CoChat
Sign Up
Cited by 133Diabetes and associated disordersDiabetes Management and ResearchPancreatic function and diabetes

Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors

Open access
Oram, Richard A., McDonald, Timothy J., Shields, Beverley M., Hudson, Michelle M., Shepherd, Maggie H., Hammersley, Suzanne, Pearson, Ewan R., Hattersley, Andrew T. +1 more·2015·Diabetes Care
DOI 10.2337/dc14-0871PMC PMC5646646
Open this paper in CoChat — free account

Abstract

OBJECTIVE: Small studies using ultrasensitive C-peptide assays suggest endogenous insulin secretion is frequently detectable in patients with long-standing type 1 diabetes (T1D), but these studies do not use representative samples. We aimed to use the stimulated urine C-peptide-to-creatinine ratio (UCPCR) to assess C-peptide levels in a large cross-sectional, population-based study of patients with T1D. RESEARCH DESIGN AND METHODS: We recruited 924 patients from primary and secondary care in two U.K. centers who had a clinical diagnosis of T1D, were under 30 years of age when they received a diagnosis, and had a diabetes duration of >5 years. The median age at diagnosis was 11 years (interquartile range 6-17 years), and the duration of diabetes was 19 years (11-27 years). All provided a home postmeal UCPCR, which was measured using a Roche electrochemiluminescence assay. RESULTS: Eighty percent of patients (740 of 924 patients) had detectable endogenous C-peptide levels (UCPCR >0.001 nmol/mmol). Most patients (52%, 483 of 924 patients) had historically very low undetectable levels (UCPCR 0.0013-0.03 nmol/mmol); 8% of patients (70 of 924 patients) had a UCPCR ≥0.2 nmol/mmol, equivalent to serum levels associated with reduced complications and hypoglycemia. Absolute UCPCR levels fell with duration of disease. Age at diagnosis and duration of disease were independent predictors of C-peptide level in multivariate modeling. CONCLUSIONS: This population-based study shows that the majority of long-duration T1D patients have detectable urine C-peptide levels. While the majority of patients are insulin microsecretors, some maintain clinically relevant endogenous insulin secretion for many years after the diagnosis of diabetes. Understanding this may lead to a better understanding of pathogenesis in T1D and open new possibilities for treatment.

Integrity signals

Registry

Crossref · 10.2337/dc14-0871

Cites

21 of 21 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 41 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    8% of participants had UCPCR of at least 0.2 nmol/mmol.

    “8% (70/924) had UCPCR≥0.2 nmol/mmol, equivalent to serum levels associated with reduced complications and hypoglycaemia.”
    • Also stated in: § Prevalence of detectable C-peptide · plain
      “8% (70/924, CI 6-9%), had a UCPCR above 0.2 nmol/mmol.”
    • Also stated in: § Discussion · plain
      “8% of participants in our study with a duration over 5 years had UCPCR≥0.2 nmol/mmol, and another 20% had UCPCR ≥0.03 pmol/L.”
    Quote in the paperSubstantial claim
  • Findingown data

    In multivariate modelling, age at diagnosis and diabetes duration were independent predictors of C-peptide.

    “Age of diagnosis and duration were independent predictors of C-peptide in multivariate modelling.”
    Quote in the paperNot a substantial claim
  • Findingown data

    52% of participants had UCPCR between 0.001 and 0.03 nmol/mmol, a range historically considered undetectable.

    “Most, 52% (483/924), had very low historically undetectable levels (UCPCR 0.0013-0.03 nmol/mmol).”
    • Also stated in: § Prevalence of detectable C-peptide · plain
      “The majority of patients 52% (483/924, CI 49-55%) had a UCPCR between 0.001 and 0.03 nmol/mmol, (Figure 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the study sample, 80% of participants had detectable endogenous C-peptide, defined as UCPCR greater than 0.001 nmol/mmol.

    “80% (740/924) had detectable endogenous C-peptide (UCPCR >0.001 nmol/mmol).”
    • Also stated in: § Prevalence of detectable C-peptide · plain
      “80% (740/924, CI 77-83%) of participants had detectable C-peptide (UCPCR >0.001 nmol/mmol).”
    • Also stated in: § Discussion · plain
      “This large study, using home post-meal UCPCR, found 80% of all people with T1D for 5 or more years, had measurable endogenous C-peptide.”
    Quote in the paperSubstantial claim
  • Findingown data

    Absolute UCPCR levels decreased as diabetes duration increased.

    “Absolute UCPCR levels fell with duration.”
    • Also stated in: § Discussion · plain
      “There was a decline in absolute C-peptide levels and in likelihood of detectable C-peptide with longer duration diabetes.”
    Quote in the paperSubstantial claim
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data

    Insulin dose and glycaemic control were similar in participants with and without detectable C-peptide.

    “Insulin dose and glycaemia was similar in those with and without detectable C-peptide (insulin dose 0.77 v 0.78 ukg-124hours-1, Table 1, HbA1c 8.7 vs 8.9% (72 v 74 mmol/mol), Table 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Median post-meal UCPCR was 1.04 nmol/mmol (IQR 0.44-2.3) in 100 individuals within the first year after diagnosis of type 1 diabetes, based on unpublished data from the UNITED study.

