The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells
Open accessAbstract
AIMS/HYPOTHESIS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
When sensitive C-peptide measurements are performed, 30-80% of people with long-term type 1 diabetes are found to be insulin microsecretors.
“When sensitive C-peptide measure ments are performed, 30–80% of people with long-term type 1 diabetes are found to be insulin microsecretors.64–67”
From Type 1 diabetes (2018) · cites this paper as [65]
Low C-peptide levels increase during a mixed meal, which suggests that a very small number of functional beta cells are present.
“Importantly, we showed that these low levels increased during a mixed meal suggesting that there are a very small number of functional beta-cells(1).”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [1]
Only two small clinic-based studies have used sufficiently sensitive C-peptide assays, with sample sizes of 74 and 182.
“There have only been two small studies using sufficiently sensitive C-peptide assays from clinic based populations (n=74(1) and 182 (144 > 5years duration)(2)).”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [1]
Sensitive C-peptide assays have found that 43-74% of people with type 1 diabetes for more than 5 years are microsecretors of endogenous insulin.
“Sensitive C-peptide assays have shown that 43-74% people with longstanding (> 5 years) type 1 diabetes (T1D) are microsecretors of endogenous insulin(1; 2) with C-peptide levels in a range not detected by previous assays (1-30 pmol/L).”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [1]
UCPCR and serum C-peptide identified similar long-duration type 1 diabetes patients as having detectable C-peptide in a mixed meal tolerance test.
“UCPCR and serum C-peptide identified similar long duration patients with T1D as having detectable C-peptide in a MMTT(1).”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [1]
Two previous smaller studies using sensitive C-peptide assays in type 1 diabetes support the high prevalence found in this study.
“The 2 previous smaller studies using sensitive C-peptide assays in T1D support the high prevalence in our study.”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [1]
An earlier study of 74 people with a median diabetes duration of 30 years found that 73% had detectable post-mixed-meal serum C-peptide.
“Our initial study on 74 people (median duration 30 years) showed 73% had detectable post mixed meal serum C-peptide (1).”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [1]
Home UCPCR is highly correlated with MMTT serum C-peptide in type 1 diabetes, and both urine and serum were equally sensitive in detecting very low level C-peptide in long-standing type 1 diabetes.
“However a home UCPCR is highly correlated with MMTT serum C-peptide in T1D (6) and both urine and serum were equally sensitive in detecting very low level C peptide in long standing T1D(1).”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [1]
The study by Wang et al found a lower proportion of detectable C-peptide (43% of 182 patients), probably because it used a fasting sample and a less sensitive ELISA than the chemiluminescence assay used in the authors' two studies.
“The study by Wang et al found a lower proportion (43% of 182 patients (median duration 15 years) (2) which probably reflected the use of a fasting sample and that the ELISA used was less sensitive than the chemiluminesence assay used in our two studies (1).”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [1]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Pathologic anatomy of the pancreas in juvenile diabetes mellitus
Gepts, W. (1965) · Diabetes · doi:10.2337/diab.14.10.619 · Cited by 1,345 · see citing works
Steffes, M. W., Sibley, S., Jackson, M., & Thomas, W. (2003) · Diabetes Care · doi:10.2337/diacare.26.3.832 · Cited by 695 · see citing works
(1998) · Annals of Internal Medicine · doi:10.7326/0003-4819-128-7-199804010-00001 · Cited by 546 · see citing works
Keenan, H. A., Sun, J. K., Levine, J., Doria, A., Aiello, L. P., Eisenbarth, G., Bonner-Weir, S., & King, G. L. (2010) · Diabetes · doi:10.2337/db10-0676 · Cited by 500 · see citing works
Meier, J. J., Bhushan, A., Butler, A. E., Rizza, R. A., & Butler, P. C. (2005) · Diabetologia · doi:10.1007/s00125-005-1949-2 · Cited by 493 · see citing works
Palmer, J. P., Fleming, G. A., Greenbaum, C. J., Herold, K. C., Jansa, L. D., Kolb, H., Lachin, J. M., Polonsky, K. S., Pozzilli, P., Skyler, J. S., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.1.250 · Cited by 491 · see citing works
Foulis, A. K., Liddle, C. N., Farquharson, M. A., Richmond, J. A., & Weir, R. S. (1986) · Diabetologia · doi:10.1007/bf00452061 · Cited by 469 · see citing works
Greenbaum, C. J., Mandrup-Poulsen, T. R., McGee, P. F., Battelino, T., Haastert, B., Ludvigsson, J., Pozzilli, P., Lachin, J. M., & Kolb, H. (2008) · Diabetes Care · doi:10.2337/dc07-2451 · Cited by 285 · see citing works
Wang, L., Lovejoy, N. F., & Faustman, D. L. (2012) · Diabetes Care · doi:10.2337/dc11-1236 · Cited by 192 · see citing works
