Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II.

The prevalence of and interrelationships among all four major complications of insulin-dependent diabetes mellitus (IDDM) and their risk factors are being examined in a large epidemiologic study of IDDM subjects diagnosed in childhood. This article focuses on the baseline prevalence of complications in the 657 subjects diagnosed between 1950 and 1980 and currently aged 8-48 yr, with a mean duration of 20 yr. In addition to background retinopathy being virtually universal after 20 yr of diabetes, proliferative retinopathy affects 70% of IDDM subjects after 30 yr duration. As with overt nephropathy, prevalence of proliferative retinopathy is marginally higher in females than in males at short durations; the previously reported male excess is limited to the subjects with IDDM of longer duration (greater than or equal to 25 yr). Somewhat different patterns of microalbuminuria are also seen by sex. Males show a threefold increase in prevalence from 10 to 25 yr duration, whereas females show a more constant prevalence across these durations. A further rise in microalbuminuria is seen in males but not females at greater than or equal to 30 yr duration, giving a combined prevalence of microalbuminuria and overt nephropathy at greater than or equal to 30 yr duration of 84% (males) and 59% (females). Distal symmetrical polyneuropathy shows a constant rise with duration and is only marginally higher in men. Prevalence of cardiovascular (coronary and cerebral) disease shows no sex difference, whereas peripheral vascular disease is particularly common in women after 30 yr duration (greater than 30%) compared with men (11%) when determined by ankle/arm blood pressure ratio less than 0.8 at rest or after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlates of insulin antibodies in newly diagnosed children with insulin-dependent diabetes before insulin therapy.

Insulin antibodies, as measured by plasma radiolabeled insulin-binding capacity, were determined in 124 newly diagnosed insulin-dependent diabetic (IDDM) children before and after 1, 3, and 5 days of insulin therapy. Controls were 35 nondiabetic children with plasma insulin binding capacity of 1.0 +/- 0.7%. The patients were divided into three groups according to their plasma insulin-binding capacity. Group 1 (N = 79) had binding within two standard deviations (SD) of the control mean, group 2 (N = 20) had insulin binding 2-6 SD above controls, and group 3 (N = 25) showed insulin-binding capacity of more than 6 SD above the control mean. After exogenous insulin therapy, plasma 125I-insulin-binding capacity dropped significantly in both groups 2 and 3, concurrent with significant increases in plasma insulin levels. The three groups differed from each other in that patients in group 3 were significantly younger than in the other groups and clinically seemed to be more severely dehydrated, as reflected in their higher levels of serum urea nitrogen, plasma glucose, potassium, and elevated pulse rate. The three groups did not differ in respect to sex, HLA-DR antigens, Coxsackie-B antibody titers, islet cell cytoplasmic antibodies, immunoglobulin level, and C-peptide levels. Only two of 446 siblings of IDDM children showed elevated insulin binding, one of whom developed IDDM 6 wk later. The presence of an insulin-binding substance probably representing insulin antibodies in some cases of newly diagnosed IDDM suggests that autoimmunity in this disorder is not limited to the B-cell membrane and cytoplasm and lends further support to the heterogeneity of IDDM.

Effect of FK 506 on spontaneous diabetes in BB rats.

From days 30-120 after birth, 59 BB rats were treated with water (n = 20) or FK 506 in intragastric doses of 1 mg.kg-1.day-1 (n = 19) or 2 mg.kg-1.day-1 (n = 20). Diabetes developed in 75, 15, and 0% of the 3 groups, respectively. Animals protected from diabetes by FK 506 had normal intraperitoneal glucose tolerance tests, virtual absence histopathologically of autoimmune insulitis, and normal pancreatic insulin content. Forty-five to 75 days after stopping FK 506, approximately 75% of the rats that were diabetes free at 120 days remained so.

The Pittsburgh insulin-dependent diabetes mellitus (IDDM) registry. The incidence of insulin-dependent diabetes mellitus in Allegheny County, Pennsylvania (1965-1976).

