The aim of the study was to investigate the use of hyperglycaemic clamp tests to identify individuals who will develop diabetes among insulinoma-associated protein-2 antibody (IA-2A)-positive first-degree relatives (IA-2A⁺ FDRs) of type 1 diabetic patients.

Hyperglycaemic clamps were performed in 17 non-diabetic IA-2A⁺ FDRs aged 14 to 33 years and in 21 matched healthy volunteers (HVs). Insulin and C-peptide responses were measured during the first (5–10 min) and second (120–150 min) release phase, and after glucagon injection (150–160 min). Clamp-induced C-peptide release was compared with C-peptide release during OGTT.

Seven (41%) FDRs developed diabetes 3–63 months after their initial clamp test. In all phases they had lower C-peptide responses than non-progressors (p < 0.05) and HVs (p < 0.002). All five FDRs with low first-phase release also had low second-phase release and developed diabetes 3–21 months later. Two of seven FDRs with normal first-phase but low second-phase release developed diabetes after 34 and 63 months, respectively. None of the five FDRs with normal C-peptide responses in all test phases has developed diabetes so far (follow-up 56 to 99 months). OGTT-induced C-peptide release also tended to be lower in progressors than in non-progressors or HVs, but there was less overlap in results between progressors and the other groups using the clamp.

Clamp-derived functional variables stratify risk of diabetes in IA-2A⁺ FDRs and may more consistently identify progressors than OGTT-derived variables. A low first-phase C-peptide response specifically predicts impending diabetes while a low second-phase response may reflect an earlier disease stage.

ClinicalTrials.gov NCT00654121

The insulin trial was financially supported by Novo Nordisk Pharma nv.