This chapter contains section titled: Materials and Methods Results Discussion Summary References Discussion

OBJECTIVE:We sought to determine the role of the acute insulin secretory response to glucose (AIRg) in predicting weight gain in normoglycemic persons with no family history of diabetes, who are at low risk for development of disease.RESEARCH METHODS AND PROCEDURES:One hundred five individuals (64 men and 41 women) who underwent measures of weight and AIRg and insulin sensitivity index (S(I)) by intravenous glucose tolerance test between 1963 and 1983 were surveyed again for weight between 1994 and 1999, with a mean follow-up of 26 +/- 4 years.RESULTS:Mean change in weight was 8 +/- 10 kg. Annualized weight change was calculated as change in kilograms divided by change in year and averaged 0.27 +/- 0.04 kg/yr. Dividing the cohort by either median AIRg or median S(I) demonstrated no association of either AIRg or S(I) with total or annualized weight gain. Subgroup analysis by ideal body weight or gender did not alter the association. Furthermore, no association between AIRg and weight gain rate was seen within insulin-sensitive or -resistant subgroups, although younger age at entry was associated with greater rates of weight gain.DISCUSSION:Our data suggest that neither AIRg nor S(I) plays a role in predicting weight gain in normoglycemic individuals with no family history of diabetes.

Previous studies suggest that after 6 years of discordance, identical twin pairs rarely become concordant for type I diabetes. With up to 39 years of follow-up from the onset of diabetes in the index twin, we determined how many discordant twins have evidence of beta-cell autoimmunity and how many develop overt diabetes. We longitudinally followed 23 pairs of identical twins (or triplets) that were selected from a total group of 30 pairs because they were discordant for type I diabetes when first ascertained. Seven developed diabetes after 3, 3, 7, 8, 9, 31 and 36 years of discordance. By survival analysis, the concordance after 10 years from the onset of diabetes in the index twin was estimated as 23% (95% confidence interval, 5-40%), increasing to 38% (95% confidence interval, 8-69%) after 31 years. Among 16 twins remaining nondiabetic at last follow-up (8-39 years of discordance), 12 were assessed with serial intravenous glucose tolerance tests and a total of 407 measurements by radioassay of antibodies against three defined autoantigens (glutamic acid decarboxylase, insulin, and the recently cloned molecule ICA512). Two-thirds (8 of 12) had evidence of beta-cell autoimmunity (persistently positive autoantibody levels) and/or first-phase insulin release less than the 1st percentile of control subjects. In summary, identical twins may develop diabetes after a prolonged period of discordance and approximately two-thirds of long-term discordant twins have evidence of persistent beta-cell autoimmunity and/or beta-cell damage. The concordance for beta-cell autoimmunity, therefore, is much higher than for overt diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

A significant proportion of relatives of patients with insulin-dependent (type I) diabetes with high titers of cytoplasmic islet cell autoantibodies (ICAs) do not progress to overt diabetes with up to 8 yr of follow-up. This may reflect that follow-up of such relatives has not been long enough to observe diabetes, that despite expression of identical ICAs, some relatives will not progress to diabetes; or that there is heterogeneity in what is identified as ICA. We identified a subset of ICA that was restricted in its species (not reacting with mouse islets) and cell-type reactivity within islets (β-cell specific). Only one of eight relatives whose sera had the restricted pattern of reactivity progressed to overt diabetes, and on sequential evaluation, all but the one relative who progressed to diabetes have maintained normal first-phase insulin secretion to intravenous glucose. In contrast, by life-table analysis, 70% of relatives expressing nonrestricted ICA became diabetic within 5 yr of follow-up (1 of 8 vs. 16 of 25 diabetic at last follow-up, P < 0.02). Moreover, preliminary data suggest a significant association of the human leukocyte antigen DQB1*0602 allele of DR2 haplotypes with the restricted ICA pattern (4 of 5 DQB1*0602 restricted vs. 0 nonrestricted ICA, P = 0.006). We propose that expression of a genetically determined restricted ICA pattern confers a markedly lower risk for progression to diabetes. Our studies suggest that relatives with restricted ICA may comprise most ICA+ relatives who do not develop diabetes or abnormal first-phase insulin secretion on follow-up of >5 yr and that expression of such autoantibodies may be associated with the ‘protective’ DQB1*0602 allele.