Besser, R. E. J., Shepherd, M. H., McDonald, T. J., Shields, B. M., Knight, B., Ellard, S., & Hattersley, A. T. (2011) · Diabetes Care · doi:10.2337/dc10-1293 · Cited by 133 · see citing works
Self-citation(2004) · Diabetes · doi:10.2337/diabetes.53.7.1934 · Cited by 120 · see citing works
Standardization of C-peptide measurements
Little, R. R., Rohlfing, C. L., Tennill, A. L., Madsen, R. W., Polonsky, K. S., Myers, G. L., Greenbaum, C. J., Palmer, J. P., Rogatsky, E., & Stein, D. T. (2008) · Clinical Chemistry · doi:10.1373/clinchem.2007.101287 · Cited by 103 · see citing works
Lessons From the Mixed-Meal Tolerance Test
Besser, R. E. J., Shields, B. M., Casas, R., Hattersley, A. T., & Ludvigsson, J. (2013) · Diabetes Care · doi:10.2337/dc12-0836 · Cited by 91 · see citing works
Self-citationBesser, R. E. J., Ludvigsson, J., Jones, A. G., McDonald, T. J., Shields, B. M., Knight, B. A., & Hattersley, A. T. (2011) · Diabetes Care · doi:10.2337/dc10-2114 · Cited by 82 · see citing works
Self-citationMcDonald, T. J., Knight, B. A., Shields, B. M., Bowman, P., Salzmann, M. B., & Hattersley, A. T. (2009) · Clinical Chemistry · doi:10.1373/clinchem.2009.129312 · Cited by 75 · see citing works
Self-citationInternational Comparison of C-Peptide Measurements
Wiedmeyer, H.-M., Polonsky, K. S., Myers, G. L., Little, R. R., Greenbaum, C. J., Goldstein, D. E., & Palmer, J. P. (2007) · Clinical Chemistry · doi:10.1373/clinchem.2006.081570 · Cited by 42 · see citing works
Jones, A. G., Besser, R. E. J., McDonald, T. J., Shields, B. M., Hope, S. V., Bowman, P., Oram, R. A., Knight, B., & Hattersley, A. T. (2011) · Diabetic Medicine · doi:10.1111/j.1464-5491.2011.03272.x · Cited by 39 · see citing works
Self-citationNordwall, M., & Ludvigsson, J. (2008) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.871 · Cited by 37 · see citing works
Rong-l, Q. (2012) · Zhongguo tangniaobing zazhi · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
DiMeglio, L. A., Evans-Molina, C., & Oram, R. A. (2018) · The Lancet · doi:10.1016/s0140-6736(18)31320-5 · Cited by 1,561 · see citing works
Self-citationDifferentiation of diabetes by pathophysiology, natural history, and prognosis
Skyler, J. S., Bakris, G. L., Bonifacio, E., Darsow, T., Eckel, R. H., Groop, L., Groop, P.-H., Handelsman, Y., Insel, R. A., Mathieu, C., et al. (2017) · Diabetes · doi:10.2337/db16-0806 · Cited by 823 · see citing works
Prevalence of detectable C-peptide according to age at diagnosis and duration of type 1 diabetes
Davis, A. K., DuBose, S. N., Haller, M. J., Miller, K. M., DiMeglio, L. A., Bethin, K. E., Goland, R. S., Greenberg, E. M., Liljenquist, D. R., Ahmann, A. J., et al. (2015) · Diabetes Care · doi:10.2337/dc14-1952 · Cited by 261 · see citing works
The α-cell in diabetes mellitus
Gromada, J., Chabosseau, P., & Rutter, G. A. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0097-y · Cited by 143 · see citing works
Oram, R. A., McDonald, T. J., Shields, B. M., Hudson, M. M., Shepherd, M. H., Hammersley, S., Pearson, E. R., Hattersley, A. T., & on behalf of the UNITED Team (2015) · Diabetes Care · doi:10.2337/dc14-0871 · Cited by 133 · see citing works
Self-citationNovel insights into genetics and clinics of the HNF1A-MODY
Valkovicova, T., Skopkova, M., Stanik, J., & Gasperikova, D. (2019) · Endocrine Regulations · doi:10.2478/enr-2019-0013 · Cited by 84 · see citing works
β cells persist in T1D pancreata without evidence of ongoing β-cell turnover or neogenesis
Lam, C. J., Jacobson, D. R., Rankin, M. M., Cox, A. R., & Kushner, J. A. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-3806 · Cited by 68 · see citing works
New therapeutic approaches for type 1 diabetes: Disease-modifying therapies
Nagy, G., Szekely, T. E., Somogyi, A., Herold, M., & Herold, Z. (2022) · World Journal of Diabetes · doi:10.4239/wjd.v13.i10.835 · Cited by 23 · see citing works
- Authors
- Oram, R. A., Jones, A. G., Besser, R. E. J., Knight, B. A., Shields, B. M., Brown, R. J., Hattersley, A. T., & McDonald, T. J.
- Affiliations
- University of Exeter (GB)
- Royal Devon & Exeter NHS Foundation Trust (GB)
- Corresponding author
- Hattersley, Andrew T.
- McDonald, Timothy J.
- ORCID
- Venue
- Diabetologia
- Published
- 2013-10-12
- Volume
- 57
- Issue
- 1
- Pages
- 187-191
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC3855529
- OpenAlex
- W2074332864
- Cited by
- 298
- References
- 19
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 21 · 2023: 17 · 2022: 26 · 2021: 26 · 2020: 21 · 2019: 31 · 2018: 28 · 2017: 25 · 2016: 19 · 2015: 24 · 2014: 22 · 2013: 2
- FWCI
- 14.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research (ACF-2008-23-001, DRF-2010-03-72, ACF-2007-23-001, NIHR-HCS-P12-03-03, NF-SI-0611-10219)
- Diabetes UK
- University of Exeter
- Linköpings Universitet
- NIHR Exeter Clinical Research Facility
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- type 1 diabetes, long-standing diabetes, C-peptide, beta-cell function, mixed meal tolerance test, disease duration, beta cell regeneration, immune evasion
- MeSH terms
- Insulin Secretion, Adult, C-Peptide, Diabetes Mellitus, Type 1, Female, Humans, Insulin, Male, Insulin-Secreting Cells, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
