We evaluated the production of antibodies against insulin in a genetically well-defined population. In the first study, 124 young patients with type I diabetes for longer than 6 mo were included. Anti-insulin antibodies were detected by polyethyleneglycol (PEG) precipitation after incubation of acidified, charcoal-stripped sera with 125I-labeled pork insulin and were expressed as microunits insulin bound per milliliter whole serum. For comparison, the patients were divided into six groups based on HLA DR antigens: 3/3, 3/-, 4/4, 4/-, 3/4, and -/-(-is non-DR3 or -DR4). The mean age of the patients was 14.7 +/- 0.5 yr; the duration of diabetes was 5.8 +/- 0.4 yr; and the glucose control, as measured by hemoglobin A1c was average (7.6 +/- 0.2%). There were no significant differences in any of these parameters among the patients in any of the HLA DR groups. Patients expressing DR3/3 had significantly lower insulin binding than the rest of the groups (2.5 +/- 0.4 vs. 13.6 +/- 1.4 microU/ml, P less than 0.0001). Patients with DR3/ - did not differ in insulin-binding capacity from the other groups. The type of insulin used for replacement was not correlated with the serum insulin-binding capacity. In a second study, sera from 48 children, newly diagnosed with type I diabetes, were examined for the presence of insulin binding before treatment with exogenous insulin and compared with sera from 80 children without diabetes or a family history of diabetes and from 103 unaffected HLA-identical or haploidentical siblings of a child with type I diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARYThyroid autoantibodies are common in Type I diabetics and their first degree relatives and may be part of the autoimmune diathesis present within such families. We have measured the prevalence of microsomal (M‐Ab) and thyroglobulin (Tg‐Ab) autoantibodies in 84 HLA‐typed families having a Type 1 diabetic child, using enzyme‐linked immunosorbent assay techniques. Thyroid autoantibodies were detectable in 201/407 (49%) individuals in these families. Both autoantibodies were significantly more frequent in the subsets of parents, diabetic children and their non‐diabetic siblings than in groups of control adults and children. The prevalence of these autoantibodies in the diabetic families was increased in both sexes with a female:male ratio of 1.4:1. Antigen DR5 was significantly associated with M‐Ab production but only for male subjects (P= 0.005 after correction for the number of DR antigens tested). No significant associations were encountered for Tg‐Ab. Within‐family analyses indicated that thyroid autoantibodies occurred with increased prevalence in HLA‐identical or haplo‐identical siblings of autoantibody‐positive index cases in comparison to control children. We conclude (1) the DR association with thyroid autoantibody production in this diabetes‐selected population was thyroiditis‐related and not diabetes‐related, and (2) the DR5 association was restricted to males and the production of M‐Ab. These data are consistent with the hypothesis that multiple genetic and non‐genetic factors played a role in the high prevalence of thyroid autoantibodies in this population.

Clinically significant proteinuria indicates a poor renal prognosis in IDDM patients. Microalbuminuria presages worsening proteinuria. Other techniques to evaluate proteinuria may allow an earlier prediction of nephropathy in time to use aggressive therapy to alter morbidity. We analyzed the patterns of proteinuria in 14 IDDM patients (compared with 8 controls) by a novel protocol utilizing spot (random, resting, single void) urines. All patients had < 1 gm/day proteinuria. Diabetic patient characteristics(diab indices): ages 3-24, duration diabetes 1.5-16 yrsf mean HgbA1c(mHA) 4.6-8.6%(nl<4.8%), current HgbA1c 3.4-10.9%. Spot urines were: obtained sterilely, mlcropore filtered, dialyzed, lyophylized, subjected to sodium dodecyl sulphate polyacrylamide GE, stained with Coomassie Blue and then analyzed by an automatic gel scanner/integrator. Peaks were grouped into the following fractions: %albumin(alb), %high molecular weight(haw,>alb>, %low molecular weight(1mw,

A longitudinal investigation was conducted from 1977 to 1984 on 178 families in which one or more of the children had insulin-dependent diabetes mellitus. Of 351 nondiabetic sibs followed up for an average of 54 months, ten have, thus far, become diabetic. Eight sibs were HLA identical to their diabetic proband and nine had HLA-DR3 and/or HLA-DR4. Islet cell surface antibody and islet cell cytoplasmic antibody were found from two to 74 months before the onset of clinical diabetes in 100% and 90%, respectively, of the children. A decrease in insulin secretion was observed in all of these children on entry into the study and was detected in the absence of elevated plasma glucose concentrations. The data suggest that the triad of HLA identity, pancreatic islet cell antibodies, and depressed insulin secretion identifies those sibs who are at high risk of developing insulin-dependent diabetes mellitus.