First-degree relatives of patients with insulin-dependent (type I) diabetes (n = 264 from 106 families) were evaluated with HLA typing and determination of competitive insulin autoantibodies (CIAAs) and islet cell autoantibodies (ICAs). The levels of CIAAs in 30 relatives exceeded our upper limit of normal (≥39 nU/ml), and 30 had high-titer ICAs (≥40 Juvenile Diabetes Foundation units [JDF U]). Eleven of the HLA-typed relatives developed diabetes during follow-up. Twenty-three percent (28 of 123) of the relatives with at least one HLA-DR4 allele were CIAA+ (CIAA ≥39 nU/ml) versus 4% (6 of 141) among DR4− relatives (P < 0.0001). Twenty-one of 22 of the highest CIAA values were all in the DR4+ group (DR4+ vs. DR4−, P = 0.003, Wilcoxon's rank-sum test). HLA-DR3 did not correlate with the level of CIAAs, and neither DR3 nor DR4 correlated with titer of ICAs measured in JDF U. We conclude that, in first-degree relatives of patients with type I diabetes, there is a striking association with HLA-DR4 in both the prevalence of relatives exceeding the normal CIAA range and in the level of CIAAs. These data suggest that a gene on HLA-DR4 haplotypes contributes to the level of anti-insulin autoimmunity, and we hypothesize that DR4-associated diabetes susceptibility, distinct from DR3-associated susceptibility, may be secondary to this influence.

AbstractThe relationship between the level of hemoglobin A1 (Hb A1) in the first trimester and major malformations and spontaneous abortions was examined in 303 insulin‐requiring diabetic gravidas. During the study period, all patients with insulin‐requiring diabetes mellitus antedating pregnancy who registered for prenatal care prior to 12 weeks' gestation and who had a known outcome were included. Thirty‐five percent of the patients entered with a first‐trimester Hb A1 of greater than 11.0% of total hemoglobin (9 standard deviations above the mean for a nondiabetic population). A broad spectrum of glycemic control was therefore represented. The risk of spontaneous abortion was 12.4% with first‐trimester Hb A1 ⩽ 9.3% and 37.5% with Hb A1 > 14.4% (risk ratio 3.0; 95% confidence interval 1.3–7.0). The risk for major malformation was 3.0% with Hb A1 ⩽ 9.3% and 40% with Hb A1 > 14.4% (risk ratio 13.2; 95% confidence interval 4.3–40.4). Although the risks for both adverse outcomes were markedly elevated following a first trimester in very poor metabolic control, there was a broad range of control over which the risks were not substantially elevated. To keep malformations and spontaneous abortions to a minimum among diabetic women does not require “excellent” control; there seems to be a fairly broad range of “acceptable” control.

The relationship between the level of hemoglobin A1 (Hb A1) in the first trimester and major malformations and spontaneous abortions was examined in 303 insulin-requiring diabetic gravidas. During the study period, all patients with insulin-requiring diabetes mellitus antedating pregnancy who registered for prenatal care prior to 12 weeks' gestation and who had a known outcome were included. Thirty-five percent of the patients entered with a first-trimester Hb A1 of greater than 11.0% of total hemoglobin (9 standard deviations above the mean for a nondiabetic population). A broad spectrum of glycemic control was therefore represented. The risk of spontaneous abortion was 12.4% with first-trimester Hb A1 less than or equal to 9.3% and 37.5% with Hb A1 greater than 14.4% (risk ratio 3.0; 95% confidence interval 1.3-7.0). The risk for major malformation was 3.0% with Hb A1 less than or equal to 9.3% and 40% with Hb A1 greater than 14.4% (risk ratio 13.2; 95% confidence interval 4.3-40.4). Although the risks for both adverse outcomes were markedly elevated following a first trimester in very poor metabolic control, there was a broad range of control over which the risks were not substantially elevated. To keep malformations and spontaneous abortions to a minimum among diabetic women does not require "excellent" control; there seems to be a fairly broad range of "acceptable" control.

