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Islet cell antibodies (ICA) in the sera of nondiabetic relatives of patients with insulin-dependent diabetes (IDD) are predictive of the disease, a finding that permits the design of intervention strategies to prevent it. However, 85% or more of patients with new onset IDD have no affected relative. We therefore screened 9,696 schoolchildren between the ages of 5 and 18 yr (mean age 10.7 yr) in Pasco County, Florida for ICA in three surveys during 1984/5, 1987/8, and 1990/1 and have followed them prospectively. Approximately 4,000 of these children have been followed for nearly 8 yr. ICA titers > or = 10 Juvenile Diabetes Foundation units on replicate tests were detected in 57 of the children (0.59%). 10 children have developed diabetes so far, and all had ICA detected beforehand. The likelihood of developing IDD among the ICA-positive children was compared with 2,959 age-matched nondiabetic first degree relatives of IDD probands who were screened for ICA by our laboratory during the same time period and also followed prospectively. Of 103 (3.5%) ICA-positive relatives, 31 have developed IDD. Life table analysis reveals no statistically significant differences in the probability of developing IDD between the ICA-positive schoolchildren and ICA-positive first degree relatives (P = 0.3). The estimated risk of developing IDD by 7 yr in the ICA-positive schoolchildren was 45% (95% confidence interval 15-74%) compared with 43% (confidence interval 22-63%) in the relatives. We conclude that ICA appear to be as predictive of IDD in low-risk schoolchildren as they are in high-risk relatives. These data suggest that it is feasible to predict IDD by screening a general population of schoolchildren for ICA and that those found to be positive could be considered, in addition to relatives, for intervention protocols to prevent the disease.

Using time-dependent methods, the temporal relationships between the detection of insulin and islet cell autoantibodies and the onset of insulin dependent diabetes (IDDM) were analyzed in a prospective study of 4694 nondiabetic relatives of 1929 patients with IDDM who had been followed for a median of 4 yr. Insulin autoantibodies were detected in 1.5% of relatives at their initial test whereas an additional 1.0% subsequently became positive for these antibodies during follow-up. Islet cell autoantibodies were detected in 2.6% of the relatives at the time of their first test and an additional 0.9% were observed to develop them during the follow-up period. The risk of developing IDDM was significantly higher (P = 0.0001) among those who were found to have one of these antibodies, but was highest among those under the age of 20 yr at inception of this study who tested positive for both. Among older relatives, the detection of insulin autoantibodies among those who were islet cell antibody positive did not convey an additional risk of IDDM. In a subset of relatives, the presence of either antibody was associated with a higher frequency (P < 0.001) of diabetes associated human leukocyte antigen-DR 3/4 heterozygotes. Islet cell autoantibodies were highly associated with elevated fasting and 60-min glucose concentrations (P = 0.0001) as well as decreased early phase (1 and 3 min) insulin response to an iv glucose tolerance test (P = 0.0001). Insulin antibodies were significantly associated with decreased early phase insulin response to iv glucose (P = 0.0003). These data confirm independent risks associated with each antibody and suggest that their temporal relationship may be an important reflection of the pathogenic process underlying IDDM observations which facilitate its predictability.

Prospective studies of the relatives of people with Type 1 diabetes can provide insights into risk factors for processes leading to the ultimate destruction of the pancreatic islet B-cells. Relatives ascertained through the Children's Hospital of Pittsburgh diabetes registry were followed and rates of conversion to diabetes were determined. We studied the role of genetic and immunological markers, and used the oral glucose tolerance test (OGTT) to study metabolic disturbances among first-degree relatives. A group of siblings was serotyped for the HLA-A and -B antigens, and the degree of HLA haplotype sharing with the diabetic sibling was established. Later, islet cell antibody (ICA) assays were performed, and subjects were followed to determine the predictive value of ICA testing for the subsequent development of diabetes. The rate of conversion to diabetes among the siblings was 14 times greater than the rate observed in the general population from which they come. This is comparable to rates observed by other centres following relatives of people with Type 1 diabetes. Impaired glucose tolerance (by National Diabetes Data Group (USA) criteria) carried a three-fold greater risk for subsequent Type 1 diabetes than did a normal OGTT. Those relatives with detectable ICA were about 50 times more likely to convert to diabetes than were those without ICA. In a group of siblings in whom HLA haplotype sharing was determined, the prevalence of detectable ICA was greater among those who were HLA-identical to the diabetic sibling (9.9%) than among those who were haplo-identical (5.3%) or completely dissimilar (2.4%) at the HLA-A and -B regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Human CD5+ B lymphocytes produce autoantibodies that bind to self- and exogenous antigens. Extremely high percentages of CD5+ B lymphocytes are present in the fetal and newborn periods, whereas they constitute only a minority of B lymphocytes in healthy adults. Increased percentages of circulating CD5+ lymphocytes have previously been demonstrated in several autoimmune diseases, including rheumatoid arthritis, progressive systemic sclerosis, Graves' disease, and Sjögren's syndrome. We measured the percentages of B lymphocytes that expressed the CD5 determinant in 93 control subjects (age range 1 day to 59 yr, mean +/- 22.6 +/- 17.7 yr), 17 subjects with newly diagnosed insulin-dependent diabetes mellitus (IDDM; range 5-29 yr, mean +/- SD 13 +/- 5.9 yr), 31 high-risk islet cell antibody (ICA)-positive nondiabetic subjects (range 4-45 yr, mean +/- SD 19.8 +/- 14.1 yr), and 13 subjects with IDDM of greater than 5 yr duration (range 10-43 yr, mean +/- SD 24.2 +/- 9.9 yr). We report that CD5+ B-lymphocyte percentages are strikingly age dependent in healthy control subjects, declining progressively from the newborn period to the middle-age years (r = -0.75, P = 0.0001). In ICA+ nondiabetic and recent-onset IDDM subjects less than 29 yr of age, the percentage of circulating CD5+ B lymphocytes fell within the 95% confidence intervals established for control subjects. However, the age-dependent rate of decline in the percentage of CD5+ B lymphocytes within the control range was slower in ICA+ and newly diagnosed IDDM subjects than in control subjects.

Islet cell autoantibodies (ICA) and other organ-specific autoantibodies were detected in 27 Chinese children with insulin-dependent diabetes mellitus (IDDM). The frequency of ICA within the first year of diagnosis was 67%, and it declined as the duration of the disease increased. The frequencies of thyroid microsomal autoantibodies and gastric parietal cell autoantibodies were 26% and 11%, respectively. None of the patients had adrenal autoantibodies. These results are comparable to those reported in Caucasian patients. Similar frequencies of islet cell autoantibodies and other organ-specific autoantibodies in children with IDDM between Chinese and Caucasians suggest that the autoimmune process may play an important role in the pathogenesis of Chinese children with IDDM.

Background: The presence of cytoplasmic islet-cell autoantibodies has been recognized as a risk factor for the development of diabetes mellitus in relatives of patients with insulin-dependent diabetes mellitus (IDDM), but the magnitude of the risk is unknown, as is the influence of other factors, such as age, sex, and race., Methods: From 1979 through 1989, we studied 4015 initially nondiabetic relatives of 1590 probands with IDDM to determine the risk of IDDM according to the presence and titer of autoantibodies, as well as other factors., Results: Of the 4015 nondiabetic relatives, 125 (3.1 percent) had islet-cell antibodies in their initial serum samples, and 40 contracted IDDM. Islet-cell antibodies were most frequent (4.3 percent) in relatives who were under 20 years of age (P = 0.001) and in those (4.8 percent) from families with more than one affected member (a multiplex pedigree) (P = 0.003). Independent risk factors for the development of diabetes in the relatives included age of less than 10 years at the time of the initial study (P = 0.001), membership in a multiplex pedigree (P = 0.02), and a positive test for islet-cell antibodies in the initial serum sample (P = 0.0001). Twenty-seven of the relatives in whom diabetes developed (67.5 percent) had positive tests for islet-cell antibodies before the diagnosis of IDDM, giving a relative risk of IDDM of 68 (95 percent confidence interval, 34 to 134) for antibody-positive relatives. Islet-cell-antibody titers of 20 Juvenile Diabetes Foundation units or higher were associated with an increasing risk of diabetes., Conclusions: Nondiabetic relatives of probands with IDDM who are in the first two decades of life, are members of multiplex pedigrees, and have increased titers of islet-cell antibodies are the most likely to contract IDDM themselves.

The occurrence of autoantibodies to an islet-cell protein of 64,000 Mr (64KA) was examined in relation to development of insulin-dependent diabetes. 64KA were absent in 26 normal controls and present in only 1 of 41 first-degree relatives who lacked islet-cell cytoplasmic autoantibodies (ICA) or insulin autoantibodies (IAA). Among first-degree relatives at high risk for IDD, 64KA were identified in 23 of 28 persons positive for ICA and 4 of 5 with IAA but no ICA. Among 31 patients with newly diagnosed IDD, 64KA were found in 26. 64KA were identified in 23 of 28 persons studied up to 75 months before clinical onset of IDD. Of these 23 64KA-positive prediabetic subjects, 5 were ICA-negative and 10 lacked IAA. 64KA were most predictive in those who became diabetic before age 34 (22/24). In several individuals, 64KA were detected before the other autoantibodies appeared. These findings suggest that 64KA may be an early and useful predictive marker for IDD.

The identification of at-risk individuals before the onset of insulin-dependent diabetes mellitus with islet cell-antibody (ICA) screening programs could have significant psychological sequelae. We initiated a descriptive study of ICA+ subjects and their family members in which reactions to study participation, anxiety, and coping responses are monitored. Described here are preliminary results from 18 ICA+ youngsters, 6 ICA+ adults, and their family members. ICA+ identification resulted in clinically significant anxiety that dissipated to normal levels over time for all participants. Both ICA+ subjects and family members coped with the news in similar ways, relying primarily on problem-focused and social-support coping strategies. Few blamed themselves for their own or their loved one's ICA+ status. There was some evidence that the ICA+ participants may minimize the potential impact of their at-risk status. Compared with family members, ICA+ subjects used more avoidance coping strategies, and few believed they would ever develop diabetes. In contrast, many family members believed their loved one would ultimately develop diabetes. Although the initial findings support the resiliency of this population, the long-term effects of ICA screening remain to be seen.

The extent to which autoimmunity contributes to thyroid dysfunction in Down Syndrome (DS) individuals has not been clarified. We studied 61 persons (34 males and 27 females) with DS (age 5 months to 48 years) for the presence of thyroid autoantibodies (thyroid microsomal antibodies and thyroglobulin antibodies), pancreatic islet cell autoantibodies, gastric parietal cell autoantibodies, and adrenocortical autoantibodies. Thyroid function was determined by measurement of TSH. HLA-A, B and -DR typing was performed on 52 subjects. Forty of 61 subjects (66%) had thyroid dysfunction: elevated TSH values (greater than 5 mcIU/ml) were found in 35 of 61 individuals; 3 subjects had previously documented Hashimoto thyroiditis and were on therapy for hyperthyroidism; and 2 persons had Graves disease. No age or sex variation was detected. Seventeen (28%) subjects had thyroid autoantibodies. Fifteen of the 17 had thyroid dysfunction. Twelve of 25 subjects (48%) over 10 years with thyroid dysfunction had thyroid autoantibodies compared to only 3 of 15 (20%) under the age of 10 years. However, children less than of 10 years tended to have higher TSH values. Only 1 individual who had thyroid antibodies had gastric parietal cell autoantibodies present. Islet cell and adrenocortical autoantibodies were not found in any individuals. Neither thyroid dysfunction nor thyroid autoantibodies correlated with any HLA allele. These findings suggest that thyroid dysfunction in individuals with DS of all ages is a common heterogeneous disorder which cannot be solely explained on the basis of autoimmunity. We recommend that thyroid function be followed closely whether or not thyroid autoantibodies are present.

Antibodies to pancreatic islet cells and insulin were studied in the Genetic Analysis Workshop 5 (GAW5) families, as indicators of an autoimmune component of pathogenesis. The rationale for these studies is summarized briefly, and references to the laboratory methods used are provided.

BB rats were found to have autoantibodies to gastric parietal cells, thyroid colloid antigens, smooth muscle, and thymocytes. No autoantibodies reactive with pancreatic islet cells (cytoplasmic), thyroid epithelial cells, adrenal cortex, testes, or anterior pituitary sections were identified. BB rats with gastric parietal autoantibodies had modest degrees of lymphocytic gastritis, but none developed iron or vitamin B12 deficiencies. These results suggest that BB rats have an underlying autoimmune diathesis. In addition, reports of peripheral T lymphopenia in such rats were confirmed, and markedly reduced helper T cell and cytotoxic-suppressor T cell subsets were demonstrated. Histological studies also revealed depletions of the T cell areas of spleen and lymph nodes. Furthermore, BB rats exhibited a profound inability to reject skin grafts across major and minor histocompatibility barriers. This was confirmed by mixed lymphocyte culture studies in vitro. BB-rat lymphocytes from either spleen or peripheral blood also showed profoundly reduced responses to T cell mitogens. Although BB-rat lymphocytes could produce normal levels of interleukin-2, they were unable to respond to this T cell growth factor. However, examination of thymuses from BB rats showed largely normal histologies, normal numbers of thymocyte subsets, and good mitogenic responses to con A. Thus, it appears that BB rats may have a thymic or post thymic defect in T lymphocyte maturation. The relevance of the immunologic lesion to the etiology of IDD in BB rats remains to be shown.

A longitudinal study of circulating autoantibodies in the sera of 48 BB rats was performed by indirect immunofluorescence. No pancreatic islet cell, adrenocortical, or thyroid microsomal autoantibodies were found. However, autoantibodies reactive to gastric parietal cells (PCA), smooth muscle, and thyroid colloidal antigens were identified, PCA were not detected in Wistar-Furth or BB x Wistar-Furth F1 hybrid rats. The range of ages at the time of first appearance of PCA was the same as that of onset of insulin-dependent diabetes (IDD) in the BB rats, suggesting that the processes leading to PCA and IDD were occurring at the same time of life in these animals. The presence of PCA was associated with degrees of lymphocytic gastritis and with squamous metaplasia of the gastric mucosa in the oldest BB rats (9 mo of age). Levels of serum iron and vitamin B12 did not differ between PCA-positive and PCA-negative BB rats, nor was achiorhydria found in any rat studied. The identification of PCA (and chronic gastritis) and other autoantibodies in the BB rat suggests that these animals have an underlying autoimmune diathesis. These findings thus provide indirect support for an autoimmune pathogenesis for IDD in the BB rat.

Islet cell antibodies (ICA) were detected in 168 (33%) of 504 patients with insulin-dependent diabetes mellitus (IDDM). Mean age of onset of IDDM was 8.6 +/- 0.2 yr and mean age at testing was 13.4 +/- 0.3 yr. None of 162 controls without diabetes (mean age 21.8 +/- 0.9 yr) had ICA. Caucasian patients (404) had a 74% frequency of ICA within 3 mo of diagnosis and an overall ICA frequency of 36%. These results were similar to those reported from Europe. Black patients (100) had lower frequencies of ICA (P < 0.01) and thyroid antibodies (P < 0.05). Caucasian patients with onset of IDDM before 5 yr of age (107) had a lower frequency (P < 0.01) of ICA (21%) than those (297) with a later age of onset (42%). Patients with persistent ICA beyond 5 yr of IDDM had increased frequencies of gastric parietal and adrenal cortex cell antibodies. Thyroid microsomal antibodies were less frequent (P < 0.05) in blacks (4%) than in Caucasians (20%). The former did not have adrenal antibodies. Similar ICA frequencies among Caucasians with IDDM in the U.S. and in Europe suggest that etiologic factors are similar in the two geographic regions. The lower frequencies of ICA in patients with IDDM onset before 5 yr of age suggest that some of these patients may have a different etiology and/or a more rapid disappearance of islet cell antigens than patients with a later onset.l The lower ICA frequencies in black patients can be explained by heterogeneity of IDDM in this group and by admixture of IDDM susceptibility genes from the Caucasian genome to the black genome.

Thyroid microsomal, gastric parietal, and adrenocortical autoantibodies were sought in 1456 Caucasian and 240 black patients with insulin-dependent diabetes mellitus (IDDM), in 1467 of the Caucasian patients' immediate family members, and in 1519 normal Caucasian control subjects. Positive clinical significances and predictive values of these autoantibodies for associated gland dysfunctions were found. In all groups, thyroid and gastric autoantibodies were more common in female subjects. In the control group, thyroid and gastric autoantibodies were more frequent with advancing age, affecting more than one-third of Caucasian women after age 60 yr. This age-augmented increase occurred very prematurely in patients with IDDM and their relatives. Among the patients with IDDM and thyroid and gastric autoantibodies, these autoantibodies appeared by the time of onset of IDDM in the large majority of cases; however, they were more common among patients with later ages of onset of IDDM. Occurrence of thyroid and gastric autoantibodies in 404 siblings of patients with IDDM was not affected by their degree of HLA-haplotype sharing with their diabetic sibling, suggesting that the inherited predisposition to thyroid and gastric autoimmunity is not HLA-related. In light of this, the increased frequencies of these antibodies in patients with IDDM and their relatives suggest that "thyroid and gastric autoimmunity genes" may also predispose to IDDM.

Recent studies have shown that insulin autoantibodies occur in patients with newly diagnosed insulin-dependent diabetes mellitus (IDDM) before exogenous insulin treatment. Our study was designed to test the hypothesis that insulin autoantibodies, like cytoplasmic islet cell antibodies (ICAs), can identify individuals with ongoing autoimmune beta-cell destruction and increased risk of IDDM development. Insulin autoantibodies detected by use of a radioligand-binding assay were found in 1.4% of normal controls, 4% of first-degree relatives of IDDM patients, and in 37% of newly diagnosed IDDM patients. A strong positive correlation between insulin autoantibodies and ICAs was observed. HLA typing of insulin-autoantibody-positive first-degree relatives of IDDM patients, as well as in the general population, revealed a strong association with HLA-DR3 and/or-DR4, suggesting that insulin autoantibodies are restricted to persons genetically susceptible to IDDM. In an ongoing study of beta-cell function in ICA-positive nondiabetic individuals, the additional presence of insulin autoantibodies significantly increased the likelihood of beta-cell dysfunction. After intravenous glucose stimulation, insulinopenia was present in 70% of ICA and insulin-autoantibody-positive individuals in contrast to only 23% of ICA-positive, insulin-autoantibody-negative persons. These data document a significant association between insulin autoantibodies and ICAs and support the contention that insulin autoantibodies, like ICAs, are markers of ongoing beta-cell destruction.

Autoantibodies to the adrenal cortex (AA) were sought by indirect immunofluorescence using unfixed human adrenal tissue in 1675 patients with insulin-dependent diabetes (IDD), 2032 relatives of patients with IDD, and 2543 normal subjects. The frequencies of AA were significantly greater in patients with IDD (1.8%) and their relatives (1.4%) than in normal subjects (0.6%; P less than 0.013). Women more frequently had AA than men (P less than 0.011). There were no differences in the frequencies of AA between caucasoid and black individuals in all three patient groups. Patients with AA had higher frequencies of thyroid microsomal and gastric parietal cell autoantibodies than age-, sex-, and race-matched normal subjects (P less than 0.01). Adrenal function was studied in 30 asymptomatic patients (13 with AA, including 5 with IDD, and 17 subjects with no AA, including 8 with IDD). The mean plasma levels of ACTH at 0600 and 2000 h were significantly higher in those with AA than in matched subjects with no AA (P less than 0.01). The mean PRA levels (both recumbent and upright) were also significantly higher in those with AA than in subjects without AA (P less than 0.01). However, serum cortisol and aldosterone concentrations or 24-h urinary cortisol and aldosterone excretion were no different between the groups. These patients, therefore, appear to have compensated adrenal hypofunction, with the compensation maintained by increased ACTH and renin secretion. Whether these patients will remain in this compensated state of adrenal dysfunction or whether they will develop overt adrenal insufficiency requires longer follow-up.

Islet cell antibodies (ICA) are associated with insulin-dependent diabetes mellitus (IDD) and have been proposed as predictive markers for the disease. To determine whether ICA result from the activation of single autoreactive B-lymphocyte clones or are the result of polyclonal B-cell activation, we assayed ICA using polyvalent antisera specific to kappa or lambda light chains as well as monoclonal antibodies to IgG1, IgG2, IgG3 and IgG4 heavy chains by indirect immunofluorescence. Sera from 38 newly diagnosed IDD patients with IgG-ICA titers greater than 1:8 by end-point dilution were studied. ICA of both kappa and lambda light chains were present in all sera. The ICA were predominantly of the IgG1 subclass (38/38), although ICA were also found to be IgG2 in 53% (20/38), IgG3 in 29% (11/38) and IgG4 in 16% (6/38). The distribution of IgG heavy chains in ICA was compared to the ICA titer, age of onset of IDD and HLA-DR phenotype of the patient. No statistical correlation could be detected at a P value less than 0.05. Our findings more likely exclude the occurrence of a single aberrant lymphocyte clone secreting ICA that may have arisen by somatic mutation in individual patients. Rather, these results are consistent with the hypothesis that ICA arise by polyclonal B-lymphocyte activation as a result of a defect of immune regulation. Since human antibodies to protein antigens are found predominantly in the IgG1 subclass, our findings support the belief that the autoantigen involved in the stimulation of ICA formation is comprised, at least in part, of protein.

We have determined thyroid microsomal and gastric parietal cell autoantibodies in 972 patients with onset of Type 1 (insulin-dependent) diabetes before age 20 years. In a cross sectional study, the frequencies of these autoantibodies did not change significantly over the ensuing 20 years following diagnosis of diabetes. In a longitudinal study of 424 patients with Type 1 diabetes followed up to 5.3 years, few new patients with thyro-gastric autoantibodies were identified. Whereas the frequencies of these autoantibodies among the diabetic patients were more than fivefold greater than for age, sex and race matched controls, they resembled those seen in the non-diabetic general population (n = 1524) for the over 60 year age group. We conclude that in patients with thyro-gastric autoantibodies and Type 1 diabetes, the onset of autoimmune processes affecting the thyroid, gastric mucosa and pancreatic islets tend to be simultaneous, although the resultant diseases have different natural histories.

The frequency and significance of gastric parietal cell autoimmunity was assessed in 771 patients with insulin-dependent diabetes (IDD) of onset before 30 yr of age. Gastric parietal autoantibodies (PCA) were found 4 times more frequently in the patients with IDD (9%) than among 600 matched nondiabetic controls (2%). Caucasian female patients with IDD had PCA twice as frequently as male patients. Thyroid microsomal autoantibodies were more frequent in patients with IDD and PCA, than in those with IDD alone (Caucasian 46% versus 18%, black 25% versus 2.5%). A history of pernicious anemia and/or PCA was found in 25 or 40 families of IDD probands with PCA. Achlorhydria was demonstrated in 6 of 11 patients (54%) with PCA but in none of seven IDD patients without PCA. The six patients with achlorhydria had significantly lower uptakes of oral radiolabeled cobalamin, lower serum cobalamin levels, lower intrinsic factor-R protein ratios in their gastric aspirates, and lower plasma ferritin levels than patients with IDD but without PCA. None of the study group had IF antibodies in their serum or gastric juice. Overt pernicious anemia and neuropathy were found in one patient with PCA. Young patients with IDD at risk for atrophic gastritis and cobalamin deficiency can initially be identified by screening for PCA. Many of these young patients with PCA already have achlorhydria and evidence of decreased absorption of cobalamin. These patients can then be followed with cobalamin levels and/or with complete blood counts to identify those requiring therapy.

The sera from 325 normal individuals, 21 patients with Turner's syndrome, 505 patients with insulin-dependent diabetes mellitus, 15 patients with unexplained ovarian insufficiency, and 37 patients with Addison's disease or serological evidence of adrenal autoimmunity were examined for the presence of gonadal autoantibodies by an indirect immunofluorescent technique using sections of human testis. All 12 patients found to have gonadal autoantibodies also had adrenocortical autoantibodies. These autoantibodies were completely absorbed with powdered adrenal cortex and thus were "steroidal cell" antibodies (SCA), cross-reactive with a cytosolic antigen in the steroid-producing cells of adrenal cortex, placental syncytiotrophoblast, Leydig areas of testis, and theca interna/granulosa layer of ovarian follicles. Sera with SCA had reduced titers of adrenal antibodies after repeated absorptions with gonadal or placental tissues, suggesting that adrenal-specific autoantibodies were also present. Sera from patients with only adrenal antibodies had no significant changes in antibody titers after repeated absorptions with gonadal or placental tissues. In conclusion, all gonadal autoantibodies found were SCA. SCA were only found in patients with adrenal autoimmunity, many of whom had hypogonadism. In other patients or in normal individuals, the existence of SCA or gonadal autoimmunity in the absence of adrenocortical autoantibodies must be rare.

The frequency and significance of cytoplasmic pancreatic alpha cell autoantibodies (ACA) were investigated in 2102 healthy controls, 879 patients with insulin-dependent diabetes mellitus (IDDM) who were negative for islet cell autoantibodies (ICA), and 1567 relatives of IDDM patients. ACA were found in approximately 1 in 200 people of all ages and were not significantly associated with IDDM, the IDDM-associated HLA phenotypes DR3 and DR4, or thyrogastric or adrenal autoantibodies. Of 11 ACA-positive patients studied by arginine stimulation tests, none had frank glucagon deficiency. Thus, ACA do not appear to be associated with defective alpha cell function or with IDDM.

Of 771 young diabetic patients, thyroid microsomal autoantibodies occurred in 136 (17.6%) at a female/male ratio of nearly 2:1 and with a predominance of white patients (20.1%) over black patients (5.5%) (P less than 0.001). Thus, one in every four white female patients with insulin-dependent diabetes mellitus had TMA. Thyroglobulin autoantibodies were no more common in patients with IDDM than among controls. Of the 117 patients (out of the 136) with serologic evidence of chronic thyroiditis who could be studied, eight (7%) had hyperthyroidism and 45 (38%) were hypothyroid. Hyperthyroidism usually preceded or coincided with the appearance of IDDM, whereas hypothyroidism occurred with or following the onset of IDDM. Hypothyroidism appeared irreversible in most patients, but in three, periods of hypothyroidism were followed by euthyroidism, presumably explained by a compensatory hyperplasia of the thyroid gland. In the 136 patients with TMA, gastric and adrenocortical autoantibodies also occurred at relatively high frequencies (16.8% and 5.1%, respectively). On the basis of these studies, we urge that all patients with IDDM be screened for TMA and that those with positive results undergo annual thyroid function tests as well as determinations of gastric parietal and adrenocortical autoantibodies.

Three patients demonstrated transient neonatal hypothyroidism, presumably secondary to maternally derived thyrotropin (TSH)-blocking antibodies. Although transient, this disorder might not have been benign in the first child, who exhibited significant developmental delay. A thyroid scan was not helpful in making this diagnosis. Although uncommon, this disorder should be suspected in infants with a maternal history of autoimmune thyroid disease, multiple siblings with congenital hypothyroidism, or a clinical course characterized by continually suppressed TSH levels, despite low doses of levothyroxine sodium replacement. Measurement of TSH-blocking antibodies may be used in the diagnosis of transient neonatal hypothyroidism at birth and is becoming more readily available from reference laboratories. Once diagnosed, the patient may then be prepared for monitored withdrawal of levothyroxine replacement therapy at 2 to 3 years of age and will not be committed to lifelong replacement therapy.

Stored sera from 466 patients with insulin-dependent diabetes mellitus and from 144 controls were examined for organ-specific antibodies to human adrenal cortex. Adrenal antibodies were found in seven of the patients with IDDM (1.5%) and in one control (0.7%). None of 91 black patients with IDDM had adrenal antibodies. All of the seven patients with adrenal antibodies had other organ-specific antibodies. Three had clinical hypothyroidism and one was thyrotoxic. All of these seven patients had a HLA-B8-bearing haplotype, suggesting that the B8-bearing haplotype confers an extremely high "relative risk" for adrenal autoimmunity in IDDM. Organ-specific autoimmune disease and/or organ-specific antibodies were found in 30% of the first-degree relatives of these eight probands with the adrenal antibodies (seven with IDDM and one control). We conclude that screening patients with IDDM for adrenal antibodies of low yield (1.9% among white patients). Further, adrenal antibodies may be present for at least two years without the development of Addison disease. Antibodies reactive only to the zona glomerulosa of the adrenal cortex may be benign. Patients with IDDM and thyroid microsomal antibodies are more likely to have adrenal antibodies (6.5%), as are patients with IDDM and a B8-bearing haplotype and those with IDDM and family histories of organ-specific autoimmunity.

A quantitative fluid-phase radioassay for autoantibodies reacting with insulin (competitive insulin autoantibody assay, CIAA) was developed. The assay's features include 1) use of a physiologic amount of 125I-labeled insulin, 2) parallel incubations with supraphysiologic cold insulin (competitive), and 3) an incubation time of 7 days and a single-step multiple-wash polyethylene glycol separation. Mean +/- SE CIAA levels in 50 controls were 8 +/- 1.4 nU/ml (range -16-33.3). In 36 cytoplasmic islet cell antibody (ICA)-positive nondiabetic first-degree relatives of type I (insulin-dependent) patients less than 30 yr of age, CIAA levels exceeded the normal range in 20 (55.6%) of 36 (mean 86.8 +/- 17.1 nU/ml). In 26 ICA-positive relatives greater than 30 yr of age, only 5 (19.2%) of 26 exceeded the normal range (mean 26.1 +/- 9.4 nU/ml); P less than .001 compared with younger ICA-positive relatives). Six ICA-negative HLA-identical siblings of type I diabetic patients had normal CIAA levels (mean 3.6 +/- 5.8 nU/ml), and only 2 of 13 ICA-negative identical twins discordant for diabetes (mean 15.4 +/- 6.6 nU/ml) exceeded the normal range. Nine (50%) of 18 ICA-positive schoolchildren exceeded the normal range (mean 105.3 +/- 36.7 nU/ml). Genetically susceptible subjects negative for CIAA (with only 3 exceptions) remained negative for CIAA on multiple determinations (3 conversions observed), and CIAA levels of positive subjects were relatively stable. Linear regression of the first CIAA level versus last (interval between sampling 1 mo to 10 yr) in genetically susceptible individuals showed a highly significant correlation (r = .95, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)