An insulin-dependent Diabetes Mellitus Registry has been developed in Allegheny County, Pennsylvania, through hospital record review and surveillance of pediatric practices. The yearly incidence ranged from 10/100,000 for nonwhite males to 16/100,000 for white males. There were no temporal trends in incidence for 1965-1976 nor major sex differences. Nonwhites had a slightly lower incidence, primarily in the younger age groups.

The Pittsburgh insulin-dependent diabetes mellitus (IDDM) morbidity and mortality study. Mortality results.

A follow-up study of 1966 patients with insulin-dependent diabetes mellitus (IDDM) who were diagnosed at Children's Hospital of Pittsburgh (CHP) between 1950 and 1981 has been completed. The mean age of the population at follow-up was 21.2 yr with a mean duration of IDDM of 12.9 yr. Nine percent of the patients were deceased, a sevenfold excess in mortality compared with the U.S. population. The relative increase in mortality was greater for females than males and greater for blacks than whites. Before age 20, the primary excess in mortality was at onset of IDDM, or within 6 mo after onset, and was due to acute diabetic complications. After age 20, the annual mortality risk was approximately 2%, which was more than 20 times greater than for the U.S. population. Renal disease was responsible for the majority of these deaths. There was a reduced risk of dying for diabetic patients who were diagnosed between 1966 and 1971 compared with patients diagnosed during earlier years.

Epidemiological correlates of diabetic neuropathy. Report from Pittsburgh Epidemiology of Diabetes Complications Study.

The natural history of diabetic neuropathy and its risk factors are not well understood, apart from the recognition that prevalence increases with duration and, in many studies, degree of glycemia. The role of potential risk factors was therefore evaluated in a cross-sectional analysis from the baseline examination of the Pittsburgh Epidemiology of Diabetes Complications Study. We present results from the first 400 subjects seen at baseline examination. Neuropathy was determined by a trained internist with a standardized examination and was defined as the presence of at least two of three criteria: abnormal sensory or motor signs, symptoms consistent with neuropathy, and decreased tendon reflexes. The prevalence of neuropathy in this cohort was 34% (18%, 18-29 yr old, 58% greater than or equal to 30 yr old) with no difference by sex. By focusing on subjects greater than or equal to 18 yr old, all significant univariate variables (e.g., duration, glycosylated hemoglobin [HbA1]) were analyzed in 3 multiple logistic regression models: all subjects greater than or equal to 18 yr old and separating the same subjects into two groups based on age (18-29 and greater than or equal to 30 yr). Duration, HbA1, smoking status, and high-density lipoprotein cholesterol were found to be associated with neuropathy in the models for the greater than or equal to 18-yr-old group and the greater than or equal to 30-yr-old group. In the 18- to 29-yr-old group, duration, HbA1, and hypertension status were found to be significantly associated with neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA heterogeneity of insulin-dependent diabetes mellitus at diagnosis. The Pittsburgh IDDM study.

Although some previous studies have suggested that insulin-dependent diabetes mellitus (IDDM) is a heterogeneous condition with variant forms being associated with HLA-DR types, the evidence, thus far, is conflicting. To address this issue, we have examined the presenting characteristics of a consecutive admission series of 200 newly diagnosed cases of IDDM from the Children's Hospital of Pittsburgh. Because HLA-DR frequencies vary by race, data are presented only for the 172 white cases with complete HLA-DR typing. HLA-DR3 was found more frequently among male cases and DR4 among female cases (P less than 0.005). Generally, patients with DR4 presented with a severer clinical picture, being more likely to have impaired consciousness and significant dehydration. In addition, patients with DR4 were more likely to be acidotic, ketotic, and to more frequently report a recent viral infection. This latter finding was supported by a greater frequency of antibodies to Coxsackie-B viruses in the DR4 cases at presentation. These results therefore suggest that there is considerable heterogeneity in IDDM, at least in presenting characteristics, according to HLA-DR type.