Antibodies to insulin appear prior to the development of Type I diabetes and their concentration may correlate with the rate of autoimmune beta cell destruction. In order to study potential mechanisms involved in the production of antibodies to insulin, we transplanted different strains of mice with histoincompatible non-islet cells (AtT20-Ins and NIH-3T3-Ins) synthesizing homologous insulin, in contrast to immunization with non-transfected cells and insulin in Freund's adjuvant. The pituitary cell line (AtT20) and the fibroblast cell line (NIH-3T3) were transfected with the rat insulin-II gene (which encodes an insulin molecule identical to that of mouse insulin-II). No antibodies to insulin were found after subcutaneous injection of AtT20-control cells (without the integrated rat insulin gene) or after injection of rat insulin complete Freund's adjuvant. After subcutaneous injections of living AtT20-Ins or NIH-3T3-Ins cells producing insulin (40 to 60 ng insulin/106 cells per injection) in two strains (BALBcJ, C3HHeJ) but not in a third (SJLJ), antibodies to insulin rapidly appeared. In addition, when AtT20-Ins cells were transplanted into Wistar-Furth rats, insulin antibodies appeared in three out of four animals. The level of antibodies induced was similar to the concentrations of insulin antibodies of prediabetic NOD mice. This finding suggests that during the immune destruction of a cell synthesizing insulin, humoral ‘tolerance’ to insulin can be rapidly abrogated. Genetic control of this response is suggested by the difference between response of BALBcJ and C3HHe vs SJLJ.

Is non-insulin-dependent diabetes (NIDDM) a disease of insulin deficiency, a disease of insulin resistance, or both? This problem has confronted diabetologists and researchers for years.

Fifty-two normal non-obese males and 77 male offspring of two diabetic parents, aged 15-72 years, were studied to identify possible reasons for discordance between the oral glucose tolerance test (OGTT) and hemoglobin A1c (Hb A1c). Subjects were classified into four study groups: group 1 (n = 83), normal OGTT and normal Hb A1c; group 2 (n = 19), normal OGTT and abnormal Hb A1c; group 3 (n = 9), abnormal OGTT and normal Hb A1c; and group 4 (n = 18), abnormal OGTT and abnormal Hb A1c. Glucose and insulin response were analyzed in each study group. Group 2 showed slightly higher mean glucose areas during the first 60 min of OGTT testing when compared with group 1 (P less than 0.01). Insulin levels, insulin areas and insulin/glucose regression coefficients on group 2 did not differ significantly from group 1 during OGTT. Group 3 showed significantly higher mean blood glucose levels than subjects in group 1 (P less than 0.0001) or group 2 (P less than 0.001), but significantly lower mean blood glucose levels than subjects in group 4 (P less than 0.04) throughout the OGTT. During the OGTT, group 3 showed marked absolute hyperinsulinism when compared with all other groups (P less than or equal to 0.002). Also, relative hyperinsulinism in group 3 was suggested by the elevated insulin/glucose regression coefficient (1.86 +/- 0.50) when compared with group 1 (1.17 +/- 0.09), group 2 (0.92 +/- 0.011) or group 4 (0.55 +/- 0.17) (P less than or equal to 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Labrie, Christy RN; Soeldner, J. Stuart MD; Lee, N. Cunningham DPE; Ray, E. Gleason PhD Author Information

In order to determine if congenital rubella infection is associated with persistent T cell abnormalities, T cell subsets were quantitated in 16 non-institutionalized subjects (ages nine to 21) with the clinical stigmata and history of congenital rubella. Flow cytometric analysis revealed a decreased T4/T8 ratio (mean ± SEM in subjects with rubella, 1.57 ± 0.15, p <0.01; in normal subjects, 2.3 ± 0.4; in subjects with type I diabetes, 2.3 ± 0.3), decreased percent of T4-positive “helper” cells (42.6 ± 2.3) different from that in both normal subjects (52.6 ± 2.4, p <0.01) and subjects with recent-onset diabetes (51.5 ± 2.4), and increased percent of T8-positive “suppressor/cytotoxic” T cells (29.9 ± 1.4, p <0.02) relative to that in normal subjects (24.2 ± 1.5) and subjects with type I diabetes (23.9 ± 1.4). Five of 16 subjects with congenital rubella had an elevation of la-positive T cells. Approximately 20 percent had antimicrosomal antibodies. One subject had diabetes mellitus and hypothyroidism, one had hypoglobulinemia, and one had previously undiagnosed hyperthyroidism. Glycosylated hemoglobin levels were normal in all except the diabetic subject, and none of the subjects was islet cell antibody-positive. The T cell abnormalities documented may predispose persons with congenital rubella to the development of organ-specific autoimmunity.

