autoimmune type 1 diabetes ( type 1a diabetes ) is an organ - specific autoimmune endocrine disease , which is caused by immune destruction of pancreatic    cells . antibodies to islet - related antigens including glutamic acid decarboxylase antibodies ( gadas ) and insulinoma - associated antigen 2 ( ia-2 ) antibodies are markers for autoimmunity to islet cells [ 2 , 3 ] . when these antibodies are positive , the patient 's diabetes is usually considered to be type 1 even if they are not insulin dependent [ 46 ] . antibodies to islet - related antigens are present before the onset of type 1 diabetes ( t1d ) , and their predictive value for the development of t1d has been repeatedly investigated in close relatives of t1d patients and the general population [ 712 ] . graves ' disease , which is also an organ - specific autoimmune endocrine disease , is frequently associated with t1d . in these patients , titers of gada tend to be high , which may indicate powerful ability of producing autoimmune process to islet antigens . on the other hand , gada is sometimes positive in graves ' patients without diabetes [ 1517 ] . in these patients however , the fate of graves ' patients who are positive for gada is obscure , and the predictive value of gada for the development of t1d in graves ' patients remains to be clarified . we examined gada in patients with graves ' disease and followed up patients who were positive for gada for 8 years . gada was measured by a highly sensitive ligand - binding assay in 158 patients with graves ' disease ( 50 untreated , 108 treated ) who had not been diagnosed to have diabetes . most patients other than new patients were under the treatment with antithyroid drugs . in the patients who were positive for gada by ligand - binding assay ( positive when detected ) , gada was again measured by radioimmunoassay ( cosmic corporation , standard value was < 1.5  u / ml ) , and antibodies to islet cell antibodies ( icas ) 512/ia-2 were measured by a ligand - binding assay ( positive when detected ) . details of the ligand - binding assay for gada and antibodies to ica512/ia-2 have been described elsewhere [ 18 , 19 ] . glucose intolerance was assessed by either oral glucose tolerance test or hba1c ( reference range : 4.35.8% ) within a half year after the detection of gada . diabetes was diagnosed by criteria of american diabetes association . in the cases in which only hba1c was measured for the detection of glucose intolerance , less than 5.8% patients positive for gada by ligand - binding assay were followed up whether or not type 1 diabetes developed . in seven patients whose gada titers by ligand - binding assay were relatively high and gada by ria were positive , hba1c and occasional plasma glucose were measured at least every two years for eight years . in other three patients who were negative for gada by ria , physicians inquired whether or not diabetes developed at every visiting to the outpatient clinic . the patients who were negative for gada at the start of the study were not followed up . ten patients out of 158 ( 6.3% ) were positive for gada by the ligand - binding assay . eight of these patients were treated with antithyroid drugs ( atds ) and 2 were untreated ( treatment naive ) . the overall prevalence of positivity for gada among treated and untreated patients was 7.4% and 4.0% , respectively ( table 1 ) . gada was again investigated by standard radioimmunoassay ( ria ) in 9 of the 10 patients , and 6 were positive ( table 2 ) . in 4 patients , titers by ria were over 20  u / ml . ica512/ia-2 antibodies were weakly positive in 2 patients . an oral glucose tolerance test was performed in 5 of the 10 gada - positive patients . of these , one patient showed a diabetic pattern and another had impaired glucose tolerance ( this patient dropped out from study 3 years after the initial workup ) . hba1c levels of the other 5 patients were within the normal range . during the 8-year followup period , t1d developed with marked hyperglycemia and ketosis in two patients whose graves ' disease was long standing and uncontrollable by antithyroid drug . one of them showed diabetic pattern in gtt at the initial work up , but hba1c was within a normal range ( section 3.1 and table 2 ) . patient 1 was a 44-year - old man ( at the diagnosis of t1d ) , in whom graves ' disease developed at age 21 . he took an antithyroid drug ( atd ) , but 1020  mg of methimazole was needed to maintain euthyroid . at age 42 , gada was detected . his oral glucose tolerance test the next year showed a diabetic pattern ( fpg 7.8  mmol / l ( 141  mg / dl ) , 2 hours 14.3  mmol / l ( 257  mg / dl ) ) . his insulin response to oral glucose was very low ( insulinogenic index , 0.08 ) . calorie restriction was recommended , but symptoms of severe hyperglycemia including thirst and polyuria developed the following year . plasma glucose was 29.6  mmol / l ( 534  mg / dl ) , and urine