Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes

Abstract

Background The objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes. Methods C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics. Results Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype. Conclusions Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence. Electronic supplementary material The online version of this article (10.1186/s12916-019-1392-8) contains supplementary material, which is available to authorized users.

The clinical consequences of heterogeneity within and between different diabetes types

“…adult onset, obese) and type 1 diabetes (childhood onset, thin and white race) appear increasingly blurred. At the genetic level, both type 1 and type 2 diabetes have been positively associated with four loci-BMP8A, HLA region, CENPW and ASCC2-and show associations in opposite directions for an SNP in the BCAR1/CTRB1/CTRB2 region [10].…”

“…Older age, lower HbA 1c and higher BMI at diagnosis predict slower loss of C-peptide [9]. Beyond clinical characteristics, 26% of variability in beta cell function persistence post diagnosis is explained by genetic factors, including the HLA region (although not the DR3/DR4 genotype that confers the highest risk of type 1 diabetes), PTPN22, INS region, and rs559047 (a long non-coding RNA [lncRNA] in chromosome 1 that is not associated with type 1 diabetes risk) [10]. Therefore, although many loci simultaneously determine type 1 diabetes risk, lower C-peptide levels and younger age of onset, this is not always the case.…”

“…Type 2 diabetes-associated loci (e.g. JAZF1 and TCF7L2) also influence C-peptide persistence in type 1 diabetes [10]. In addition, clinical heterogeneity in type 1 diabetes is reflected by differences in the risk of complications, which is related to a wide array of factors, from hyperglycaemia and longer diabetes duration, to race, ethnicity and socioeconomic factors.…”

Allostasis and the origins of adult-onset diabetes

“…C-peptide levels vary across the age range and with disease duration, even for individuals diagnosed clinically and immunologically with type 1 diabetes (Fig. 1) [21]. Older GADA-positive patients, as studied here, with moderate GRS for type 1 diabetes may clinically resemble patients with type 2 diabetes in that they could have substantial C-peptide.…”

“…The diffrence in detectable C-peptide both at baseline and years after diagnosis between younger patients (<15 years old) and older patients (>35 years old) is clear since differences in persistent C-peptide relate to disease age at onset and duration, especially the former. Data from Mckeigue et al [21] positives. But the argument does not extend to positive predictive values, which can be altered by reconfiguring cut-off points in specific cohorts, enriching the cohort for clinical features such as adult-onset diabetes, even altering the assay itself [10,13].…”