    “Median post-meal UCPCR was 1.04 IQR (0.44-2.3)nmol/mmol in 100 individuals within the first year from diagnosis of type 1 diabetes (unpublished data from the UNITED study)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    97% of the study participants were white European.

    “97% of participants were white European.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The study did not find an association between persistent C-peptide secretion and either insulin dose or HbA1c.

    “We did not find an association of persistent C-peptide secretion with either insulin dose or HbA1c.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In a logistic regression including diabetes duration, age at diagnosis and BMI, both diabetes duration and age at diagnosis were associated with UCPCR of at least 0.2 nmol/mmol.

    “In a logistic regression with duration of diabetes, age of diagnosis and BMI as covariates, diabetes duration and age of diagnosis were both associated with a UCPCR ≥0.2 nmol/mmol (Supplementary table 2, multivariate logistic regression).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Median post-OGTT UCPCR was 3.8 nmol/mmol (IQR 2.4-7.0) in 38 non-diabetic controls.

    “and median post OGTT (n=38) UCPCR was 3.8 (IQR 2.4-7.0) in 38 non-diabetic controls (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Oram, 2013, Urine C-peptide creatinine ratio can be used to assess insulin resistance and insulin production in people without diabetes: an observational study, BMJ Open source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Oram, 2014, The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells, Diabetologia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    If beta cells persist in most people with type 1 diabetes, then those cells are either regenerating or evading immune attack.

    “The implications of these studies could be important, as if beta cells remain in most people with T1D, then they are either regenerating or evading immune attack.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A UCPCR of at least 0.2 nmol/mmol corresponds to a serum C-peptide level of 200 pmol/L, which is clinically associated with fewer microvascular complications and less hypoglycaemia.

    “8% (70/924) had UCPCR≥0.2 nmol/mmol, equivalent to serum levels associated with reduced complications and hypoglycaemia.”
    • Also stated in: § C-peptide thresholds · plain
      “UCPCR≥0.03 nmol/mmol and ≥0.2nmol/mmol, which are equivalent to serum C peptide of 30 pmol/L (a common historical limit of detection(3; 11; 12)) and 200 pmol/L (a clinically defined level associated with reduced microvascular complications and hypoglycaemia(13)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] The Diabetes Control and Complications Trial 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, Ann Intern Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    If age at diagnosis marks the rate of immune destruction of beta cells, then the lack of association between age at diagnosis and detection of low-level C-peptide may suggest that other factors are more important in determining whether a few functional beta cells remain, or may reflect that the impact of age at diagnosis is too small to detect with this sample size.

    “If age of diagnosis is a marker of the rate of immune destruction of the beta cells, then the lack of association between age of diagnosis and detection of low level C-peptide may suggest other factors are more important in determining whether a few functional beta cells remain or it may reflect that the impact of age of diagnosis is small and not detectable by our sample size.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    UCPCR requires only a single spot urine sample and remains stable for 3 days at room temperature, which makes large community studies feasible because samples can be posted.

    “UCPCR involves a single, spot urine measurement and has the advantage of long term stability (3 days) at room temperature which facilitates large scale community studies as samples can be posted.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [4] McDonald, 2009, Stability and reproducibility of a single-sample urinary C-peptide/creatinine ratio and its correlation with 24-h urinary C-peptide, Clin Chem source

      Not checked in the free run.

    • cites [5] Bowman, 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 source

      Not checked in the free run.

    • cites [6] Besser, 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 source

      Not checked in the free run.

    • cites [7] Jones, 2011, Urine C-peptide creatinine ratio is an alternative to stimulated serum C-peptide measurement in late-onset, insulin-treated diabetes

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Even after 5 years of diabetes, diabetes duration predicts both C-peptide level and the presence of detectable C-peptide.

    “Even after 5 years of diabetes, duration of diabetes is a predictor of both C-peptide level and the presence of detectable C-peptide.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    More than 60% of eligible participants were recruited into the study.

    “Over 60% of eligible participants were recruited.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    Any bias from the variable meal or insulin administration is small and would only make C-peptide less likely to be detected.

    “Any bias is small from the variable meal(6) or insulin administration(10) and would only result in C-peptide being less likely to be detected.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Besser, 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 source

      Not checked in the free run.

    • cites [10] Besser, 2012, The impact of insulin administration during the mixed meal tolerance test

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Wang, 2012, Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay, Diabetes Care source

      Not checked in the free run.

    • cites [1] Oram, 2014, The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells, Diabetologia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study did not assess renal function.

    “We did not assess renal function in this study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The presence of a spectrum of endogenous insulin production at all durations of type 1 diabetes is relevant to studying and treating the disease process.

    “The presence of a spectrum of endogenous insulin production at all durations of T1D is relevant to the study and treatment of the disease process in T1D.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A recent analysis of DCCT by Lachin et al demonstrated a continuous relationship between stimulated serum C-peptide and HbA1c and insulin dose, but only in patients assigned to intensive therapy.

