Heterogeneity in clinically diagnosed type 1 diabetes: characterising a unique cohort with maintained C-peptide secretion in Ghana.

AIMS/HYPOTHESIS: In sub-Saharan Africa, type 1 diabetes is typically diagnosed clinically, which can be challenging due to atypical diabetes presentations such as ketosis-prone type 2 diabetes or type 2 diabetes in the absence of overweight and obesity. C-peptide, a marker of residual insulin secretion capacity, is crucial for understanding these variations but understudied in the region. Here, we investigated whether C-peptide measurement and concomitant genetic, autoimmune and metabolic characterisation of individuals with clinically diagnosed type 1 diabetes confirm diabetes classification and highlight population-specific features. METHODS: In this case-control study from Ghana, we recruited 266 individuals with clinically diagnosed and insulin-treated long-term type 1 diabetes and 266 healthy control individuals. We compared clinical features, HLA class II haplotypes, autoantibodies, and inflammatory and metabolic serum profiles across control and patient groups classified by random C-peptide levels: low (<0.2 nmol/l), mid (0.2-0.6 nmol/l) and high (>0.6 nmol/l). RESULTS: Only 28.9% of individuals with clinically diagnosed type 1 diabetes had low C-peptide concentrations. They were the youngest and leanest group, with higher frequencies of HLA class II risk haplotypes and GAD and ZnT8 autoantibodies compared with all other groups. By contrast, 34.6% and 36.5% had mid-range or high C-peptide levels, respectively. These subgroups resembled the control group in terms of low autoantibody titres and one protective HLA class II haplotype. Ketosis at onset was most prevalent in individuals with high C-peptide. Serum proinflammatory biomarkers differed between individuals with diabetes and control participants, but not between C-peptide subgroups. Aromatic and branched-chain amino acids varied between diabetes subgroups and positively correlated with C-peptide levels. CONCLUSIONS/INTERPRETATION: Maintained C-peptide levels in two-thirds of individuals with long-term type 1 diabetes in Ghana, combined with the absence of autoantibodies and HLA risk association, highlight the necessity for better differentiation from atypical diabetes presentations to optimise patient care and improve health outcomes in resource-limited settings.