Twelve of 129 black patients with youth-onset diabetes were identified as having an unusual clinical course, with apparent insulin dependence at the time of presentation followed by absence of ...dependence months to years later. This atypical form of diabetes was found in at least two generations in 9 of the 12 families of the propositi. Fourteen of the diabetic relatives, as well as the 12 propositi, were studied. Islet-cell autoantibodies were not found in any of the patients, and thyroid microsomal auto-antibodies were found in only one. The frequencies of the insulin-dependent-diabetes-associated antigens HLA-DR3 and DR4 were not increased among the propositi, and diabetes did not cosegregate with HLA haplotypes in the informative families. Insulin secretion, as measured by C-peptide responses to a liquid mixed meal (Sustacal), was intermediate between secretion in nondiabetic controls and that in patients with classic insulin-dependent diabetes. Peripheral-blood monocytes expressed increased numbers of insulin receptors as well as decreased empty-site affinities. The atypical form of diabetes in black Americans can be distinguished from classically defined insulin-dependent diabetes and may be best classified as a form of maturity-onset diabetes of youth.
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.
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.
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.
We randomly assigned 46 patients (mean age, 11.7 years; range, 4.5 to 32.8) with newly diagnosed insulin-dependent diabetes mellitus within two weeks of beginning insulin to receive either ...corticosteroids for 10 weeks plus daily azathioprine for one year or no immunosuppressive therapy. Half the 20 immunosuppressed patients completing the one-year trial had satisfactory metabolic outcomes (hemoglobin A1c less than 6.8 percent; stimulated peak C peptide greater than 0.5 nmol per liter; insulin dose less than 0.4 U per kilogram of body weight per day) as compared with only 15 percent of the controls. Three of 20 immunosuppressed patients, but no controls, were insulin independent at one year. Two of these continue to receive azathioprine without insulin after more than 27 months of follow-up. The response to immunosuppression correlated with older age, better initial metabolic status, and lymphopenia (less than 1800 lymphocytes per cubic millimeter) resulting from immunosuppression. The side effects of azathioprine included vomiting in one patient and mild hair loss in several others. Prednisone use resulted in a transient cushingoid appearance, weight gain, and hyperglycemia. The growth rate remained normal in all patients. We conclude that early immunosuppression with short-term use of corticosteroids plus daily azathioprine can improve metabolic control in some patients with insulin-dependent diabetes mellitus, but results from this unblinded study are preliminary and require further confirmation and long-term follow-up.
In making a decision to redesign a cramped or inefficient maintenance facility within a built urban environment, the cost of relocation must consider the change in operating costs due to rerouting ...transit routes and potentially changed deadhead costs (i.e., those costs associated with the trip a bus vehicle takes between the maintenance base and the start or end of a route). A sketch-level method for estimating bus deadhead costs that can serve as an input to high-level decision-making processes is described. In a recent analysis for TransLink in Vancouver, British Columbia, Canada, this methodology helped to quantify the total net change in deadhead costs associated with various location options. A geographic information systems (GIS) tool was used to calculate the shortest path among alternative maintenance base locations and start and end points of bus routes. Shortest-path calculations were based on estimated travel speeds, congestion, and known geographic constraints provided by the operator. Total deadhead-related costs were then estimated for each of the three maintenance base location options under consideration. The difference between these costs served as one component in the decision-making process, along with other factors such as property acquisition and construction cost. This analysis serves as an example of how GIS use can provide a low-cost sketch-planning tool to inform investment decisions.
Development of IDDM after donating kidney to diabetic sibling.
W J Riley ,
N K Maclaren and
R P Spillar
Department of Pathology and Laboratory Medicine, University of Florida, Gainesville.
Abstract
...The goal of this study was to describe a patient who developed insulin-dependent diabetes mellitus (IDDM) after donating a
kidney to his sibling and to suggest a possible solution to prevent such an occurrence. A 42-yr-old man was found to have
islet cell autoantibodies (ICAs) as part of a screening program of first-degree relatives with IDDM. Two years previously,
he had donated his kidney to his HLA-identical sibling with long-standing IDDM. Both oral and intravenous glucose tolerance
tests demonstrated a gradual loss of insulin secretion and increasing glucose intolerance until the patient developed IDDM
6 yr after the nephrectomy. Whether the presence of ICA is an absolute contraindication to being a kidney donor could be debated.
Nonetheless, ICA should be used as a screening test to identify individuals at risk for subsequent IDDM. For those found to
be positive, counseling should be provided.
Youngster's knowledge about insulin-dependent diabetes was assessed across three domains: (1) general information; (2) problem solving and (3) skill at urine testing and self-injection. These ...youngster's parents completed the general information and problem-solving components of the assessment battery. All test instruments were showed good reliability. The test of problem solving was more difficult than the test of general information for both parents and patients. Mothers were more knowledgeable than fathers and children. Girls performed more accurately than boys, and older children obtained better scores than did younger children. Nevertheless, more than 80% of the youngsters made significant errors on urine testing and almost 40% made serious errors in self-injection. A number of other knowledge deficits were also noted. Duration of diabetes was not related to any of the knowledge measures. Intercorrelations between scores on the assessment instruments indicated that skill at urine testing or self-injection was not highly related to other types of knowledge about diabetes. Furthermore, knowledge in one content are was not usually predictive of knowledge in another content area. The results of this study emphasize the importance of measuring knowledge from several different domains. Patient variables such as sex and age need to be given further consideration in the development and use of patient educational programs. Regular assessment of patients' and parents' knowledge of all critical aspects of diabetes home management seems essential.
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.
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