Most People With Long-Duration Type 1 Diabetes in a Large Population-Based Study Are Insulin Microsecretors

Abstract

OBJECTIVESmall 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 METHODSWe 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. RESULTSEighty 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. CONCLUSIONSThis 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.Recent studies have challenged the traditional view of type 1 diabetes (T1D) leading to absolute insulin deficiency. Sensitive C-peptide assays have shown that 43-74% people with long-standing (.5 years) T1D are microsecretors of endogenous insulin (1,2) with C-peptide levels in a range not detected by previous assays (1-30 pmol/L).

Early prediction of autoimmune (type 1) diabetes

“…Recent studies employing highly sensitive C-peptide assays suggest that individuals with long-term type 1 diabetes secrete residual amounts of insulin [104]. This is consistent with histological evidence that functional beta cells can be found in long-standing type 1 diabetes [105].…”

A run on the biobank

“…The CD20 high population was termed hyperimmune, had statistically significantly higher numbers of CD4þ and CD8þ T cells per islet section, fewer insulin containing islets, and were obtained from younger donors; autoantibody and inflammatory cytokine differences were also found in the peripheral blood, but from a different cohort of recent T1D donors. Though b-cell function was not measured in this study, the data fit well with the concept of heterogeneity in disease progression, as has been recently demonstrated in a clinical study on the basis of c-peptide levels [47]. Likewise, RodriguezCalvo et al [16 & ] segregated T1D donors on the basis of tissue insulin staining and found differences in the CD8þ T cell islet infiltrate density.…”

Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

“…WFS1 heterozygous variants and loss-of-function variants in the APPL1 gene were shown to be a rare cause of MODY 3, 4 . The reason for this limited success is the difficulty of distinguishing monogenic diabetes patients from those with type 1 diabetes 5, 6 , or from the increasing number of patients with early-onset type 2 diabetes due to rising rates of obesity. Another important reason is the lack of large pedigrees with an autosomal dominant pattern of inheritance of diabetes which would allow classical linkage analysis to be performed and which was used to discover the most common forms of MODY such as GCK , HNF1A and HNF4A 7–10 .…”