GADA-positive Patients Research Articles

The clinical characteristics of latent autoimmune diabetes in adults and its relation with chronic complications in metabolically poor controlled Turkish patients with Type 2 diabetes mellitus

It has been reported that some patients with Type 2 diabetes mellitus (DM) have latent autoimmune diabetes in adults (LADA) and may show different clinical characteristics than those with Type 2 DM. We aimed to determine the ratio and clinical features of LADA in patients with diagnosed initially as Type 2 DM. We measured glutamic acid decarboxylase antibodies (GADA) in 54 patients, diagnosed clinically with Type 2 DM. Of 54 patients, 17 (31%) were GADA positive. GADA-positive patients had significantly earlier diabetes onset age ( P<.001), lower BMI ( P<.05), and lower serum C-peptide value ( P<.001) than did those who were GADA negative. A higher proportion of the GADA-positive patients were receiving insulin therapy ( P<.01). With respect to the duration of DM, familial history of DM, and the levels of blood pressures, fasting plasma glucose, and HbA1c, there was no difference between the two groups. Nephropathy and retinopathy were more frequent in GADA-positive than in GADA-negative patients. The prevalence of neuropathy was comparable between the two groups. GADA was negatively associated with BMI, C-peptide levels, and diabetes-onset age, but positively related to retinopathy, nephropathy, and insulin treatment. This study indicated that the important portion of the patients who were initially diagnosed as Type 2 DM may have LADA. In Type 2 diabetic patients who have lower BMI and diagnosis of diabetes in relatively younger age, the possibility of LADA should be taken into consideration. The higher prevalence of nephropathy and retinopathy in GADA-positive patients also suggests the importance of early diagnosis and strict metabolic control in these patients.

Subtle hyperproinsulinaemia characterises the defective insulin secretory capacity in offspring of glutamic acid decarboxylase antibody-positive patients with latent autoimmune diabetes mellitus in adults

We set out to assess whether hyperproinsulinaemia is an early finding in latent autoimmune diabetes in adults (LADA). We measured plasma proinsulin and C-peptide responses during a 2-h oral glucose tolerance test (OGTT) and in the hyperglycaemic clamp in 21 normoglycaemic offspring of LADA patients testing positive for glutamic acid decarboxylase antibodies (GADA) or islet cell antibodies (ICA), and in 17 healthy control subjects without a family history of diabetes. The study groups had comparable areas under the curves of blood glucose, plasma proinsulin, C-peptide and proinsulin/C-peptide in the OGTT. However, the offspring of LADA patients had higher proinsulin/C-peptide in the hyperglycaemic clamp (P < 0.01 versus the control group). The offspring of GADA-positive LADA patients (n = 9) had higher proinsulin and proinsulin/C-peptide than did the control group in the OGTT (P < 0.05 for both comparisons) and in the hyperglycaemic clamp (P < 0.001 and P < 0.05 respectively). They also had higher proinsulin than the offspring of ICA-positive LADA patients (n = 12) (P < 0.001) in the hyperglycaemic clamp. The offspring of ICA-positive LADA patients did not clearly show hyperproinsulinaemia during the tests, but they had lower maximal glucose-stimulated insulin secretory capacity than the control group (P < 0.05) and the offspring of GADA-positive LADA patients (P < 0.05) in the hyperglycaemic clamp. These results suggested that insulin secretion in the offspring of GADA-positive LADA patients is characterised by subtle defects in the processing of insulin precursors. Furthermore, various proinsulin responses among the offspring of LADA patients with different autoimmune markers provided further evidence that LADA is a heterogeneous disorder.

Gender differences in GAD antibody-positive diabetes mellitus in relation to age at onset, C-peptide and other endocrine autoimmune diseases.

