C Peptide and Type 1 Diabetes: Concise Review of Fundamental Concepts

Radhika Narla, Jerry Palmer


Analyzing the loss of insulin secretion has strengthened our understanding of type 1 diabetes mellitus (T1D) pathogenesis.  Pancreatic beta cell injury is fundamental to this disease process. It is generally accepted that we can evaluate B cell function by measuring C peptide levels. We will discuss the various ways to measure C peptide that are used in clinical and research settings and emphasize the reasons for assessing insulin secretion, C peptide levels and shapes of oral glucose curves in response to mixed meal or oral glucose tolerance tests (OGTT) in investigative trials.  This review will highlight the patterns and variations that occur metabolically before the clinical presentation of T1D and their significance, specifically emphasizing data that shows the decline in beta cell function is most rapid during the last 6 months before T1D diagnosis. Preserving Beta cell function has essential long term advantages and consequences for patients with T1D.  We will draw attention to data that comes from several landmark trials including Diabetes Control and Complications Trial (DCCT), Diabetes Prevention Trial- Type 1 (DPT-1) and Trial Net. It is extremely valuable to be able to quantify and monitor risk of future T1D. A main message from this review is to have an understanding and appreciation of temporal C peptide changes that occur before T1D diagnosis as most future research questions and trials investigating therapies continue to direct efforts to intervene earlier and target this peri-diagnosis period before accelerated C peptide decline is observed. 


C peptide; Type 1 Diabetes; metabolic progression

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Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, Chase HP, Eisenbarth GS: Prediction of type 1 diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 45:926–933, 1996.

Sosenko JM, Skyler JS, Herold KC, Palmer JP, the Type 1 Diabetes TrialNet and Diabetes Prevention Trial–Type 1 Study Groups. The Metabolic Progression to Type 1 Diabetes as Indicated by Serial Oral Glucose Tolerance Testing in the Diabetes Prevention Trial–Type 1. Diabetes. 2012;61(6):1331-1337.

Koskinen MK, Helminen O, Matomäki J, et al. Reduced β-cell function in early preclinical type 1 diabetes. European Journal of Endocrinology. 2016;174(3):251-259.

Sosenko JM, Palmer JP, Rafkin-Mervis L, et al. Glucose and C-Peptide Changes in the Perionset Period of Type 1 Diabetes in the Diabetes Prevention Trial–Type 1 . Diabetes Care. 2008;31(11):2188-2192.

Insel R, Dutta S, Hedrick J, Type 1 Diabetes: Disease Stratification. Biomed Hub 2017;2(suppl 1):14-14.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;37(Suppl. 1):S81–S90.

Ferrannini E, Mari A, Nofrate V, Sosenko JM, Skyler JS, for the DPT-1 Study Group. Progression to Diabetes in Relatives of Type 1 Diabetic Patients: Mechanisms and Mode of Onset. Diabetes. 2010;59(3):679-685.

VanBuecken DE, Greenbaum CJ. Residual C-peptide in type 1 diabetes: what do we really know? Pediatr Diabetes. 2014 Mar;15(2):84-90.

Van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes. 1992 Mar;41(3):368-77.

Polonsky KS, Pugh W, Jaspan JB, Cohen DM, Karrison T, Tager HS, Rubenstein AH.C-peptide and insulin secretion. Relationship between peripheral concentrations of C-peptide and insulin and their secretion rates in the dog. J Clin Invest.1984 Nov;74(5):1821-9.

Zavaroni I, Deferrari G, Lugari R, Bonora E, Garibotto G, Dall'Aglio E,Robaudo C, Gnudi A. Renal metabolism of C-peptide in man. J Clin Endocrinol Metab. 1987 Sep;65(3):494-8.

Covic AM, Schelling JR, Constantiner M, Iyengar SK, Sedor JR. Serum C-peptide concentrations poorly phenotype type 2 diabetic end-stage renal disease patients.Kidney Int. 2000 Oct;58(4):1742-50.

Huttunen NP, Knip M, Kaar ML, Puukka R, Akerblom HK. Clinical significance of urinary C-peptide excretion in children with insulin-dependent diabetes mellitus. Acta Paediatr Scand. 1989;78:271–277.

Meistas MT, Rendell M, Margolis S, Kowarski AA. Estimation of the secretion rate of insulin from the urinary excretion rate of C-peptide. Study in obese and diabetic subjects. Diabetes. 1982;31:449–453.