Clinical care of the patient with diabetes. What is the role of the diabetes professional?

A review of diabetes management problems will be presented from the biased perspective of children and adolescents with insulin-dependent diabetes mellitus (IDDM), their families, and the team of professionals who attempt to provide broadly based quality care to ensure that these young people move into effective adult life with minimal physical and/or emotional disability from the disease or its management. Although there are many unique aspects of diabetes in the child and adolescent, it is expected that recommendations for future care of this group of patients will, in most cases, have direct relevance to management issues to most patients with IDDM.

Impact of physical fitness and glycemic control on in vivo insulin action in adolescents with IDDM.

The relationship of in vivo insulin-mediated glucose utilization to the state of physical fitness and the degree of glycemic control was examined in 27 adolescents with insulin-dependent diabetes mellitus (IDDM) compared with 10 nondiabetic adolescent control subjects. In vivo total-body insulin-mediated glucose metabolism was evaluated by the hyperinsulinemic-euglycemic clamp. Physical fitness was assessed by maximal oxygen consumption (VO2 max) during cycle ergometry. Patients and control subjects had similar levels of VO2 max (34.9 +/- 8.6 vs. 38.6 +/- 9.9 ml.kg-1.min-1, P = 0.3). Patients had lower total-body insulin-mediated glucose metabolism compared with control subjects (33.9 +/- 14.3 vs. 63.8 +/- 17.2 mumol.kg-1.min-1, P = 0.0002). Among the patients, females had lower total-body insulin-mediated glucose metabolism compared with males (24.2 +/- 2.8 vs. 40.7 +/- 3.4 mumol.kg-1.min-1, P less than 0.001); however, this difference disappeared after correcting for sex differences in fitness levels. Insulin-mediated glucose metabolism correlated with VO2 max in patients and control subjects (r = 0.83, r = 0.81, P less than 0.05). The regression of total-body insulin-mediated glucose metabolism on VO2 max for patients was -2.84 +/- 0.255 VO2 max and for control subjects was 7.12 +/- 0.143 VO2 max, indicating that for similar degrees of physical fitness patients have lower total body insulin-mediated glucose metabolism levels than control subjects. In patients, total-body insulin-mediated glucose metabolism correlated with the degree of glycemic control as assessed by the level of glycosylated hemoglobin (r = -0.63, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma catecholamine responses to hypoglycemia in children and adolescents with IDDM.

OBJECTIVE: The goal of this study was to assess whether children and adolescents with insulin-dependent diabetes mellitus (IDDM) have decreased catecholamine responses to insulin-induced hypoglycemia as has been reported in adults and to explore the pathogenesis of the decreased response in terms of possible relationships to autonomic neuropathy or hyperinsulinism. RESEARCH DESIGN AND METHODS: A before-and-after trial on the effects of 3 days of intensive insulin therapy was conducted on 60 subjects with IDDM (age 15.4 +/- 2.6 yr, duration of diabetes 7.8 +/- 3.5 yr). The control group consisted of 5 children with non-growth hormone-deficient short stature (age 14.8 +/- 3.2 yr). Hypoglycemia was induced with an intravenous insulin bolus (0.15-0.75 U/kg) after insulin withdrawal and 3 days of intensive insulin therapy in diabetic subjects on an inpatient basis to assess the role of hyperinsulinism in suppressing the catecholamine response to hypoglycemia. Control subjects were studied once and received an insulin bolus of 0.1 microU/kg. Autonomic neuropathy was assessed by computerized assessment of the basal R-R variation during inspiration and expiration and the pancreatic polypeptide response to hypoglycemia. RESULTS: Basal plasma catecholamine levels were lower in diabetic subjects after intensive insulin therapy than in control subjects (P = 0.008). The peak and incremental catecholamine responses after insulin withdrawal and intensive insulin therapy in IDDM subjects were significantly decreased compared with control subjects (P less than 0.001). Peak catecholamine responses to hypoglycemia in IDDM were decreased after intensive insulin therapy (P = 0.002). This was particularly true in those with plasma glucose nadir levels of less than 2.2 mmol (P less than 0.001). The diminished catecholamine responses were primarily due to decreased peak epinephrine responses after intensive insulin therapy compared with insulin withdrawal (P = 0.011). There were no significant correlations between the catecholamine response to hypoglycemia and age, duration of diabetes, pancreatic polypeptide, or R-R interval. CONCLUSIONS: These results suggest that children and adolescents with IDDM after insulin withdrawal have diminished catecholamine response to hypoglycemia compared with control subjects and indicate that short-term intensive insulin therapy diminishes this response further. Thus, hyperinsulinism may play a role in suppressing the catecholamine response to hypoglycemia. There is no evidence for a clinical or subclinical role of autonomic neuropathy to explain the altered catecholamine responses.

