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Cited by 697Diabetes Management and ResearchDiabetes and associated disordersPancreatic function and diabetes

β-Cell Function and the Development of Diabetes-Related Complications in the Diabetes Control and Complications Trial

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Steffes, Michael W., Sibley, Shalamar, Jackson, Melissa, Thomas, William·2003·Diabetes Care
DOI 10.2337/diacare.26.3.832
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Abstract

In patients with type 1 diabetes, measurement of connecting peptide (C-peptide), cosecreted with insulin from the islets of Langerhans, permits estimation of remaining β-cell secretion of insulin. In this retrospective analysis to distinguish the incremental benefits of residual β-cell activity in type 1 diabetes, stimulated (90 min following ingestion of a mixed meal) C-peptide levels at entry in the Diabetes Control and Complications Trial (DCCT) were related to measures of diabetic retinopathy and nephropathy and to incidents of severe hypoglycemia. Based on the analytical sensitivity of the assay (0.03 nmol/l) and study entry criteria, the DCCT subjects were divided into four groups of stimulated C-peptide responses: ≤0.03, 0.04–0.20, 0.21–0.50 nmol/l at entry, and 0.21–0.50 nmol/l at entry and at least 1 year later (sustained C-peptide secretion). Uniformly in the intensive and partially in the conventional DCCT treatment groups, any C-peptide secretion, but especially at higher and sustained levels of stimulated C-peptide, was associated with reduced incidences of retinopathy (both a single three-step change and a repeated three-step change on the Early Treatment of Diabetic Retinopathy Study [ETDRS] scale at the next 6 month visit) and nephropathy (both albuminuria >40 mg/24 h once and repeated at the next annual visit). There were also differences in severe hypoglycemia across C-peptide levels in both treatment groups. In the intensively treated cohort there were essentially identical prevalences of severe hypoglycemia (∼65% of participants) in the first three groups; however, those subjects with mixed-meal stimulated C-peptide level >0.20 nmol/l for at least baseline and the first annual visit in the DCCT experienced a reduced prevalence of ∼30%. Therefore, even modest levels of β-cell activity at entry in the DCCT were associated with reduced incidences of retinopathy and nephropathy. Also, continuing C-peptide (insulin) secretion is important in avoiding hypoglycemia (the major complication of intensive diabetic therapy).

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  • Although endogenous insulin secretion is typically low, maintenance is important since it is associated with less retinopathy and less severe hypoglycaemia at later stages of the disease.

    “Although this endogenous secretion is typically low, maintenance is important since it is associated with less retinopathy and less severe hypoglycaemia at later stages of the disease.86”

    From Type 1 diabetes (2014) · cites this paper as [86]

    The paper reports that sustained C-peptide (and thus insulin) secretion was associated with less retinopathy and fewer episodes of severe hypoglycemia in DCCT participants with type 1 diabetes (p. 1). It does not establish those associations specifically at later stages of disease; its discussion notes that most patients eventually lose β-cell function (p. 4). (LLM, conf=0.80)

    Experimental — accuracy not yet measured

  • Natural history studies, intervention trials, and transplantation studies consistently show that higher C-peptide responses to a mixed meal are associated with improved glycaemic control, fewer hypoglycaemic episodes, and reduced long-term complications.

    “natural history studies, intervention trials, and transplantation studies consistently show that higher Cpeptide responses to a mixed meal are associated with improved glycaemic control, fewer hypoglycaemic episodes, and reduced longterm complications.[55][56][57]”

    From The future of type 1 diabetes therapy (2025) · cites this paper as [57]

    The study reports that higher or sustained mixed-meal-stimulated C-peptide was associated with lower mean HbA1c (Results, p. 2), fewer severe hypoglycaemic episodes, and less retinopathy and nephropathy (opening summary, p. 1). It is a retrospective analysis of DCCT participants, however, and does not establish the claimed consistency across natural history, intervention, and transplantation studies. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Persistent C-peptide secretion was associated with reduced development of retinopathy, nephropathy, and hypoglycaemia in the Diabetes Control and Complications Trial.

    “This finding is noteworthy because in the Diabetes Control and Complications Trial68,69 persistent C-peptide secretion was associated with reduced development of retinopathy, nephropathy, and hypoglycaemia.”

    From Type 1 diabetes (2018) · cites this paper as [69]

  • A UCPCR of at least 0.03 nmol/mmol corresponds to a serum C-peptide level of 30 pmol/L, a common historical limit of detection.

    “In addition, we analysed two other thresholds: 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)).”

    From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [11]

  • Higher and sustained levels of C-peptide are most beneficial.

    “The strongest evidence to date, however, finds that while higher and sustained levels of C-peptide are most beneficial, even modest levels of β-cell function in some with long-term disease are associated with lower rates of hypoglycemia and lower incidence of retinopathy and nephropathy (9,11).”

    From Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay (2012) · cites this paper as [11]

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Authors
Steffes, M. W., Sibley, S., Jackson, M., & Thomas, W.
Affiliations
University of Minnesota (US)
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2003-03-01
Volume
26
Issue
3
Pages
832-836
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/diacare.26.3.832
OpenAlex
W1988519907
Cited by
695
References
25
Citations by year
2026: 20 · 2025: 26 · 2024: 30 · 2023: 34 · 2022: 39 · 2021: 49 · 2020: 38 · 2019: 29 · 2018: 31 · 2017: 32 · 2016: 30 · 2015: 44 · 2014: 32 · 2013: 53 · 2012: 37
FWCI
8.55
Type
journal article
Language
en
Open access
Locations
  • Diabetes Care (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Center for Research Resources (M01RR000400, M01-RR00400)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
type 1 diabetes, residual beta-cell function, C-peptide, diabetic retinopathy, diabetic nephropathy, albuminuria, severe hypoglycemia, intensive insulin therapy, diabetes complications, Diabetes Control and Complications Trial
MeSH terms
Adult, Blood Glucose, C-Peptide, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Diabetic Retinopathy, Female, Glycated Hemoglobin, Humans, Hypoglycemia, Islets of Langerhans, Male, Retrospective Studies

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