Females have an increased incidence of autoimmune diseases. However, no gender difference in the incidence of type 1 diabetes is found. The frequency of antibodies against glutamic acid decarboxylase (GADA) in diabetes mellitus depends on age at diagnosis and also gender. Several studies have shown that high GADA levels can predict future beta-cell failure and need for insulin treatment. The aim of this study was to investigate possible gender differences in relation to GADA levels, fasting plasma C-peptide levels and frequency of other autoimmune endocrine diseases in GADA-positive patients with different age at diabetes diagnosis. GADA were screened in 4974 patients from a local diabetes registry, and plasma C-peptide was measured and a history of other autoimmune endocrine diseases was recorded. Of these patients, 822 were GADA positive and were further divided into four groups depending on the age at diagnosis of diabetes; Group 1: <20 years, Group 2: 20-39 years, Group 3: 40-59 years and Group 4: > or =60 years. Female patients in Group 3 had lower fasting plasma C-peptide levels (median 0.21[0.00-0-56] vs. 0.41[0.00-0.73] nmol/L, p=0.02), higher GADA levels (median 7 [4-9] vs. 5 [2-7] Arbitrary Unit (AU), p=0.0003) and higher frequency of other autoimmune endocrine diseases (22.4 vs. 5.3%, p=0.0001) than male patients. In a stepwise logistic regression analysis, diabetes duration (p<0.000001), high GADA levels (Exp (B) 3.68 CI 1.69-7.98, p=0.001) and low BMI (p=0.00002) were associated with total beta-cell failure in Group 3. GADA-positive female diabetic patients with an age at diagnosis between 40 and 59 years have higher GADA levels and a more severe loss of beta-cell function than male patients with the same age at diagnosis. This could be due to the effect of sex steroids and/or GnRH on the regulation of the immune system. Female patients with high GADA levels also had a high prevalence of other autoimmune endocrine diseases, especially autoimmune thyroid disease, which further emphasises the need for screening of thyroid function in female patients with high GADA levels.

Immune responses to glutamic acid decarboxylase and insulin in patients with gestational diabetes.

Pregnancy is a natural state of immunoprotection and tolerance. We studied subjects with gestational diabetes (GDM) to evaluate the influence of pregnancy on the humoral immune response to the autoantigen GAD and to injected insulin. Antibodies against glutamic acid decarboxylase (GADA) subclasses and epitope reactivity were determined in 34 GADA-positive pregnant patients with GDM, in 20 GADA-positive relatives of people with TID and in 25 GADA-positive patients with newly diagnosed TID. Partum levels of insulin antibodies (IA), IgG1- and IgG4-IA were measured in 131 women with GDM treated with human insulin from the time of diabetes diagnosis (including 22 with GADA) and were compared to 19 patients with TID after 3 months of insulin treatment. GADA titre and subclasses were similar among all groups. GADA in GDM patients bound fewer epitopes than GADA in relatives of patients with TID (all epitopes being present in 23%versus 65%, P < 0.01). In particular, antibodies to the minor GADA epitopes GAD6596-249, GAD651-100 and GAD67 were less frequent in patients with GDM compared to relatives (P < 0.01). Antibodies to insulin (IA) were found in 17% of patients with GDM. They were more frequent in GDM patients with GADA compared to GADA-negative patients (41%versus 12%, P < 0.005). IgG1 was the dominant insulin antibody subclass response in both patients with GDM and TID but levels of IgG1-IA and IgG4-IA were significantly lower in patients with GDM compared to patients with TID (P < 0.004). Antibody responses in women with gestational diabetes appear to be dampened and restricted, but without change in subclass usage.

Retinopathy in latent autoimmune diabetes of adults: the Fremantle Diabetes Study.

To determine the prevalence of retinopathy and its associations in patients diagnosed clinically with Type 2 diabetes and serum antibodies to glutamic acid decarboxylase (GADA) from a community-based sample. In a case-control design, 24 GADA-positive Type 2 patients from the Fremantle Diabetes Study (FDS) cohort were recruited and matched as closely as possible for age, sex and diabetes duration with 72 GADA-negative Type 2 patients from the FDS. Each patient had a detailed clinical and biochemical assessment including slit lamp biomicroscopy and colour fundus photography with Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) grading. The GADA-positive patients had a significantly higher HbA1c (median (interquartile range); 8.4 (7.3, 9.6)%) than those who were GADA-negative (7.2 (6.5, 8.1)%: P = 0.002). The overall prevalence of retinopathy amongst the 96 subjects was 26.0%. The majority (92%) of the retinopathy detected was mild and non-proliferative. GADA-positive patients had double the retinopathy prevalence of the GADA-negative group (41.7% vs. 20.8%; P = 0.044). In a logistic regression model, diabetes duration, HbA1c, systolic blood pressure and current smoking were each significantly and independently predictive of retinopathy (P < 0.025), but GADA status was not. These data show that GADA-positive patients have an increased prevalence of retinopathy compared with GADA-negative controls with Type 2 diabetes from an urban Australian community. This increased prevalence is due mainly to relatively poor glycaemic control in the GADA-positive group.

