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


CONCLUSIONS
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.


BACKGROUND
ClinicalTrials.gov NCT00654121


BACKGROUND
The insulin trial was financially supported by Novo Nordisk Pharma nv.
Vandemeulebroucke
E
E
Diabetes Research Center, Brussels Free University-VUB, 1090 Brussels, Belgium.
Keymeulen
B
B
Decochez
K
K
Weets
I
I
De Block
C
C
Féry
F
F
Van de Velde
U
U
Vermeulen
I
I
De Pauw
P
P
Mathieu
C
C
Pipeleers
D G
DG
Gorus
F K
FK
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D002096:C-Peptide / Q000097:blood; D003920:Diabetes Mellitus / Q000453:epidemiology* / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D005190:Family; D015309:Glucose Clamp Technique; D006683:HLA-DQ Antigens / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia; D007328:Insulin / Q000097:blood; D008487:Medical History Taking; D012016:Reference Values; D018570:Risk Assessment; D055815:Young Adult
D001323:Autoantibodies; D002096:C-Peptide; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; C096322:ICA512 autoantibody; D007328:Insulin