Glucagon responses to hypoglycemia in children and adolescents with IDDM.

To investigate plasma glucagon counterregulatory responses to hypoglycemia, an intravenous insulin bolus was given over 2 min to 73 children, aged 8.5-18.8 yr, with diabetes duration 1.2-17.1 yr. The plasma glucagon responses of the 61 children without glucagon antibodies or abnormal glucagon molecules were compared with those of 13 nondiabetic control subjects, aged 8.3-18.3 yr. Glucagon increments from baseline (73 +/- 10 pg/ml) and peak glucagon responses (212 +/- 13 pg/ml) were markedly lower in diabetic patients than in control subjects (341 +/- 49 and 462 +/- 51 pg/ml, respectively, P less than .001). Glucagon responses were found to correlate positively with the age of the patients at the time of testing (r = .478, P less than .001) and inversely with metabolic control as measured by glycosylated hemoglobin (r = -.342, P less than .02). There was no relationship between glucagon responses and diabetes duration. There was also no relationship between the glucagon increments and free-insulin levels during the test. Glucose recovery from the nadir was impaired in diabetic subjects compared with control subjects and correlated inversely with free-insulin levels. However, glucose recovery did not correlate with the rise of plasma glucagon. Glucose recovery was not different in patients with glucagon antibodies. In this study, we have demonstrated a deficient glucagon response to hypoglycemia in children with insulin-dependent diabetes mellitus. However, the clinical significance of this deficit is not clear.

A comparison of the epidemiology of youth-onset insulin-dependent diabetes mellitus between Japan and the United States (Allegheny County, Pennsylvania).

Children in the United States are almost 20 times more likely to develop insulin-dependent diabetes mellitus (IDDM) than children in Japan. Little is known about the differences between the two countries that might account for this very large difference in risk. The current research compared the characteristics of IDDM in Japan with those of the United States (Allegheny County, Pennsylvania). Seasonality, relationship to socioeconomic status, and age at onset were similar. There was some suggestion of a sex difference. Of interest was that reported recent infections at onset were much higher in the United States. In addition, the risk to first-degree relatives in Japan appeared to be somewhat lower than in the United States, although this may have been the result of differences in ascertainment. These results are discussed in relation to potential factors that might account for the major incidence differences.

Residual beta-cell function in children with IDDM: reproducibility of testing and factors influencing insulin secretory reserve.

