Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study
Open accessAbstract
OBJECTIVE: To evaluate the extent of pancreatic β-cell function in a large number of insulin-dependent diabetic patients with a disease duration of 50 years or longer (Medalists). RESEARCH DESIGN AND METHODS: Characterization of clinical and biochemical parameters and β-cell function of 411 Medalists with correlation with postmortem morphologic findings of 9 Medalists. RESULTS: The Medalist cohort, with a mean ± SD disease duration and age of 56.2 ± 5.8 and 67.2 ± 7.5 years, respectively, has a clinical phenotype similar to type 1 diabetes (type 1 diabetes): mean ± SD onset at 11.0 ± 6.4 years, BMI at 26.0 ± 5.1 kg/m2, insulin dose of 0.46 ± 0.2 u/kg, ∼94% positive for DR3 and/or DR4, and 29.5% positive for either IA2 or glutamic acid decarboxylase (GAD) autoantibodies. Random serum C-peptide levels showed that more than 67.4% of the participants had levels in the minimal (0.03–0.2 nmol/l) or sustained range (≥0.2 nmol/l). Parameters associated with higher random C-peptide were lower hemoglobin A1C, older age of onset, higher frequency of HLA DR3 genotype, and responsiveness to a mixed-meal tolerance test (MMTT). Over half of the Medalists with fasting C-peptide >0.17 nmol/l responded in MMTT by a twofold or greater rise over the course of the test compared to fasting. Postmortem examination of pancreases from nine Medalists showed that all had insulin+ β-cells with some positive for TUNEL staining, indicating apoptosis. CONCLUSIONS: Demonstration of persistence and function of insulin-producing pancreatic cells suggests the possibility of a steady state of turnover in which stimuli to enhance endogenous β cells could be a viable therapeutic approach in a significant number of patients with type 1 diabetes, even for those with chronic duration.
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Recent data suggest that although most patients with longstanding type 1 diabetes have few β cells, if any, there is evidence for β-cell regeneration in infants and very young children, but not in adolescents or adults.
“Recent data suggest that although most patients with longstanding type 1 diabetes have few β cells, if any, there is evidence for β-cell regeneration in infants and very young children (but not in adolescents or adults).51,52”
From Type 1 diabetes (2014) · cites this paper as [52]
The Discussion (page unavailable in our copy) says β-cells can be replenished despite prolonged autoimmune stress and reports evidence of β-cell proliferation in people with type 1 diabetes for over 50 years. That is contrary to the claim that regeneration does not occur in adults. The paper does not establish the claimed contrast with infants and very young children. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAfter diagnosis, the ability to retain residual β-cell function (assessed by production of C-peptide) is heterogeneous, in terms of the time it takes to reach an undetectable stage and the number of patients who, despite decades with type 1 diabetes, retain the ability to produce C-peptide.
“After diagnosis, the ability to retain residual β-cell function (assessed by production of C-peptide) is heterogeneous, in terms of the time it takes to reach an undetectable stage and the number of patients who, despite decades with type 1 diabetes, retain the ability to produce C-peptide.84”
From Type 1 diabetes (2014) · cites this paper as [84]
The Results report that 67.4% of the Medalist cohort had detectable C-peptide after at least 50 years of diabetes, while 33.0% had undetectable levels. The Discussion also describes a wide range of C-peptide levels. These findings support variation in long-term residual function, but the study does not establish how long individuals took after diagnosis to reach undetectable levels. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDisease heterogeneity is an important aspect of type 1 diabetes, and suggests a role for genetics, age at disease onset, and intensity of disease management on the ability to retain β-cell function.
“Thus, disease hetero geneity is an important asp of type 1 diabetes, and suggests a role for genetics, age at disease onset, and intensity of disease management on the ability to retain β-cell”
From Type 1 diabetes (2014) · cites this paper as [84]
The Results and Discussion (page unavailable in our copy) show substantial variation in residual C-peptide and associate higher levels with HLA genotype, later age at onset, and better glycemic control. They do not assess the intensity of disease management or establish that management intensity affects retention of β-cell function; glycemic control is not the same measure. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAnalyses of pancreata from individuals with recent-onset type 1 diabetes suggest that around 70% of islets display complete insulin absence.
