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.

Keywords: Age at diagnosis; C-Peptide; Cross-sectional studies; Diabetes mellitus type 1; Genetics; Insulin secretion.

Fig. 1

Geometric mean plasma C-peptide (pmol/l) by age at onset and duration. A smoothed fit of log C-peptide to age at onset and duration was computed by LOESS regression of polynomial degree 2 and span 0.25, then evaluated over a grid of values of the predictor variables. The C-peptide level (pmol/l) of each panel is encoded both as its colour and as its coordinate on the vertical axis

Fig. 2

Joint probability contours of genotypic scores for type 1 and type 2 diabetes excluding those classified as possible type 2. Labels show probability enclosed by each contour. Scores standardized to zero mean and unit standard deviation in UK Biobank White British participants without diabetes

Fig. 3

Manhattan plot of genome-wide association study of age at onset (vertical axis truncated at 15). Type 1 diabetes-associated regions in green

Fig. 4

Manhattan plot of genome-wide association study of C-peptide levels, adjusted for age at onset, duration and predicted age at onset given genotype (vertical axis truncated at 15). Type 1 diabetes-associated regions in green

Fig. 5

Locus-specific genotypic scores for type 1 or type 2 diabetes: plot of univariate effects on log10 C-peptide (adjusted for age at onset and duration) against univariate effect on square root age at onset. Effect sizes are the effect of a change of one standard deviation in each locus-specific score