Reproducibility of C-peptide secretion was assessed in 20 children (group 1) by their responses to two Sustacal- (a mixed liquid meal) stimulation tests performed 7-14 days apart. For the 12 C-peptide-positive children (basal C-peptide greater than or equal to 0.03 pmol/ml) there were no differences in the basal or stimulated values between tests 1 and 2. The effect of exogenous insulin on C-peptide secretion was assessed in 20 other children (group 2) by their responses to two Sustacal tests, one test without and one with soluble insulin (0.25 U/kg) injected subcutaneously before testing. Eleven children were C-peptide positive and had no differences in C-peptide response between tests 1 and 2. The results from test 1 in groups 1 and 2 were combined with those from 44 others undergoing a single Sustacal test (group 3, N = 84). There was a close correlation between basal and peak C-peptide concentrations in the 44 C-peptide-positive children (r = .88, P less than .001). Peak C-peptide concentrations correlated inversely with HbA1 (r = -.29, P less than .01), insulin dose in units per kilogram (r = -.40, P less than .001), and duration of diabetes (r = .33, P less than .001) and positively with age at onset of diabetes (r = .34, P less than .001). The C-peptide-positive children had reduced glucose response to Sustacal, lower HbA1 concentration, lower insulin requirement, later age of onset, and shorter duration of diabetes than children who were C-peptide negative.

Was there an epidemic of diabetes in nonwhite adolescents in Allegheny County, Pennsylvania?

OBJECTIVE: To determine the incidence of IDDM in children aged < 20 years at diagnosis in Allegheny County, Pennsylvania, for the period from 1 January 1990 to 31 December 1994 and to compare the incidence between whites and nonwhites in the same area and for the same time period. RESEARCH DESIGN AND METHODS: All new patients diagnosed between January 1990 and December 1994 who were aged < 20 years, on insulin, and residents of Allegheny County at diagnosis were identified from medical records of 23 hospitals in the Allegheny County area. To verify the completeness of the hospitals using the capture-recapture method, pediatricians and diabetologists were used as a secondary source. RESULTS: A total number of 257 patients were identified. The overall age-standardized incidence rate was 16.7/100,000. Nonwhites had a slightly higher incidence (17.6/100,000) than whites (16.5/100,000). In the 15-19 years age-group, the incidence in nonwhites (30.4/100,000) was almost three times higher than that in white (11.2/100,000) and more than two times higher than that in the previous period (from 1985 to 1989) (13.8/100,000). CONCLUSIONS: For the first time in the Allegheny County registry, and in any other registry, nonwhites showed a higher incidence of IDDM than whites. The high incidence in the 15-19 years age-group was responsible for this phenomenon. This epidemic of diabetes in adolescent nonwhites may be the result of a rising incidence of classical IDDM or another type of diabetes. Further studies using population-based registries are needed to determine whether this increase is being seen in other areas and other ethnic groups and to clarify the reasons for the increase in IDDM among blacks.

Potentiometric measurement of glucose concentration with an immobilized glucose oxidase/catalase electrode.

A series of enzyme electrodes for measurement of glucose have been constructed. The electrodes contain glucose oxidase immobilized on platinum, either with or without co-immobilization of catalase. When placed in buffered glucose, the enzyme electrodes show a potentiometric response to glucose with respect to a Ag/AgCl reference electrode. This response is reproducible in the physiologic range of glucose concentrations. The immobilization technique, some of the environmental variables such as oxygen concentration and pH, and several compounds that might interfere with the selectivity of the enzyme electrodes for glucose have received preliminary study. This direct potentiometric approach is undergoing further evaluation to determine the basic electrochemical mechanism responsible for the potentiometric signal and whether it can be adapted for continuous in vivo monitoring of the glucose concentration in body fluids.

Cyclosporin therapy for prevention and cure of IDDM. Epidemiological perspective of benefits and risks.

Cyclosporin and other immunosuppressive agents have been proposed as a preventive treatment against the development of insulin-dependent diabetes mellitus (IDDM) in relatives at increased risk for the disease, based on the understanding that its etiology is an ongoing process of autoimmune beta-cell destruction. We used an epidemiological approach to evaluate several recent trials of cyclosporin in newly diagnosed IDDM patients to determine the degree of benefit that is to be expected. We assessed these and other studies to estimate the potential adverse effects of such treatment, were it to be used in the future, either in newly diagnosed subjects or healthy high-risk relatives. Standard sample-size calculations were used to quantify the number of study subjects necessary to allow adequate statistical power to test the positive and negative effects of a future treatment (alpha = 0.05, beta = 0.20). The estimates were based on the data available from published studies of cyclosporin treatment. The importance of conducting an adequate trial of such a therapy, both from an ethical and a practical viewpoint, is discussed. Five small immunosuppression trials were evaluated. Remission rates in treated subjects exceeded those in control subjects by 15-59%. Variability in defining remission may account for the differences in rates across the studies. Estimates of the major beneficial and adverse effects of cyclosporin were derived from these trials and studies of patients who have undergone long-term immunosuppression. Indicators of kidney damage associated with cyclosporin treatment were reported in 5-47% of treated subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Health, life, and automobile insurance characteristics in adults with IDDM.