Tillil H, Shapiro ET, Given BD, Rue P, Rubenstein AH, Galloway JA, et al. Reevaluation of urine C-peptide as measure of insulin secretion. Diabetes. 1988;37:1195–1201.

Tatovic D, Luzio S, Dunseath G, Liu Y, Alhadj Ali M, Peakman M, Dayan CM; MonoPepT1De Study Group. Stimulated urine C-peptide creatinine ratio vs serum C-peptide level for monitoring of β-cell function in the first year after diagnosis of Type 1 diabetes. Diabet Med. 2016 Nov;33(11):1564-1568.

Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, Lachin JM, Polonsky KS, Pozzilli P, Skyler JS, Steffes MW: C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve β-cell function: report of an ADA workshop, 21–22 October 2001. Diabetes 53:250–264, 2004.

Cernea S, Raz I, Herold KC, Hirshberg B, Roep BO, Schatz DA, Fleming GA, Pozzilli P, Little R, Schloot NC, Leslie RD, Skyler JS, Palmer JP; D-Cure Workshop. Challenges in developing endpoints for type 1 diabetes intervention studies. Diabetes Metab Res Rev. 2009 Nov;25(8):694-704.

Scheen AJ, Castillo MJ, Lefèbvre PJ. Assessment of residual insulin secretion in diabetic patients using the intravenous glucagon stimulatory test:methodological aspects and clinical applications. Diabetes Metab. 1996. Dec;22(6):397-406. Review.

Sosenko JM. Staging the progression to type 1 diabetes with prediagnostic markers. Curr Opin Endocrinol Diabetes Obes. 2016 Aug;23(4):297-305.

Besser REJ, Shields BM, Casas R, Hattersley AT, Ludvigsson J. Lessons From the Mixed-Meal Tolerance Test: Use of 90-minute and fasting C-peptide in pediatric diabetes. Diabetes Care. 2013;36(2):195-201. doi:10.2337/dc12-0836.

Greenbaum C, Buckingham B, Chase H, Krischer J. Metabolic Tests to Determine Risk for Type 1 Diabetes in Clinical Trials. Diabetes/metabolism research and reviews. 2011;27(6):584-589.

Greenbaum CJ, Mandrup-Poulsen T, McGee PF, et al. Type 1 Diabetes Trial Net Research Group. European C-Peptide Trial Study Group Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care 2008;31:1966–1971.

Greenbaum CJ, Harrison LC: Guidelines for intervention trials in subjects with newly diagnosed type 1 diabetes. Diabetes 52 : 1059 –1065,2003.

Greenbaum CJ, Mandrup-Poulsen T, McGee PF, et al. Mixed-Meal Tolerance Test Versus Glucagon Stimulation Test for the Assessment of β-Cell Function in Therapeutic Trials in Type 1 Diabetes. Diabetes Care. 2008;31(10):1966-1971.

The DCCT Research Group Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual beta-cell function: observations during eligibility testing for the Diabetes Control and Complications Trial (DCCT). J Clin Endocrinol Metab 1987;65:30–36.

Insel RA, Dunne JL, Atkinson MA, Chiang JL, Dabelea D, Gottlieb PA, Greenbaum CJ, Herold KC, Krischer JP, Lernmark Å, Ratner RE, Rewers MJ, Schatz DA, Skyler, JS, Sosenko JM, Ziegler AG. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association.

Diabetes Care. 2015 Oct;38(10):1964-74.

Ferrannini E, Mari A, Nofrate V, Sosenko JM, Skyler JS, for the DPT-1 Study Group. Progression to Diabetes in Relatives of Type 1 Diabetic Patients: Mechanisms and Mode of Onset. Diabetes. 2010;59(3):679-685. doi:10.2337/db09-1378.

Sosenko JM, Palmer JP, Rafkin LE, et al. Trends of Earlier and Later Responses of C-peptide to Oral Glucose Challenges With Progression to Type 1 Diabetes in Diabetes Prevention Trial–Type 1 Participants. Diabetes Care. 2010;33(3):620-625. doi:10.2337/dc09-1770.

Verge CF, Gianani R, Yu L, Pietropaolo M, Smith T, Jackson RA, Soeldner JS, Eisenbarth GS: Late progression to diabetes and evidence for chronic beta-cell autoimmunity in identical twins of patients with type I diabetes. Diabetes44 :1176 –1179,1995.

Sherry NA, Tsai EB, Herold KC. Natural history of beta-cell function in type 1 diabetes. Diabetes. 2005 Dec;54 Suppl 2:S32-9. Review.

