The Melbourne Pre-Diabetes Study: prediction of type 1 diabetes mellitus using antibody and metabolic testing.
OBJECTIVE
To determine the utility of various autoantibodies in predicting progression to clinical diabetes in first-degree relatives of patients with type 1 diabetes mellitus.


METHODS
3315 first-degree relatives of patients with type 1 diabetes (1161 parents, 1206 siblings and 948 offspring) recruited through diabetes clinics, private endocrinologists, Diabetes Australia and the Juvenile Diabetes Foundation.


METHODS
Prevalence of islet cell antibodies (ICA) levels > or = 20 JDFu, insulin autoantibodies (IAA) levels > 100 nU/mL, and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine phosphatase IA2 (IA2Ab); change in beta cell function over time; and development of clinical diabetes.


RESULTS
2.6% of relatives had elevated ICA levels, 1.3% had elevated IAA levels and 0.3% had both. High ICA levels were significantly more frequent in siblings than in offspring or parents, and were more frequent in relatives younger than 20 years. GADAb were detected in 68% and IA2Ab in 57% of relatives with elevated ICA and/or IAA levels. Diabetes developed in 33 relatives (25 siblings, 2 offspring and 6 parents). Before diagnosis of clinical diabetes, high ICA levels were detected in 18 (58%), high IAA levels in 7 (23%), both in 5 (15%), and either in 19 (61%); GADAb were detected in 26 (84%), IA2Ab in 13 (42%), both in 11 (35%), and either in 28 (90%). First phase insulin release (FPIR) less than 50 mU/L was very strongly associated with progression to diabetes. In relatives with FPIR initially greater than 50 mU/L who eventually developed diabetes, there was a gradual and continuous reduction in FPIR over time before diagnosis.


CONCLUSIONS
Type 1 diabetes can be diagnosed in the preclinical stage. The recently described antibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 appear superior to ICA as screening tools for the preclinical diagnosis of type 1 diabetes.
Department of Diabetes and Endocrinology, Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, VIC. peterc@nursing.medrmh.unimelb.edu.au
P G
PG
Colman
P
P
McNair
H
H
Margetts
R S
RS
Schmidli
G A
GA
Werther
F P
FP
Alford
G M
GM
Ward
B D
BD
Tait
M C
MC
Honeyman
L C
LC
Harrison
D000328:Adult; D001323:Autoantibodies / Q000032:analysis*; D001324:Autoantigens; D015415:Biomarkers / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis*; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007328:Insulin / Q000276:immunology* / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D010179:Pancreas / Q000737:chemistry; D011236:Prediabetic State / Q000175:diagnosis*; D011237:Predictive Value of Tests; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology*; D012372:ROC Curve; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8
D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D007328:Insulin; D008565:Membrane Proteins; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase