Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies.

Abstract

The aim of the study was 1) to establish the prevalence of GAD antibodies (GADab) in a population-based study of type 2 diabetes in western Finland, 2) to genetically and phenotypically characterize this subgroup, and 3) to provide a definition for latent autoimmune diabetes in adults (LADA). The prevalence of GADab was 9.3% among 1,122 type 2 diabetic patients, 3.6% among 558 impaired glucose tolerance (IGT) subjects, and 4.4% among 383 nondiabetic control subjects. Islet antigen 2 antibodies (IA2ab) or islet cell antibodies were detected in only 0.5% of the GADab- patients. The GADab+ patients had lower fasting C-peptide concentrations (median [interquartile range]: 0.46 [0.45] vs. 0.62 [0.44] nmol/l, P = 0.0002) and lower insulin response to oral glucose compared with GADab- patients. With respect to features of the metabolic syndrome, the GADab+ patients had lower systolic (140 [29.1] vs. 148 [26.0] mmHg, P = 0.009) and diastolic (79.2 [17.6] vs. 81.0 [13.1] mmHg, P = 0.030) blood pressure values, as well as lower triglyceride concentrations (1.40 [1.18] vs. 1.75 [1.25] mmol/l, P = 0.003). GADab+ men had a lower waist-to-hip ratio compared with GADab- patients. Compared with GADab- patients and control subjects, the GADab+ patients had an increased frequency HLA-DQB1*0201/0302 (13 vs. 4%; P = 0.002) and other genotypes containing the *0302 allele (22 vs. 12%; P = 0.010). However, the frequency of these high-risk genotypes was significantly lower in GADab+ type 2 patients than in type 1 diabetes of young or adult onset (0201/0302 or 0302/X: 36 vs. 66 vs. 64%, P < 0.001). The GADab+ type 2 group did not differ from control subjects with respect to genotypes containing the protective DQB1-alleles *0602 or *0603, nor with respect to the type 1 high-risk genotype in the IDDM1 (Hph1 +/+). We conclude that GADab+ patients differ from both GADab- type 2 diabetic patients and type 1 diabetic patients with respect to beta-cell function, features of the metabolic syndrome, and type 1 diabetes susceptibility genes. Further, we propose that LADA be defined as GADab positivity (>5 relative units) in patients older than 35 years at onset of type 2 diabetes.

High frequency of abnormal glucose tolerance in DQA1*0102/DQB1*0602 relatives identified as part of the Diabetes Prevention Trial?Type 1 Diabetes

“…Among subjects enrolled in the DPT-1 intervention trials, the presence of IGT results in an approximately 70% 5-year risk of type 1 diabetes, as determined from life-table analysis [11]. A similar high risk is seen among people with IGT and at risk for type 2 diabetes, with about 6% annual progression [27,28]. It is possible that many of the DQA1*0102/ DQB1*0602 subjects with abnormal glucose tolerance will either never manifest overt diabetes, or will develop diabetes only later in life.…”

“…Alternatively, a slow progression of disease may result in patients being clinically classified as having type 2 diabetes or latent autoimmune diabetes of adults (LADA) [33]. In this regard, it is important to note that DQB1*0602 may not protect subjects from LADA, as one report has shown that these patients have the same frequency of this allele as seen in the general population [27]. Others report no differences in the frequency of highrisk alleles between LADA and older, but more typical type 1 patients [34].…”

Latent autoimmune diabetes in adults (LADA)—more than a name

“…the presence of GAD antibodies in a patient with age at onset of diabetes of >30 years (or 35 years, as we previously proposed), and insulin independence for at least 6 months after diagnosis. Clearly, each of these cut-off values is arbitrary, and the definition of GAD antibody positivity will influence not only the prevalence but also the phenotype of LADA [6]. As Gale points out, GAD antibodies are continuously distributed throughout the population, but this applies to most autoantibodies [7], as described as early as 1963 [8].…”

“…Among the key issues will be the demonstration that LADA has genetic features in common with both type 1 and type 2 diabetes; this information is now partially available. Patients with LADA have more type 1 high-risk HLA-DQ genotypes than patients with type 2 diabetes, but fewer than those with type 1 diabetes [6,12] and, notably, more protective HLA genotypes than patients with type 1 diabetes [6]. However, still lacking is knowledge on whether patients with LADA have the same frequency of the few type 2 diabetes susceptibility genes that have reproducibly been associated with type 2 diabetes, e.g.…”

“…Beta cell function deteriorates faster than in type 2 diabetes but slower than in type 1 diabetes [1,5,13,16], and there is no difference in hepatic or peripheral insulin sensitivity between type 1, type 2 and LADA, whether in the diabetic [3] or the prediabetic [17] state. Nevertheless, patients with LADA have fewer features of the metabolic syndrome than patients with type 2 diabetes [6,18], and have fewer macrovascular complications [18]. Unfortunately, as regards LADA as an entity, we do not yet know the treatment of choice.…”