An increased incidence of insulin-dependent diabetes mellitus (IDDM) has been reported in patients with congenital rubella syndrome (CRS). Thus, studies of children with CRS would be of great importance in following the development of IDDM in a susceptible population. A total of 242 children with CRS, 30 of whom already have diabetes (mean age, 17.4 +/- 0.3 years) have been evaluated. In this latter group, the frequency of HLA DR3 is significantly increased and that of HLA DR2 significantly decreased. While pancreatic islet cell cytotoxic or surface antibodies (ICSA) are found in 20.2% of the total population of patients with CRS, they are present in 50%-80% of patients with glucose abnormalities. In all but five of the ICSA-positive patients, glucose abnormalities are currently present. In addition, glucose intolerance is found in greater than 50% of the DR3-positive nondiabetic patients with CRS evaluated to date. The data demonstrate that patients with CRS at risk for IDDM have the same genetic and immunologic features seen in classic IDDM, namely the presence of HLA DR3 and the absence of HLA DR2 and the high prevalence of ICSA before decompensation.

Cytoplasmic pancreatic islet cell antibodies were found in 21% of 244 unaffected first degree relatives of type I diabetic patients. Twenty-five percent of HLA-identical, 35% of HLA-haploidentical, 16% of HLA-nonidentical siblings, and 14% of parents were ICA-positive. In the HLA-identical sibs, irrespective of ICA, and in the 18 ICA-positive parents but not the other groups, increased plasma glucose levels were observed after the administration of glucose. In most children, these were associated with reduced insulin levels, while in the adults elevated insulin responses were noted. In 48% of the ICA-positive children and 84% of the ICA-positive parents, other evidence of "autoimmunity" was obtained either by history or by testing for specific autoantibodies. Two of the originally unaffected HLA-identical and ICA-positive siblings developed diabetes during the course of the study. These findings, plus previously reported data in families with two diabetic sibs demonstrating that the empiric risk for developing IDDM is of the order of 30% for HLA-identical sibs but less than 5% for those that are HLA-haploidentical, suggest that HLA-identity may be a useful predictor of potential type I diabetes. The presence of ICA may, at times, portend the need for future antidiabetic therapy but prospective studies must be continued to fully elucidate this relationship.

• An adolescent girl with factitious Cushing's syndrome underwent several years of intricate (and expensive) laboratory investigations before she was discovered to have been taking large doses of prednisone. (Am J Dis Child1981;135:852-853)

A de novo bisatellited derivative of chromosome 15, inv dup (15) (pter→q11 or 12::p11 or q11 or 12 →pter), was identified by multiple banding techniques in a patient with Prader‐Willi syndrome. A comparison of familial no. 15 short arm polymorphisms indicated that the extra chromosome was the result of a non‐sister chromatid exchange between the paternal no. 15 homologs prior to or during meiosis.

The recent demonstration that glycosylated hemoglobin measurements correlate with integrated blood glucose levels over the preceding 1 to 2 months and the mounting experimental evidence that maintenance of normal blood glucose levels may reduce diabetic complications, suggests that early vigorous treatment of newly diagnosed juvenile diabetics, monitored by Hb A1C measurements, may be important in the long-range managements of these children. Fifteen youngsters, ages 3 to 18, were studied at the time of diagnosis of insulin-dependent diabetes and sequentially at 1 to 2 months intervals. Initial concentrations of Hb A1C were 8.6±1.2% of total hemoglobin (normal, non-diabetic children 2.2-4.8%), indicating the presence of hyperglycemia for a significant period of time prior to diagnosis. Within 4 to 6 weeks after diagnosis and placement of the children on a therapeutic regimen designed to promote normoglycemia, Hb A1C values declined to 5.4±0.9% and were maintained at these levels in 12 of the 15 patients for periods ranging up to one year. No significant hypoglycemic reactions occurred in any of the children on the "tight control" protocol which included high protein meals plus 3 snacks per day, daily afternoon exercise and a combination of intermediate and short acting insulin given once or twice per day. The results indicate that it is possible to maintain insulin dependent diabetic children in a relatively euglycemic state that can be monitored sequentially by Hb A1C determinations.