Elsevier

The Lancet

Volume 350, Issue 9087, 1 November 1997, Pages 1288-1293
The Lancet

Early Report
UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes

https://doi.org/10.1016/S0140-6736(97)03062-6Get rights and content

Summary

Background

Autoantibodies to islet-cell cytoplasm (ICA) and glutamic acid decarboxylase (GADA) can occur in apparently typical, non-insulin dependent diabetes mellitus (type 2). We investigated whether the presence of either or both antibodies characterises a subtype of diabetes and provides better prediction of requirement for insulin therapy by 6 years' follow-up than clinical variables.

Methods

We measured ICA and GADA at diagnosis of diabetes in a representative population of 3672 white patients with type 2 diabetes, aged between 25 and 65 years. The phenotype was assessed by age of onset, body-mass index, percentage haemoglobin A1c (HbA1c), and islet β-cell function. We investigated the need for insulin therapy among 1538 patients not assigned insulin and followed up for 6 years from diagnosis.

Findings

The proportion of patients with ICA and GADA decreased with increasing age at diagnosis (from 33 [21%] of 157 patients aged 25–65 to 66 [4%] of 1769 aged 55–65 for ICA; from 53 [34%] to 122 [7%] for GADA). Among patients younger than 35 at diagnosis, those with ICA or GADA had lower body-mass index than those without (mean 24·9 [SD 6·0] vs31·7 [7·3] kg/m2; p<0·0001 and had higher percentage of HbA1c (9·7 vs 8·7%, p<0·05). 94% of patients with ICA and 84% of those with GADA required insulin therapy by 6 years, compared with 14% of those without the antibodies (p<0·0001). Among patients older than 55 at diagnosis, the difference between those with and without antibodies in body-mass index was smaller (27·2 [5·4] vs 28·6 [4·8] kg/m2, p<0·001); 44% of those with ICA, 34% of those with GADA, and 5% with neither antibody required insulin therapy by 6 years (p<0·0001). Among patients older than 45 years, body-mass index and HbA1c provided little predictive information for insulin requirement, whereas the positive predictive values of GADA (≥60 U/L) alone, or both GADA (≥20 U/L) and ICA (>5 U/L), for insulin therapy were 52% and 68%.

Interpretation

Among young adults with type 2 diabetes, the phenotype of those with ICA or GADA antibodies was similar to that of classic juvenile-onset insulin-dependent diabetes, and either phenotype or antibodies predicted insulin requirement. In older adults, the phenotype was closer to that of patients without antibodies and only the presence of antibodies predicted an increased likelihood of insulin requirement.

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.

Section snippets

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

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