The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells
Classically, type 1 diabetes is thought to proceed to absolute insulin deficiency. Recently developed ultrasensitive assays capable of detecting C-peptide under 5 pmol/l now allow very low levels of C-peptide to be detected in patients with long-standing type 1 diabetes. It is not known whether this low-level endogenous insulin secretion responds to physiological stimuli. We aimed to assess how commonly low-level detectable C-peptide occurs in long-duration type 1 diabetes and whether it responds to a meal stimulus.
We performed a mixed-meal tolerance test in 74 volunteers with long-duration (>5 years) type 1 diabetes, i.e. with age at diagnosis 16 (9–23) years (median [interquartile range]) and diabetes duration of 30 (19–41) years. We assessed fasting and stimulated serum C-peptide levels using an electrochemiluminescence assay (detection limit 3.3 pmol/l), and also the urinary C-peptide:creatinine ratio (UCPCR).
Post-stimulation serum C-peptide was detectable at very low levels (>3.3 pmol/l) in 54 of 74 (73%) patients. In all patients with detectable serum C-peptide, C-peptide either increased (n = 43, 80%) or stayed the same (n = 11) in response to a meal, with no indication of levels falling (p < 0.0001). With increasing disease duration, absolute C-peptide levels fell although the numbers with detectable C-peptide remained high (68%, i.e. 25 of 37 patients with >30 years duration). Similar results were obtained for UCPCR.
Most patients with long-duration type 1 diabetes continue to secrete very low levels of endogenous insulin, which increase after meals. This is consistent with the presence of a small number of still functional beta cells and implies that beta cells are either escaping immune attack or undergoing regeneration.
- Palmer, JP, Fleming, GA, Greenbaum, CJ (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: pp. 250-264 CrossRef
- 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: pp. 832-836 CrossRef
- Greenbaum, CJ, Mandrup-Poulsen, T, McGee, PF (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: pp. 1966-1971 CrossRef
- Besser, RE, Shields, BM, Casas, R, Hattersley, AT, Ludvigsson, J (2013) Lessons from the mixed-meal tolerance test: use of 90-minute and fasting C-peptide in pediatric diabetes. Diabetes Care 36: pp. 195-201 CrossRef
- Nordwall, M, Ludvigsson, J (2008) Clinical manifestations and beta cell function in Swedish diabetic children have remained unchanged during the last 25 years. Diabetes Metab Res Rev 24: pp. 472-479 CrossRef
- 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: pp. 465-470 CrossRef
- Meier, JJ, Bhushan, A, Butler, AE, Rizza, RA, Butler, PC (2005) Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration?. Diabetologia 48: pp. 2221-2228 CrossRef
- Keenan, HA, Sun, JK, Levine, J (2010) Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes 59: pp. 2846-2853 CrossRef
- Gepts, W (1965) Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14: pp. 619-633
- Foulis, AK, Liddle, CN, Farquharson, MA, Richmond, JA, Weir, RS (1986) The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 29: pp. 267-274 CrossRef
- McDonald, TJ, Knight, BA, Shields, BM, Bowman, P, Salzmann, MB, Hattersley, AT (2009) Stability and reproducibility of a single-sample urinary C-peptide/creatinine ratio and its correlation with 24-h urinary C-peptide. Clin Chem 55: pp. 2035-2039 CrossRef
- Besser, RE, Ludvigsson, J, Jones, AG (2011) Urine C-peptide creatinine ratio is a noninvasive alternative to the mixed-meal tolerance test in children and adults with type 1 diabetes. Diabetes Care 34: pp. 607-609 CrossRef
- Jones, AG, Besser, RE, McDonald, TJ (2011) Urine C-peptide creatinine ratio is an alternative to stimulated serum C-peptide measurement in late-onset, insulin-treated diabetes. Diabet Med 28: pp. 1034-1038 CrossRef
- (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 128:517–523
- Besser, RE, Shepherd, MH, McDonald, TJ (2011) Urinary C-peptide creatinine ratio (UCPCR) is a practical outpatient tool for identifying HNF1A/HNF4A MODY from long duration type 1 diabetes. Diabetes Care 34: pp. 286-291 CrossRef
- Wiedmeyer, HM, Polonsky, KS, Myers, GL (2007) International comparison of C-peptide measurements. Clin Chem 53: pp. 784-787 CrossRef
- Little, RR, Rohlfing, CL, Tennill, AL (2008) Standardization of C-peptide measurements. Clin Chem 54: pp. 1023-1026 CrossRef
- The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Volume 57, Issue 1 , pp 187-191
- Cover Date
- Print ISSN
- Online ISSN
- Springer Berlin Heidelberg
- Additional Links
- Industry Sectors
- Author Affiliations
- 1. NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Barrack Road, Exeter, UK
- 2. Department of Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK