Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients

Abstract

Aims/hypothesis 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. Methods 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. Results 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 firstphase 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. Conclusions/interpretation 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.Trial registration: ClinicalTrials.gov NCT00654121 Funding: The insulin trial was financially supported by Novo Nordisk Pharma nv.

Relationship between glycaemic variability and hyperglycaemic clamp-derived functional variables in (impending) type 1 diabetes

“…Because of the 100% cross-reactivity of proinsulin in the C-peptide assay, free C-peptide levels were obtained by subtracting the proinsulin concentration from the total C-peptide result [8]. Diabetes autoantibodies (insulin autoantibodies, glutamate decarboxylase autoantibodies, IA-2A and ZnT8A) were determined by liquid-phase radiobinding assays and HLA-DQ polymorphisms by allelespecific oligonucleotide genotyping, as previously described [18].…”

“…Blood samples were collected for glucose analysis before and 2 h after an oral glucose load of 1.75 g/kg without exceeding the maximum of 75 g [8].…”

“…A hyperglycaemic clamp was performed 1-2 weeks after the OGTT, as previously described, with the omission of a glucagon injection at 150 min [8,19]. In patients treated with longacting insulin, this insulin type was replaced by an intermediately acting insulin on the evening before the clamp.…”

“…AUC C-peptide release was calculated using the trapezoidal rule and expressed per minute [8]. The glucose disposal rate between 120 and 150 min (M 120-150 min , expressed as μmol/[kg × min]) corresponds to the amount of glucose metabolised during hyperglycaemia and was calculated as the average glucose infusion rate between 120 and 150 min minus a 'space correction' [19].…”

“…Those with dysglycaemia or low stimulated Cpeptide release are likely to develop the disease rapidly (i.e. within 3 years) [8][9][10][11][12]. This subgroup can be detected by repetitive hyperglycaemic clamps or OGTTs, but these are not simple procedures to implement, especially in children [13,14].…”