Rebecca Spillar

A Prospective Study of the Development of Diabetes in Relatives of Patients with Insulin-Dependent Diabetes

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.

Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus.

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.

Maturity-Onset Diabetes of Youth in Black Americans

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.

Thyroid autoimmunity in insulin-dependent diabetes mellitus: The case for routine screening

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.

The effects of a peer-modeling film on children learning to self-inject insulin

This study investigated the effects of a peer-modeling film on anxiety reduction and skill acquisition in children learning to self-inject insulin. Twenty-eight insulin-dependent children, aged 6–9 years and attending a summer camp for youngsters with diabetes, were randomly assigned to view a peer-modeling film of children learning self-injection or another film addressing nutrition. Immediately after viewing the film, the children were taught to self-inject insulin. Physiological, self-report, and observational measures were obtained at several points during the experiment and at a follow-up, 4 days later. There was little evidence indicating that the children were anxious, preventing assessment of the films utility in anxiety reduction. On the other hand, the oldest girls viewing the peer-modeling film showed greater skill in self-injection than their counterparts viewing the nutrition film. The importance of age, sex, and previous experience as variables potentially affecting a modeling films utility was discussed.

INHERITED SUSCEPTIBILITY TO INSULIN-DEPENDENT DIABETES IS ASSOCIATED WITH HLA-DR1, WHILE DR5 IS PROTECTIVE

Of the HLA allelic associations with insulin-dependent diabetes (IDD) reported to date. DR3 and DR4 have been the most positive and DR2 the most negative. In 952 Caucasian proband patients reported here, only 57 or 6% had no DR3 or DR4 alleles. When these 57 patients were compared to 249 Caucasian controls similarly lacking DR3 and DR4 antigens, there were excesses of DR1 (P = 0.13) and DRW8 (P = 0.01) and deficiencies of DR2 (P = 0.03) and DR5 (P = 0.03) in the patient group. The most common phenotype in this group of patients was DR1/DR7 (12.3%). Only four DR-homozygous patients involving alleles other than DR3 and DR4 were found by genotyping, and all were DR1 homozygotes. Among 506 patients wuth DR3/DRX or DR4/DRX phenotypes, DR1 was more frequent (P = 0.001; Bonferronni P = 0.006), and DR2 (P = 0.001) and DR5 (P = 0.001) less frequent than 243 HLA-matched controls. Of 187 patients with a single DR3 and no DR4, DR1 was more frequent (P = 0.02), with DR2 (P = 0.001) and DR5 (P = 0.02) less frequent than 94 HLA DR-compatible controls. Among 319 patients with a single DR4 but no DR3, DR1 was again more frequent (P = 0.01) and DR2 (P = 0.001) and DR5 (P = 0.001) less frequent than 149 HLA-matched controls. We conclude that DR1 is an additional risk DR allele for IDD to that of DR3 and DR4, and DR5 an additional protective DR allele to that of DR2.

correlates of biopsy-studied nephropathy in young patients with insulin-dependent diabetes mellitus

We have correlated pathologic findings in kidney biopsies from 12 adolescents with proteinuria or hypertension with severity of limited joint mobility (LJM) and retinopathy. We compared mean glucosylated hemoglobin (GHB) and clinical findings in these patients with those in patients without proteinuria or hypertension. Severity of LJM correlated with basement membrane thickening. Protein excretion correlated with degree of mesangial matrix increase and basement membrane changes. Retinal changes were related to basement membrane thickness and duplication. Despite treatment, blood pressures were significantly higher in patients with nephropathy than in the comparison group. Glycemic control status was generally poor and did not correlate with pathologic changes. The narrow spectrum of control did not permit assessment of possible effects of milder metabolic derangement. However, the similarity of GHB values in the groups with and without nephropathy implicates other factors. The group with clinical nephropathy had more LJM than did the comparison group, reaffirming LJM as a risk factor for early microvascular disease. Biopsy changes of nephropathy may begin relatively early in the course of diabetes (less than 7 years in three of our patients) and is already advanced when proteinuria appears.

Accuracy of Two Systems for Blood Glucose Monitoring without a Meter (Chemstrip/Visidex)

Blood specimens collected from 159 campers were tested using Visidex (VD) (Ames Company, Elkhart, Indiana) and Chemstrip (CS) (Bio-Dynamics, Boehringer Mannheim, Indianapolis, Indiana) compared with glucose analyzer (GA) results. Readers were physicians, two with no prior experience using either strip and two with some experience using CS. Subsequently, 30 clinic patients and 4 staff contributed random specimens that were read by a trained novice as 68 discrete samples and compared with GA results. In both studies readers did not place blood on the strips and were thus blinded as to source and the possible previous reading with the other strip. Correlations of VD and CS with GA for camp and clinic data were calculated. Data were compared for reliability and errors greater than 20% of reference values (GA) were compared for VD and CS. CS correlated better with GA than did VD estimates. Reliability was also significantly greater for CS than for VD readings. Both of these visually read methods provided clinically useful estimates of glycemia.

Ambulatory Diabetes Management with Pulsed Subcutaneous Insulin Using a Portable Pump

A portable pump, programmed to administer intermittent pulses of insulin subcutaneously, supplemented by premeal boluses, was used by 8 patients for periods up to 12 months. Two boys, 11 and 16 years of age, sought improved growth; four young adults age 19 to 26 years desired normalization of metabo lism to forestall microvascular complications already manifest; a 14-year-old girl had been incapacitated by unstable diabetes and a 26-year-old woman had been unable to attain sufficient control to gain weight without developing hypoglycemia. Maximal possible control with conventional insulin administra tion was attempted prior to pump use and such control was measured by glycohemoglobin (HgbA1) percentage and urine and blood sugar levels during a 24-hour period and compared with control with pump use. All initially had marked reduction in 24-hour urine volume (mean 3.3 L ± 4 SEM to 1.4 ± 0.2), urine glucose (mean 198 g ± 81 to 14 ± 4) and glycemia (mean 258 mg/dl ± 29 to 133 ± 12). HgbA1% declined markedly in all but the 14-year-old girl over the first weeks and reached normal or near normal levels in three patients. Four patients continued to use the pump after 3.5 to 12 months because of improved sense of well being, weight control, and in one, marked reduction in proteinuria. Both boys had a doubling of growth pace. Four patients are no longer using the pump after 3 to 8 months because of incon venience, manipulation with intermittent usage, intolerance of normoglycemia, or overzealous control attempts with dangerous hypoglycemia. Pump use may permit the attainment of levels of control previously not possible, but is extremely demanding for patients and health personnel and must remain an experimental method in carefully selected and monitored patients.

Development of IDDM After Donating Kidney to Diabetic Sibling

The goal of this study was to describe a patient who developed insulin-dependent diabetes mellitus (IDDM) after donating a kidney to his sibling andto 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 screeningprogram 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.