPEST

Estimated C-peptide

GST

Glucagon stimulation test

IDAA1c

Insulin-dose-adjusted HbA1c

MMTT

Mixed meal tolerance test

Notes

Contribution statement

The author was the sole contributor to this paper.

Funding

Funding for the author’s lab work on residual beta cell function is supported by the Novo Nordisk Foundation and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA), which receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA, JDRF and The Leona M. and Harry B. Helmsley Charitable Trust.

Duality of interest

The author declares that there is no duality of interest associated with this manuscript.

References

  1. 1.
    Jones AG, Hattersley AT (2013) The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabet Med 30(7):803–817.  https://doi.org/10.1111/dme.12159 CrossRefGoogle Scholar
  2. 2.
    Sacks DB, Arnold M, Bakris GL et al (2011) Position statement executive summary: guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care 34(6):1419–1423.  https://doi.org/10.2337/dc11-9997 CrossRefGoogle Scholar
  3. 3.
    Handelsman Y, Bloomgarden ZT, Grunberger G et al (2015) American Association of Clinical Endocrinologists and American College of Endocrinology – clinical practice guidelines for developing a diabetes mellitus comprehensive care plan – 2015. Endocr Pract 21(Suppl 1):1–87.  https://doi.org/10.4158/EP15672.GLSUPPL CrossRefGoogle Scholar
  4. 4.
    Lachin JM, McGee P, Palmer JP, Group DER (2014) Impact of C-peptide preservation on metabolic and clinical outcomes in the Diabetes Control and Complications Trial. Diabetes 63(2):739–748.  https://doi.org/10.2337/db13-0881 CrossRefGoogle Scholar
  5. 5.
    Madsbad S, Alberti KG, Binder C et al (1979) Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetes. BMJ 2(6200):1257–1259.  https://doi.org/10.1136/bmj.2.6200.1257 CrossRefGoogle Scholar
  6. 6.
    Steele C, Hagopian WA, Gitelman S et al (2004) Insulin secretion in type 1 diabetes. Diabetes 53(2):426–433.  https://doi.org/10.2337/diabetes.53.2.426 CrossRefGoogle Scholar
  7. 7.
    Steffes MW, Sibley S, Jackson M, Thomas W (2003) Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 26(3):832–836.  https://doi.org/10.2337/diacare.26.3.832 CrossRefGoogle Scholar
  8. 8.
    Greenbaum CJ, Harrison LC, Immunology of Diabetes Society (2003) Guidelines for intervention trials in subjects with newly diagnosed type 1 diabetes. Diabetes 52(5):1059–1065.  https://doi.org/10.2337/diabetes.52.5.1059 CrossRefGoogle Scholar
  9. 9.
    Bowman P, McDonald TJ, Shields BM, Knight BA, Hattersley AT (2012) Validation of a single-sample urinary C-peptide creatinine ratio as a reproducible alternative to serum C-peptide in patients with type 2 diabetes. Diabet Med 29(1):90–93.  https://doi.org/10.1111/j.1464-5491.2011.03428.x CrossRefGoogle Scholar
  10. 10.
    Gjessing HJ, Matzen LE, Faber OK, Froland A (1989) Fasting plasma C-peptide, glucagon stimulated plasma C-peptide, and urinary C-peptide in relation to clinical type of diabetes. Diabetologia 32(5):305–311.  https://doi.org/10.1007/BF00265547 CrossRefGoogle Scholar
  11. 11.
    Palmer JP, Fleming GA, Greenbaum CJ et al (2004) C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes 53(1):250–264.  https://doi.org/10.2337/diabetes.53.1.250 CrossRefGoogle Scholar
  12. 12.
    Little RR, Wielgosz RI, Josephs R et al (2017) Implementing a reference measurement system for C-peptide: successes and lessons learned. Clin Chem 63(9):1447–1456.  https://doi.org/10.1373/clinchem.2016.269274 CrossRefGoogle Scholar
  13. 13.
