(#32) Circulating insulin C-peptide levels mirror pancreatic beta-cell loss across all ranges of age and disease duration of type 1 diabetes

PRESENTED BY: Alice Carr

Authors
First NameLast NameAffiliation/Institution
AliceCarrInstitute of Biomedical and Clinical Science, Exeter, UK
JamieInshawJDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Oxford, UK
ChristineFlaxmanInstitute of Biomedical and Clinical Science, Exeter, UK
PiaLeeteInstitute of Biomedical and Clinical Science, Exeter, UK
RebeccaWyattInstitute of Biomedical and Clinical Science, Exeter, UK
LindaWickerJDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Oxford, UK,
DavidDungerDepartment of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge UK
NoelMorganInstitute of Biomedical and Clinical Science, Exeter, UK
RichardOramInstitute of Biomedical and Clinical Science, Exeter, UK
JohnToddJDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Oxford, UK
SarahRichardsonInstitute of Biomedical and Clinical Science, Exeter, UK
RachelBesserJDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Oxford, UK
 

Purpose

C-peptide (CP) levels decline in type 1 diabetes (T1D), although many patients have low but detectable levels of CP for many years after diagnosis. Currently there is little understanding of how the levels of circulating CP relate to pancreatic beta cell retention and if this varies with age at diagnosis. In this study we used a large clinical T1D cohort and unique T1D pancreas biobanks to independently assess the CP levels in the blood and beta cell loss within the pancreas, in subjects diagnosed at increasing ages and with differing diabetes durations.
 

Methods

We studied 4,079 serum CP from the UK Genetic Resource Investigating Diabetes (UK GRID) cohort, diagnosed at <16 years as well as 235 pancreas samples recovered from people with T1D (diagnosed <18 years) from the network for Pancreatic Organ donors with Diabetes (nPOD) biobank and the Exeter Archival Diabetes Biobank (EADB). Cases were stratified by age at diagnosis (<7, 7-12, ≥13 years) and grouped by diabetes duration (<1, 1-5, 5-10, ≥10 years). We report the proportion of individuals from the UK GRID cohort with detectable CP (>9 pmol/L) and the proportion of donors from the two independent pancreatic biobanks having residual insulin containing islets (ICIs), within each age group over increasing diabetes durations.
 

Summary of Results

Detectable CP levels persisted in some individuals in all age groups over time, although this was least common in those diagnosed <7 years (detectable CP: <7 group: 372/1666 (22%), 7-12 group: 981/1887 (52%), ≥13 group 363/526 (69%)). A similar pattern was observed in the proportion of individuals with residual ICIs in the pancreas, (residual ICIs: <7 group: 33/87 (38%), 7-12 group: 51/89 (57%), ≥13 group: 42/62 (68%). In all groups, the number of individuals with detectable CP levels declined beyond the first year after diagnosis, but was most marked in those diagnosed at younger ages (detectable CP <1 year post diagnosis: <7 group: 18/20 (90%), 7-12 group: 107/110 (97%), ≥13 group 58/61 (95%) vs. detectable CP 1-5 years post diagnosis: <7 group: 172/522 (33%), 7-12 group: 604/995 (61%), ≥13 group: 225/289 (78%). This was mirrored by an equally rapid decline in individuals with residual ICIs in the pancreas (residual ICIs <1 year post diagnosis: <7 group: 24/26 (92%), 7-12 group: 32/33 (97%), ≥13 group: 22/25 (88%) vs. residual ICIs 1-5 years post diagnosis: <7 group: 1/12 (8.3%), 7-12 group: 8/13 (62%), ≥13 group: 7/8 (88%). Only 4.3% (21/489) of children diagnosed < 7y had detectable C-peptide 10y post diagnosis and a similar proportion (3/34 (8.8%)) retained cells with immunoreactive insulin positivity at this time.
 

Conclusions

Circulating C-peptide levels reflect residual beta-cell mass in patients with T1D at all ages and duration of disease, indicating progressive beta-cell loss is the main contributory factor to the decline in endogenous insulin secretion.