    “This is in contrast with studies of a recent analysis of DCCT by Lachin et al (12) that demonstrates a continuous relationship between stimulated serum C-peptide and HbA1c and insulin dose, but only in the patients assigned to intensive therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Lachin, 2014, Impact of C-peptide preservation on metabolic and clinical outcomes in the Diabetes Control and Complications Trial, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Besser, 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 source

      Not checked in the free run.

    • cites [1] Oram, 2014, The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age at diagnosis is associated with HLA risk and may reflect the strength and intensity of the underlying autoimmune process.

    “Age of diagnosis is associated with HLA risk and may reflect the strength and intensity of the underlying autoimmune process(17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Dabelea, 2012, Clinical evolution of beta cell function in youth with diabetes: the SEARCH for Diabetes in Youth study, Diabetologia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In adults screened for DCCT who were more than 5 years post diagnosis, 8% had a stimulated serum C-peptide above 200 pmol/L.

    “This is similar to the 8% of adults over 5 years post diagnosis who had a stimulated serum C-peptide >200 pmol/L when screened for DCCT(20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Palmer, 2004, 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 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The home post-meal UCPCR does not use a fixed high-carbohydrate meal, does involve taking prandial insulin, and is unsupervised, so it is likely to be less sensitive than a formal mixed meal tolerance test assessment of serum C-peptide.

    “The home post meal UCPCR does not involve a fixed high carbohydrate meal, does involve taking prandial insulin, and is not supervised so is likely to be less sensitive than a formal mixed meal tolerance test assessment of serum C-peptide performed in previous studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The findings provide strong evidence that most people with type 1 diabetes do not lose all beta cells and continue to secrete low levels of insulin for decades after diagnosis.

    “These findings provide strong evidence that most people with T1D do not develop complete beta-cell loss, and will continue to secrete low levels of insulin for decades after diagnosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The difference between this study's null association and the DCCT analysis probably reflects that this study was cross-sectional, so only a proportion of participants were receiving intensive glycaemic management, and that the low cut-off meant most participants had very low C-peptide levels unlikely to have a clinically significant effect.

    “The difference probably reflects 1. that our study was cross sectional so only a proportion will be having intensive glycaemic management and 2. the low cut off we used means the majority of the patients in our study also had very low levels of C-peptide, which are unlikely to have a clinically significant effect.”
    Quote in the paperSubstantial claim
24 of 24

  • The paper relies on this without support.

    Urine C-peptide concentrations are reduced in people with chronic kidney disease.

    “Urine C-peptide levels are lower in those with CKD so this could lead to an underestimate of the prevalence of patients with retained endogenous insulin secretion.”
1 of 1

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 [66]

    The Results (page not available in our copy) report detectable C-peptide in 80% of participants with long-duration type 1 diabetes, but very low levels in 52%. The Abstract Conclusions distinguish the majority who were insulin microsecretors from others with clinically relevant secretion. Thus the paper supports frequent microsecretion with sensitive measurement, but not the claim that 80% were microsecretors. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Discussion gives an incompatible unit for the 0.03 UCPCR threshold

    Minor

    The discussion expresses the threshold as pmol/L, while the results express UCPCR using nmol/mmol. The stated 20% group is therefore not described with the same threshold units.

  • Duration association is stated in the wrong direction

    Minor

    The first statement says detectable C-peptide is inversely associated with shorter diabetes duration, but the reported group durations show the opposite: patients with detectable C-peptide had shorter duration.

  • Regression outcome uses a different UCPCR denominator

    Minor

    The statistical methods specify nmol/mol for the 0.2 threshold, whereas the threshold definition uses nmol/mmol. Those units differ by a factor of 1,000.

3 of 3

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
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
Affiliations
  • University of Exeter (GB)
  • University of Dundee (GB)
Corresponding author
Hattersley, Andrew T.
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2014-12-17
Volume
38
Issue
2
Pages
323-328
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc14-0871
PMC
PMC5646646
OpenAlex
W2028473737
Cited by
133
References
21
Citations by year
2026: 6 · 2025: 8 · 2024: 7 · 2023: 11 · 2022: 16 · 2021: 19 · 2020: 13 · 2019: 10 · 2018: 15 · 2017: 9 · 2016: 11 · 2015: 7
FWCI
5.90
Type
journal article
Language
en
Open access
Locations
  • Diabetes Care (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Figshare (submittedVersion)
  • Open Research Exeter (University of Exeter) (submittedVersion)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
Funders
  • Wellcome Trust (091985/HICF 1009-041)
  • Department of Health (091985/HICF 1009-041)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
type 1 diabetes, endogenous insulin secretion, C-peptide, disease duration, age at diagnosis, residual beta-cell function, diabetes pathogenesis
MeSH terms
Insulin Secretion, Adult, C-Peptide, Child, Creatinine, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Female, Humans, Hypoglycemia, Insulin, Male, Time Factors, Postprandial Period, 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.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

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