    Leighton E, Sainsbury CA, Jones GC (2017) A practical review of C-peptide testing in diabetes. Diabetes Ther 8(3):475–487.  https://doi.org/10.1007/s13300-017-0265-4 CrossRefGoogle Scholar
  14. 14.
    Willemsen RH, Burling K, Barker P et al (2018) Frequent monitoring of C-peptide levels in newly diagnosed type 1 subjects using dried blood spots collected at home. J Clin Endocrinol Metab 103(9):3350–3358.  https://doi.org/10.1210/jc.2018-00500 CrossRefGoogle Scholar
  15. 15.
    Ludvigsson J (1983) Methodological aspects on C-peptide measurements. Acta Medica Scand Suppl 671:53–59Google Scholar
  16. 16.
    Mirel RD, Ginsberg-Fellner F, Horwitz DL, Rayfield EJ (1980) C-peptide reserve in insulin-dependent diabetes. Comparative responses to glucose, glucagon and tolbutamide. Diabetologia 19(3):183–188.  https://doi.org/10.1007/BF00275266 CrossRefGoogle Scholar
  17. 17.
    Greenbaum C, Seidel K, Pihoker C (2004) The case for intravenous arginine stimulation in lieu of mixed-meal tolerance tests as outcome measure for intervention studies in recent-onset type 1 diabetes. Diabetes Care 27(5):1202–1204.  https://doi.org/10.2337/diacare.27.5.1202 CrossRefGoogle Scholar
  18. 18.
    Keymeulen B, Vandemeulebroucke E, Ziegler AG et al (2005) Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 352(25):2598–2608.  https://doi.org/10.1056/NEJMoa043980 CrossRefGoogle Scholar
  19. 19.
    Berger B, Stenstrom G, Sundkvist G (2000) Random C-peptide in the classification of diabetes. Scand J Clin Lab Invest 60(8):687–693CrossRefGoogle Scholar
  20. 20.
    Greenbaum CJ, Mandrup-Poulsen T, McGee PF et al (2008) Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care 31(10):1966–1971.  https://doi.org/10.2337/dc07-2451 CrossRefGoogle Scholar
  21. 21.
    Faber OK, Binder C (1977) C-peptide response to glucagon. A test for the residual beta-cell function in diabetes mellitus. Diabetes 26(7):605–610.  https://doi.org/10.2337/diab.26.7.605 CrossRefGoogle Scholar
  22. 22.
    Panero F, Novelli G, Zucco C et al (2009) Fasting plasma C-peptide and micro- and macrovascular complications in a large clinic-based cohort of type 1 diabetic patients. Diabetes Care 32(2):301–305.  https://doi.org/10.2337/dc08-1241 CrossRefGoogle Scholar
  23. 23.
    The DCCT Research Group (1998) Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. The Diabetes Control and Complications Trial Research Group. Ann Intern Med 128:517–523CrossRefGoogle Scholar
  24. 24.
    Greenbaum CJ, Anderson AM, Dolan LM et al (2009) Preservation of beta-cell function in autoantibody-positive youth with diabetes. Diabetes Care 32(10):1839–1844.  https://doi.org/10.2337/dc08-2326 CrossRefGoogle Scholar
  25. 25.
    Sorensen JS, Vaziri-Sani F, Maziarz M et al (2012) Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years. Diabetes Res Clin Pract 96(2):204–210.  https://doi.org/10.1016/j.diabres.2011.12.013 CrossRefGoogle Scholar
  26. 26.
    Davis AK, DuBose SN, Haller MJ et al (2015) Prevalence of detectable C-peptide according to age at diagnosis and duration of type 1 diabetes. Diabetes Care 38(3):476–481.  https://doi.org/10.2337/dc14-1952 CrossRefGoogle Scholar
  27. 27.
    Xu P, Qian X, Schatz DA, Cuthbertson D, Krischer JP, Group DPTS (2014) Distribution of C-peptide and its determinants in North American children at risk for type 1 diabetes. Diabetes Care 37(7):1959–1965.  https://doi.org/10.2337/dc13-2603 CrossRefGoogle Scholar
  28. 28.
    Mortensen HB, Hougaard P, Swift P et al (2009) New definition for the partial remission period in children and adolescents with type 1 diabetes. Diabetes Care 32(8):1384–1390.  https://doi.org/10.2337/dc08-1987 CrossRefGoogle Scholar
