Early ReportUKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes
Introduction
Autoimmune destruction of the insulin-secreting β-cells of the pancreas is the major cause of insulin-dependent diabetes mellitus (type 1 diabetes).1 Although this process generally leads to juvenile-onset diabetes, it can occur at any age.2 Islet-cell antibodies (ICA)3 and glutamic acid decarboxylase antibodies (GADA)4 are markers of the autoimmune form of β-cell damage and are present at onset in 70–80% of patients with type 1 diabetes.5, 6 The antibodies are present before the onset of clinical symptoms, as seen in the first-degree relatives of type 1 diabetes patients.7
ICA8, 9, 10 and GADA11 also occur in a subset of adults with non-insulin-dependent diabetes mellitus (type 2 diabetes).12 These patients can have pronounced hyperglycaemia, and after therapy with oral hypoglycaemic agents for several months to years, they may become insulin dependent. Therefore, these patients are thought to have a slowly evolving form of type 1 diabetes, sometimes called latent,10 type 1 1/213 or latent autoimmune diabetes in adults (LADA).14 Adult diabetic patients, with and without autoantibodies, have varied age of onset and phenotype, and are therefore difficult to distinguish from each other.11, 12, 13, 14
The presence of GADA is a sensitive and specific marker for future insulin dependency in patients with latent type 1 diabetes.15, 16 Previous studies, with a few exceptions,17 were small, and most assessed patients attending diabetic clinics, who may, therefore, have been very hyperglycaemic. No studies have compared prospectively the relative merits of ICA and GADA measurement in a large cohort of unselected patients with type 2 diabetes. We studied 3672 patients with type 2 diabetes who were representative of such patients in the general population, since general physicians in 23 centres referred all newly diagnosed patients as part of recruitment to the UK Prospective Diabetes Study.18 ICA and GADA were measured in plasma samples taken at diagnosis. We assessed the proportion of patients with autoantibodies at different ages of diagnosis, the association with specific clinical characteristics, such as near-normal weight, pronounced hyperglycaemia, or impaired β-cell function, and whether the presence of ICA, GADA, or both was a reliable predictor of future insulin requirement. We also investigated whether associated clinical characteristics, such as pronounced hyperglycaemia or normal weight, provided similarly useful information about insulin requirement.
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Patients and methods
We studied 3672 white patients with newly diagnosed type 2 diabetes (figure 1) aged between 25 and 65 years. All patients were recruited to the UK Prospective Diabetes Study from 23 centres in the UK.18 Most patients were recruited through general physicians who had been asked to refer all newly diagnosed diabetic patients to avoid selection of only patients with pronounced hyperglycaemia. The entry criteria were: two fasting plasma glucose results of more than 6 mmol/L, excluding those thought
ICA and GADA at different ages
The proportion of the 3672 patients who had ICA was 6% and GADA 10%, with 12% of patients having either ICA or GADA, and 4% having both antibodies. The presence of both ICA and GADA was more frequent among patients aged 25–34 years (ICA 21%, GADA 34%; table 2) than among older patients and decreased with age to 4% and 7%, respectively, among those aged 55–65 years (figure 2). GADA was always more frequent than ICA. 94% of patients with ICA also had GADA, and 58% of those with GADA also had ICA
Discussion
At all ages, the presence of ICA and GADA in patients with type 2 diabetes suggested an increased likelihood that insulin therapy would be required which supports other findings.10, 15, 16 94% of patients aged 34 years or younger with ICA and 84% of those with GADA required insulin therapy after 6 years. In the older age-groups, the presence of either ICA alone or GADA alone was a weaker predictor of insulin requirement, since among patients older than 55 years, only 34% with GADA and 44% with
References (30)
On the honey disease: a dialogue with Socrates
Diabetes
(1993)- et al.
Epidemiological approach to the etiology of Type 1 diabetes mellitus and its complications
NEngl J Med
(1987) - et al.
Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies
Lancet
(1974) - et al.
Identification of the 64k autoantigen in insulin-dependent diabetes as the GABA synthesising enzyme glutamic acid decarboxylase
Nature
(1990) - et al.
Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity
Diabetologia
(1995) - et al.
Antiglutamate decarboxylase and other antibodies at the onset of childhood IDDM: a population-based study
Diabetologica
(1994) - et al.
A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes
N Engl J Med
(1990) - et al.
Clinical and pathogenic significance of pancreatic-islet cell antibodies in diabetics treated with oral hypoglycaemic agents
Lancet
(1977) - et al.
Correlation of islet cell antibodies and HLA-DR phenotypes with diabetes mellitus in adults
Diabetologia
(1984) - et al.
Islet cell antibodies identify latent type 1 diabetes in patients aged 35–37 years at diagnosis
Diabetes
(1986)
Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of diabetes
Diabetes
Time course of islet cell antibodies and β-cell function in non-insulin-dependent stage of type 1 diabetes
Diabetes
Insulin-dependent?
Lancet
Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency
Diabet Med
Sundkvist G, Hogopian WA. Glutamic decarboxylase antibody levels predict rate of B-cell decline in adult-onset diabetes
Diabetes Res Clin Pract
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