ketone bodies were 2 + . insulin therapy was started , and the requirement of insulin was reduced to 2  units / day but increased to 34 to 40 units thereafter . patient 2 is a 34-year - old woman ( at the diagnosis of t1d ) . after atd therapy , she had remission at age 19 , but graves ' disease relapsed at age 21 . at age 26 , graves ' disease was exacerbated 9 months after delivery . postprandial glucose was 5.3  mmol / l ( 95  mg / dl ) , and hba1c was 5.0% . she needed 60  mg methimazole to maintain euthyroid and she took radioisotope therapy , but an antithyroid drug was continued as she was still thyrotoxic . one year after ri therapy , her postprandial plasma glucose was 123  mg / dl and hba1c was 5.6% . next year t1d developed with the manifestations of hyperglycemia such as thirst , polydipsia , polyuria , and weight loss . on the laboratory examinations , plasma glucose was 34.6  mmol / l ( 623  mg / dl ) , hba1c was 14.1% , urine ketone bodies were positive , and arterial blood ph was 7.41 . after initial therapy for hyperglycemia , she took 24 units of insulin daily , and her cpr before lunch was 0.18  nmol / l . type 1 diabetes ( t1d ) and graves ' disease , both endocrine organ - specific autoimmune diseases , frequently coexist and in combination are classified as autoimmune polyglandular syndrome type iii . there are common genetic backgrounds for both diseases   such as the ctla-4 gene [ 2123 ] and ptpn-22 gene [ 2427 ] . in japanese adults , thus , graves ' disease is a risk factor for t1d , as seen in the present study in which two out of 158 patients with graves ' disease developed t1d during the course of 8 years . in this study , the prevalence of gada in graves ' patients without previously diagnosed diabetes was high , similar to those in previous reports [ 1517 ] . furthermore , the prevalence was high in the treated patients but the difference of the prevalence between treated patients and treatment - nave patients was not statistically significant . among the patients positive for gada , t1d developed in two patients with long - standing graves ' disease who were not easily controlled by antithyroid drug ( atd ) therapy . one needed a 10 to 20  mg methimazole for control of the disease and finally had a thyroidectomy after exacerbation . their titers of gada both by ligand - binding assay and radioimmunoassay were very high . it is conceivable that autoimmune reaction to islet antigens is strong in the graves ' patients with high titer of gada , and that those patients are susceptible to t1d . antibodies to islet antigens are present before the onset of type 1 diabetes . on the other hand , many individuals positive for antibodies to islet antigens do not develop t1d . in finland , where the incidence of t1d is very high , it was reported that t1d developed only in 26% of gada - positive young subjects from general population over 25 years . in the same study , only 0.26% of gada - negative subjects developed t1d . previous studies have revealed that positivity for more than 2 kinds of islet - associated antibodies , especially the combination of gada and ia-2 antibodies , has predictive value . of the patients in the present study who developed t1d , one had ia-2 antibodies and the other did not . on the contrary , one patient who had both antibodies in low titers did not develop t1d during the followup period . the number of patients was small and we could not obtain conclusive results , but the presence of both gada and ia-2 antibodies seems to indicate a high risk also in graves ' patients . screening of gada followed by examination of ia-2 antibodies may allow detecting those patients at greater risk for development of t1d , and careful followup may provide earlier detection of the onset of t1d in these patients . we show preliminarily that graves ' patients with long duration and high titers of gada are at high risk for developing t1d . to clarify what factors are involved in the susceptibility to t1d in graves ' disease , greater numbers of patients need to be followed up intensively over a long period of time .
glutamic acid decarboxylase antibodies ( gadas ) are one of the markers of islet cell autoimmunity and are sometimes present before the onset of type 1 diabetes ( t1d ) . 
 gada can be present in graves ' patients without diabetes ; however , the outcome of gada - positive graves ' patients is not fully understood , and the predictive value of gada for the development of t1d in graves ' patients remains to be clarified . 
 we investigated the prevalence of gada in 158 patients with graves ' disease and detected gada in 10 patients . 
 they were followed up to discover whether or not t1d developed . in the course of eight years , 2 patients with high titers of gada developed t1d , both had long - standing antithyroid drug - resistant graves ' disease . 
 thus , graves ' disease with high gada titer seems to be at high risk for t1d .