  29. 29.
    Andersen ML, Rasmussen MA, Pörksen S et al (2013) Complex multi-block analysis identifies new immunologic and genetic disease progression patterns associated with the residual β-cell function 1 year after diagnosis of type 1 diabetes. PLoS One 8(6):e64632.  https://doi.org/10.1371/journal.pone.0064632 CrossRefGoogle Scholar
  30. 30.
    Max Andersen ML, Hougaard P, Pörksen S et al (2014) Partial remission definition: validation based on the insulin dose-adjusted HbA1c (IDAA1C) in 129 Danish children with new-onset type 1 diabetes. Pediatr Diabetes 15(7):469–476.  https://doi.org/10.1111/pedi.12208 CrossRefGoogle Scholar
  31. 31.
    Nagl K, Hermann JM, Plamper M et al (2017) Factors contributing to partial remission in type 1 diabetes: analysis based on the insulin dose-adjusted HbA1c in 3657 children and adolescents from Germany and Austria. Pediatr Diabetes 18(6):428–434.  https://doi.org/10.1111/pedi.12413 CrossRefGoogle Scholar
  32. 32.
    Nielens N, Polle O, Robert A, Lysy PA (2018) Integration of routine parameters of glycemic variability in a simple screening method for partial remission in children with type 1 diabetes. J Diabetes Res 2018:5936360CrossRefGoogle Scholar
  33. 33.
    Redondo MJ, Libman I, Cheng P et al (2018) Racial/ethnic minority youth with recent-onset type 1 diabetes have poor prognostic factors. Diabetes Care 41(5):1017–1024.  https://doi.org/10.2337/dc17-2335 CrossRefGoogle Scholar
  34. 34.
    Lundberg RL, Marino KR, Jasrotia A et al (2017) Partial clinical remission in type 1 diabetes: a comparison of the accuracy of total daily dose of insulin of <0.3 units/kg/day to the gold standard insulin-dose adjusted hemoglobin A1c of ≤9 for the detection of partial clinical remission. J Pediatr Endocrinol Metab 30(8):823–830.  https://doi.org/10.1515/jpem-2017-0019 CrossRefGoogle Scholar
  35. 35.
    Boyle KD, Keyes-Elstein L, Ehlers MR et al (2016) Two- and four-hour tests differ in capture of c-peptide responses to a mixed meal in type 1 diabetes. Diabetes Care 39(6):e76–e78.  https://doi.org/10.2337/dc15-2077 CrossRefGoogle Scholar
  36. 36.
    Wentworth JM, Bediaga NG, Giles LC et al (2018) Beta cell function in type 1 diabetes determined from clinical and fasting biochemical variables. Diabetologia.  https://doi.org/10.1007/s00125-018-4722-z
  37. 37.
    Barker A, Lauria A, Schloot N et al (2014) Age-dependent decline of beta-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study. Diabetes Obes Metab 16(3):262–267.  https://doi.org/10.1111/dom.12216 CrossRefGoogle Scholar
  38. 38.
    Ludvigsson J, Carlsson A, Deli A et al (2013) Decline of C-peptide during the first year after diagnosis of type 1 diabetes in children and adolescents. Diabetes Res Clin Pract 100(2):203–209.  https://doi.org/10.1016/j.diabres.2013.03.003 CrossRefGoogle Scholar
  39. 39.
    Kuhtreiber WM, Washer SL, Hsu E et al (2015) Low levels of C-peptide have clinical significance for established type 1 diabetes. Diabet Med 32(10):1346–1353.  https://doi.org/10.1111/dme.12850 CrossRefGoogle Scholar
  40. 40.
    Wang L, Lovejoy NF, Faustman DL (2012) Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay. Diabetes Care 35(3):465–470.  https://doi.org/10.2337/dc11-1236 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Steno Diabetes Center CopenhagenGentofteDenmark
  2. 2.Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  3. 3.Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics EHerlev HospitalHerlevDenmark

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