“Through these and other studies, analyses of pancreata from individuals with recent-onset type 1 diabetes suggest that around 70% of islets display complete insulin absence;51,52”
From Type 1 diabetes (2014) · cites this paper as [52]
The Results (Histology; page not available) report that most islets in seven long-duration Joslin Medalists were atrophic and showed no insulin staining. The paper examines people with at least 50 years of diabetes, not recent-onset cases, and does not report that around 70% of islets lacked insulin. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAnalysis of pancreatic sections from individuals with long-term type 1 diabetes shows the presence of residual β cells decades after diagnosis.
“However, analysis of pancreatic sections from individuals with long-term type 1 diabetes show the presence of residual β cells decades after diagnosis.62,63”
From Type 1 diabetes (2018) · cites this paper as [62]
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 [3]
The lower absolute C-peptide levels in this study compared with the Joslin Medallists probably reflect increased survival of people with retained C-peptide at longer durations.
“This probably reflects increased survival of those with retained C-peptide at the longer durations found in the Joslin medallists.”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [3]
The results support histological evidence that occasional insulin-producing beta cells are visible in most pancreas samples from people with long-duration type 1 diabetes.
“These results support the histological data(3; 16) that occasional insulin-producing beta cells are visible in most histological pancreas samples of people with long duration T1D.”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [3]
The high prevalence of retained C-peptide in the 382 Joslin Medallists probably reflects survival bias, because patients with maintained endogenous C-peptide have reduced complication risk.
“The 382 Joslin Medallists studied by Keenan and colleagues were defined on the basis of their long term survival (>50 years): the high prevalence of retained C-peptide (67% > 30 pmol/L) is likely to reflect survival bias because complications risk is reduced in patients with maintained endogenous C-peptide(3).”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [3]
Absolute C-peptide levels in this study are lower than those in the very long duration participants of the Joslin Medallists, where 67% had serum C-peptide above 30 pmol/L.
“The absolute levels of C-peptide in our study are lower than those seen in the very long duration participants (>50 years) in the Joslin Medallists, where 67% had serum C-peptide above 30 pmol/L(3).”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [3]
The relationship between age at diagnosis and C-peptide levels may be explained by age at diagnosis reflecting the strength and intensity of the underlying autoimmune process.
“This may explain the relationship seen in our data and numerous other studies(3; 18; 19).”
From Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors (2015) · cites this paper as [3]
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- Authors
- Keenan, H. A., Sun, J. K., Levine, J., Doria, A., Aiello, L. P., Eisenbarth, G., Bonner-Weir, S., & King, G. L.
- Affiliations
- Joslin Diabetes Center (US)
- Barbara Davis Center for Childhood Diabetes, Denver, Colorado.
- Research Division, Joslin Diabetes Center, Boston, Massachusetts;
- Corresponding author
- King, George L.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2010-08-10
- Volume
- 59
- Issue
- 11
- Pages
- 2846-2853
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2963543
- OpenAlex
- W2114552310
- Cited by
- 500
- References
- 26
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 23 · 2023: 28 · 2022: 30 · 2021: 43 · 2020: 33 · 2019: 39 · 2018: 36 · 2017: 36 · 2016: 46 · 2015: 39 · 2014: 25 · 2013: 40 · 2012: 24
- FWCI
- 15.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k12ey016335-17)
- U.S. Public Health Service (K12-16335)
- National Eye Institute (K12-EY016335)
- National Institute of Diabetes and Digestive and Kidney Diseases (R24DK083957, T32DK007260, P30DK036836)
- National Center for Research Resources (S10RR025065)
- 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, residual beta-cell function, beta-cell turnover, C-peptide, mixed meal tolerance test, beta-cell apoptosis, HLA-DR3, autoantibodies, beta cell regeneration
- MeSH terms
- Aged, Awards and Prizes, C-Peptide, Diabetes Mellitus, Type 1, Female, HLA-DQ Antigens, HLA-DR Antigens, Humans, Insulin, Male, Middle Aged, Numismatics, Tissue and Organ Procurement, Phenotype, Time Factors, Cohort Studies, Insulin-Secreting Cells, HLA-DRB1 Chains, HLA-DQ beta-Chains
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