In their BMC Medicine article, McKeigue and colleagues [4] explored detectable C-peptide in a large cohort from Scotland, representing a cross-sectional analysis of one-third of the population diagnosed with type 1 diabetes over age 16 years. Patients were diagnosed both clinically, by exclusion of other causes, and with one or more diabetes-associated autoantibody. Detectable C-peptide levels varied substantially, with age and disease duration being key variables: C-peptide was lowest in the youngest 15 years from diagnosis (19%) and highest in the oldest, close to diagnosis (92%). Genetic analysis using single nucleotide polymorphisms indicated some heritability for C-peptide variance (26%) [4]. As expected, both human leucocyte antigen (HLA) and insulin gene regions reflected the most aggressive disease process. Persistence of C-peptide was associated with gene risk scores for both type 1 and type 2 diabetes, but also strikingly with HLA regions, not accounted for by high gene-risk HLA serotypes. In other words, the genetics of C-peptide persistence may be distinct from the genetics of C-peptide loss, invoking multiple genetic networks linked to both type 1 and type 2 diabetes.
This paper opens a can of worms regarding our understanding of diabetes and its stratification. The apparent categorical difference between the two major types of diabetes has been challenged, with the realisation that some adult-onset type 1 diabetes cases may not initially need insulin treatment and can have similar C-peptide levels as in type 2 cases [1, 3]. The characteristic type 1 diabetes inflammatory infiltrate, or insulitis, turns out to be not so prevalent as thought, and has been dubbed ‘the elusive lesion’ [5]. Indeed, islet beta-cell function and mass may be compromised in multiple ways, e.g. apoptosis and de-differentiation. There may also be many mechanisms to explain the persistence of C-peptide secretion, including new growth, trans-differentiation with the appearance of islet delta cells or, perhaps, distinct beta-cells, impervious to aggressive autoimmune attack [5]. However, any explanation must account for the remarkable spectrum of C-peptide, in which decline follows a pattern of ‘younger, faster, greater’, while C-peptide persistence is also associated with genes distinct from type 1 diabetes susceptibility genes, implicating type 2 diabetes networks [4].