In a prospective study to evaluate the prevalence and predictive potential of circulating islet-cell antibodies, we have screened 1723 "normal" first-degree relatives (parents, siblings, and offspring) of patients with insulin-dependent diabetes mellitus. The prevalence of islet-cell antibodies on initial screening was 0.9 per cent (16 of 1723). Over a maximal follow-up period of two years, insulin-dependent diabetes mellitus developed in 2 of 16 relatives with islet-cell antibodies and in 1 of 1707 without antibodies. In addition, 6 of 12 nondiabetic relatives with islet-cell antibodies had abnormally low insulin responses — below the third percentile in 6 and below the first percentile in 4 — on their initial intravenous glucose challenge. Thus, prospective islet-cell antibody screening of high-risk first-degree relatives, in combination with intravenous glucose-tolerance testing, is capable of identifying immunologically abnormal persons with profoundly diminished beta-cell function, who are presumably at increased risk of insulin-dependent diabetes mellitus. (N Engl J Med 1985; 313:461–4.)

Article Diazoxide Treatment of Neonatal and Infant Hypoglycemia: A Review and Reassessment was published on January 1, 1985 in the journal Journal of Pediatric Endocrinology and Metabolism (volume 1, issue 1).

Nondiabetic adult subjects (N = 12) were studied to determine the effect of an approximately 450-ml acute blood loss upon glycosylated hemoglobin measurements. After blood loss, the hematocrit significantly decreased by week 1 (P < 0.001) and the reticulocyte count peaked by week 2. All glycosylated hemoglobins measured showed significant decreases post blood loss. The nadir was at week 4 for total A1, A1c, and irreversible A1c by high-pressure liquid chromatography (HPLC), and at week 6 for irreversible A1 by HPLC and A1 by electrophoresis. The mean percent decrease in glycosylated hemoglobins ranged from 4.6% (irreversible A1 by HPLC) to 8.6% (total A1c by HPLC).

Since 1972, young type I diabetic patients seen by Joslin Clinic physicians have been advised to use a low cholesterol diet with a high proportion of polyunsaturated fat. Mean fasting cholesterol and triglyceride levels at admission to the Joslin Boys Camp for the years 1971 (N = 129) and 1979 (N = 79) were compared. In 1979, the mean cholesterol level was lower by 44 mg/dl (P < 0.001) and the mean triglyceride by 21 mg/dl (P < 0.001) compared with 1971. The incidence of hyperlipoproteinemia decreased from 21.6% to 7.6% with a complete disappearance of types IV and V during the same period. A decrease in the development of arteriosclerotic cardiovascular diseases in type I diabetic patients might be anticipated from this diet modification.

A diabetic subgroup identified from a base population who have experienced idiopathic sudden hearing loss (ISHL) has been studied. In order to assess the relationship between diabetes and ISHL, two non-diabetic control groups were formed, and a comparison of the audiological data between the diabetic and non-diabetic ISHL patient was made. Mean degree of hearing loss and recovery, as well as the mean hearing level of the contralateral ear were analyzed. No statistically significant differences were noted in the audiological pattern of ISHL in diabetics and controls. A similar incidence of recovery was noted for the two groups throughout the mid frequencies; however, diabetic ISHL patients fail to recover as well as in the high frequencies. Preliminary data, while not statistically significant, suggest an increased hearing loss in both the affected and unaffected ear of the older diabetic patient.

Two maturity-onset diabetic patients developed severe insulin resistance during the course of monoclonal gammopathies. One patient had Waldenström macroglobulinemia and the other had multiple myeloma with IgA gammopathy. The maximum insulin binding capacity (MIBC) was 121 U/liter and 54.7 U/liter, respectively, during insulin resistance. The clinical courses of insulin resistance paralleled the activity of the monoclonal gammopathies (MG) with the insulin resistance disappearing after the monoclonal gammopathies were controlled. Six other diabetic patients with concurrent insulin resistance and monoclonal gammopathies are reviewed.

Control of diabetes was studied during an 8-wk camp program in 18 insulin-dependent counselors with a mean age of 19.3 yr and a mean duration of diabetes of 11.4 yr. A composite score was obtained for each subject derived from three factors: percent sugar-free urine tests, 24-h glucose excretion as percent of carbohydrate intake, and mean preprandial blood glucose (MPBG). The mean hemoglobin A1c (HbA1c) at the end of the period was 8.3 ± 1.6% (± SD) (normal range, 4–6%). Scores ranging from 24 (fair control) to 45 (excellent control) showed a significant inverse correlation with HbA1c (r = – 0.807, P < 0.001) and MPBG (r = – −0.674, P < 0.01). HbA1c showed a significant correlation with the MPBG (r = 0.693, P < 0.01). The HbA1c level was predicted better by percent sugar-free urine tests than by the 24-h glucose excretion. Thus it appears that accurate quantification of control may be obtained by using a scoring system. Critical comparison of HbA1c levels to various glycemic indices may provide useful alternatives for estimating diabetes control.