A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes.

To clarify the relationships between islet antibodies (islet cell antibody [ICA], GAD antibody [GADA], and IA-2 antibody [IA-2A]) versus the progression of beta-cell dysfunction, we have followed a group of diabetic patients from their diagnosis at 21-73 years of age. Patients with ICA had high levels of GADA and/or IA-2A at diagnosis and a more severe beta-cell dysfunction 5 years after diagnosis than those with only GADA in low concentrations. The aim of the current 12-year follow-up study was to examine the further progression of beta-cell dysfunction in relation to islet antibodies at and after diagnosis. Among 107 patients, complete beta-cell failure 12 years after diagnosis was restricted to those with islet antibodies at diagnosis (16 of 21 [77%] with multiple antibodies and 4 of 5 [80%] with only GADA). In contrast, among antibody-negative patients, fasting P-C-peptide levels were unchanged. Most GADA-positive patients (22 of 27 [81%]) remained GADA positive after 12 years. Associated with decreasing fasting P-C-peptide levels (0.85 nmol/l [0.84] at diagnosis vs. 0.51 nmol/l [0.21] 12 years after diagnosis, P < 0.05), ICA developed after diagnosis in 6 of 105 originally antibody negative mostly overweight patients. In conclusion, multiple islet antibodies or GADA alone at diagnosis of diabetes predict future complete beta-cell failure. After diagnosis, GADA persisted in most patients, whereas ICA development in patients who were antibody negative at diagnosis indicated decreasing beta-cell function.

High-Titer Autoantibodies against Glutamic Acid Decarboxylase Plus Autoantibodies against Insulin and IA-2 Predicts Insulin Requirement in Adult Diabetic Patients

Antibodies against glutamic acid decarboxylase (GADA) is known to be a good predictive marker for insulin-dependency among adult diabetic patients. However, since not all of the GADA-positive patients will develop insulin requirement, we investigated whether other markers, that is, antibodies against IA-2 (IA-2A), insulin autoantibodies (IAA) and HLA class II type, would affect its predictive value for insulin requirement. Adult diabetic patients in the non-insulin-requiring stage were screened for GADA and registered in the study if positive. At the end of the follow-up period, 15 of the 43 GADA-positive patients required insulin. Among GADA-positive patients, the GADA titers of the insulin-requiring patients were significantly higher (199Uvs.5.8U,P<0.001) and high-titer GADA was more frequently detected among insulin-requiring patients (80%vs.11%,P<0.0001). IAA was more frequently detected in insulin-requiring patients (40%vs.0%,P<0.001), and IA-2A was detected only among insulin-requiring patients. Combinations of these three antibodies (GADA with either IAA or IA-2A) had 100% positive predictive value. In conclusion, the GADA test is a good screening test for predicting insulin requirement in adult diabetic patients and both the IAA and IA-2A tests are useful second line tests.

Measurement of antibodies against glutamic acid decarboxylase 65 (GADA): two new 125I assays compared with [35S]GAD 65-ligand binding assay

Recently, 65-kDa glutamic acid decarboxylase (GAD 65) antibodies (GADA) have been introduced as autoimmune markers in blood to confirm the diagnosis of insulin-dependent diabetes mellitus (IDDM). In this study, to evaluate two new assays that use 125I-labeled GAD 65, we assayed samples from 100 children with recent onset of diabetes and 100 control children, the results were compared with those of a [35S]GADA assay and with results for islet cell antibodies (ICA), the conventional autoimmune marker. Receiver operating characteristic (ROC) curve analysis showed one of the new assays (from RSR) to be more sensitive (P = 0.01) than the comparison ([35S]GADA) assay, whereas the second new assay (from Elias) was less sensitive (P < 0.001). The GADA frequency at 97.5% specificity was greatest in the comparison assay: 63 of 100 vs 41 of 100 (P < 0.01) and 53 of 100 (P = 0.16) in the RSR and Elias assays, respectively. Almost all GADA-positive patients had ICA, but one-third of the ICA-positive patients was GADA-negative. Accordingly, adding GADA analysis results to ICA testing increased the frequency of detection of autoimmune markers only slightly (from 81% to 85%). In conclusion, at 97.5% specificity the [35S]GADA assay seemed to be more efficient than the 125I assays, although the difference was significant only for the Elias 125I assay. Antigen-specific antibodies other than GADA may explain the difference in GADA and ICA frequencies.