Impact of C-peptide preservation on metabolic and clinical outcomes in the Diabetes Control and Complications Trial
Open accessAbstract
The Diabetes Control and Complications Trial established that a stimulated C-peptide concentration ≥0.2 nmol/L at study entry among subjects with up to a 5-year diabetes duration is associated with favorable metabolic and clinical outcomes over the subsequent 7 years of follow-up. Herein we further examine the association of both fasting and stimulated C-peptide numerical values with outcomes. In the intensive treatment group, for a 50% higher stimulated C-peptide on entry, such as from 0.10 to 0.15 nmol/L, HbA1c decreased by 0.07% (0.8 mmol/mol; P = 0.0003), insulin dose decreased by 0.0276 units/kg/day (P < 0.0001), hypoglycemia risk decreased by 8.2% (P < 0.0001), and the risk of sustained retinopathy was reduced by 25% (P = 0.0010), all in unadjusted analyses. Other than HbA1c, these effects remained significant after adjusting for the HbA1c on entry. While C-peptide was not significantly associated with the incidence of nephropathy, it was strongly associated with the albumin excretion rate. The fasting C-peptide had weaker associations with outcomes. As C-peptide decreased to nonmeasurable concentrations, the outcomes changed in a nearly linear manner, with no threshold or breakpoint. While preservation of stimulated C-peptide at ≥0.2 nmol/L has clinically beneficial outcomes, so also does an increase in the concentration of C-peptide across the range of values.
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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 [68]
The Results (Intensive Therapy, 1–5-Year Duration; page unavailable) associate higher entry C-peptide with less retinopathy progression and severe hypoglycemia. Nephropathy risk was lower among responders, but the difference was not statistically significant. The Discussion (page unavailable) says C-peptide was principally measured at entry and that longitudinal associations could not be examined, so the paper does not establish an association for persistent secretion over time. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHigher C-peptide levels have been associated with better A1C, lower risk of retinopathy, lower risk of nephropathy, and lower risk of severe hypoglycemia.
“Higher C-peptide levels have been associated with better A1C, lower risk of retinopathy, lower risk of nephropathy, and lower risk of severe hypoglycemia (85).”
From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [85]
The Discussion reports that higher C-peptide was associated with lower HbA1c, less severe hypoglycemia, and less risk of retinopathy. The Results (Intensive Therapy, 1–5-Year Duration) report a lower observed risk of nephropathy, but the reduction was not statistically significant, so that part of the claim needs qualification. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA 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 [12]
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.”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [12]
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- Authors
- Lachin, J. M., McGee, P., Palmer, J. P., & for the DCCT/EDIC Research Group
- Affiliations
- George Washington University (US)
- University of Washington (US)
- Corresponding author
- Lachin, John M.
- ORCID
- Lachin, John M.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2014-01-16
- Volume
- 63
- Issue
- 2
- Pages
- 739-748
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3900540
- OpenAlex
- W2147072756
- Cited by
- 283
- References
- 14
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 30 · 2023: 28 · 2022: 30 · 2021: 35 · 2020: 30 · 2019: 21 · 2018: 16 · 2017: 15 · 2016: 15 · 2015: 16 · 2014: 6
- FWCI
- 9.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000041, UL1TR001449)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK017047)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- C-peptide, fasting C-peptide, type 1 diabetes, Diabetes Control and Complications Trial, intensive insulin therapy, HbA1c, insulin dose, hypoglycemia, diabetic retinopathy, diabetic nephropathy, urinary albumin excretion rate, beta-cell function, glycemic control
- MeSH terms
- Adult, C-Peptide, Diabetes Mellitus, Diabetic Retinopathy, Female, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Insulin, Male, Time Factors, Young Adult
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