Matveyenko AV, Butler PC 2008. Relationship between β-cell mass and diabetes onset. Diabetes Obes Metab 10: 23–31.

The DCCT Research Group: Effect of intensive therapy on residual β-cell function in patients with type I diabetes in the Diabetes Control and Complications Trial. Ann Intern Med 128:517–523, 1998.

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 Mar;26(3):832-6.

Asa K. Davis, Stephanie N. DuBose, Michael J. Haller, Kellee M. Miller, Linda A. DiMeglio, Kathleen E. Bethin, Robin S. Goland, Ellen M. Greenberg, David R. Liljenquist, Andrew J. Ahmann, Santica M. Marcovina, Anne L. Peters, Roy W. Beck, Carla J. Greenbaum. Prevalence of Detectable C-Peptide According to Age at Diagnosis and Duration of Type 1 Diabetes. Diabetes Care Mar 2015, 38 (3) 476-481.

Greenbaum CJ, Beam CA, Boulware D, Gitelman SE, Gottlieb PA, Herold KC, Lachin JM, McGee P, Palmer JP, Pescovitz MD, Krause-Steinrauf H, Skyler JS, Sosenko JM; Type 1 Diabetes TrialNet Study Group. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1

Diabetes TrialNet data. Diabetes. 2012 Aug;61(8):2066-73.

Hillary A. Keenan, Jennifer K. Sun, Jared Levine, Alessandro Doria, Lloyd P. Aiello, George Eisenbarth, Susan Bonner-Weir, George L. King. Residual Insulin Production and Pancreatic β-Cell Turnover After 50 Years of Diabetes: Joslin Medalist Study. Diabetes Nov 2010, 59 (11) 2846-2853.

Yu HW, Lee YJ, Cho WI, Lee YA, Shin CH, Yang SW. Preserved C-peptide levels in overweight or obese compared with underweight children upon diagnosis of type 1 diabetes mellitus. Annals of Pediatric Endocrinology & Metabolism. 2015;20(2):92-97.

Sosenko JM, Geyer S, Skyler JS, Rafkin LE, Ismail HM, Libman IM, Liu YF,DiMeglio LA, Evans-Molina C, Palmer JP. The influence of body mass index and age on C-peptide at the diagnosis of type 1 diabetes in children who participated in the diabetes prevention trial-type 1. Pediatr Diabetes. 2017 Nov 24.

Orban T, Sosenko JM, Cuthbertson D, Krischer JP, Skyler JS, Jackson R, Yu L, Palmer JP, Schatz D, Eisenbarth G. Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1 (DPT-1) Diabetes Care. 2009;32:2269–2274.

Sosenko JM, Krischer JP, Palmer JP, Mahon J, Cowie C, Greenbaum CJ, Cuthbertson D, Lachin JM, Skyler JS Diabetes Prevention Trial-Type 1 Study Group. A risk score for type 1 diabetes derived from autoantibody positive participants in The Diabetes Prevention Trial-Type 1. Diabetes Care. 2008;31:528–533.

Sosenko JM, Skyler JS, Palmer JP, The Diabetes Type 1 TrialNet and Diabetes Prevention Trial-Type 1 Study Groups (see Online-Only Supplement). The Development, Validation, and Utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS). Current diabetes reports. 2015;15(8):626. doi:10.1007/s11892-015-0626-1.

Sosenko JM, Skyler JS, DiMeglio LA, Beam CA, Krischer JP, Greenbaum CJ, Boulware D, Rafkin LE, Matheson D, Herold KC, Mahon J, Palmer JP; Type 1 Diabetes TrialNet Study Group; Diabetes Prevention Trial-Type 1 Study Group. A new approach for diagnosing type 1 diabetes in autoantibody-positive individuals based on prediction and natural history. Diabetes Care. 2015 Feb;38(2):271-6.

Ismail HM, Xu P, Libman IM, Becker DJ, Marks JB, Skyler JS, Palmer JP, Sosenko JM; Type 1 Diabetes TrialNet Study Group. The shape of the glucose concentration curve during an oral glucose tolerance test predicts risk for type 1 diabetes. Diabetologia. 2018 Jan;61(1):84-92.

Steck AK, Dong F, Taki I, Hoffman M, Klingensmith GJ, Rewers MJ. Early hyperglycemia detected by continuous glucose monitoring in children at risk for type 1 diabetes. Diabetes Care. 2014 Jul;37(7):2031-3.

DOI: http://dx.doi.org/10.18103/imr.v4i5.706


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