OBJECTIVE: To determine whether people with insulin-dependent diabetes mellitus (IDDM) were compromised in their access to insurance. RESEARCH DESIGN AND METHODS: A case-control study of 158 people with IDDM and 158 nondiabetic siblings matched for age and sex was conducted to evaluate the health, life, and automobile insurance characteristics and history of people with IDDM. RESULTS: Health insurance coverage (yes/no) among the IDDM and sibling control subjects was similar. More than 90% of the IDDM and control respondents had insurance through a private third-party source, and this insurance did not differ by type of plan, coverage, or premium. However, Medicare coverage was more common among the IDDM subjects and was associated with the presence of severe diabetic complications. IDDM subjects were also more likely to have been denied a health insurance policy by an insurer than were the control subjects (23 vs. 1%, P less than 0.001). Similarly, there was no difference between the IDDM and sibling control subjects in the number who had a life or automobile insurance policy. However, life and automobile insurance refusal was much more frequent among the IDDM respondents, more so for life (55 vs. 0%, P less than 0.001) than for automobile (12 vs. 4%, P less than 0.05) insurance. CONCLUSIONS: These results suggest that access to insurance is severely compromised for people with IDDM. Although most of those with IDDM are able to find some form of insurance, it is evident that on average they must go to extra lengths to find it. These data and a changing insurance environment emphasize the need to reexamine, as a society, the importance of insurance for people with chronic disease, particularly IDDM.

Motor vehicle accidents and IDDM.

A case-control study examining the 1-yr motor vehicle accident experiences of 158 insulin-dependent diabetes mellitus (IDDM) cases and 158 nondiabetic siblings was undertaken to evaluate the risk of motor vehicle accidents among drivers with IDDM. In multivariate analyses the overall accident risk of the cases and control subjects did not differ significantly. Female diabetic drivers, however, showed a marked increased risk for motor vehicle accidents. The accident risk among female cases was five times higher than among the female control subjects (P less than .05). Age and marital status were also significantly associated with accident probability in the multivariate model. The results suggest that IDDM could have an effect on the accident rate of diabetic drivers, particularly women. However, the traditional risk factors for automobile accidents, i.e., age and marital status, appear to have an equally strong influence on accident occurrence. Further studies are needed to 1) document the role of IDDM in accidents among representative samples of the IDDM population and 2) properly evaluate the licensing restrictions recommended for diabetic drivers.

Geographic differences in the risk of insulin-dependent diabetes mellitus: the importance of registries.

There are marked geographic differences in the incidence of insulin-dependent diabetes mellitus (IDDM); for example, children in countries such as Finland are over 35 times more likely to develop IDDM than children in Japan. An understanding of the reasons for the geographic differences is likely to be important for understanding and, hopefully, preventing IDDM. There are problems, however, because of the lack of registries with adequate standardization. The major needs for the future studies include (1) to clarify the definition of IDDM for epidemiologic study, (2) to establish a standardized approach for IDDM registries, (3) to use registries to evaluate viral, immunologic, and genetic differences in order to explain differential risks across populations, and (4) to encourage the development of new population-based registries worldwide.

The Pittsburgh Insulin-Dependent Diabetes Mellitus (IDDM) Morbidity and Mortality Study: case-control analyses of risk factors for mortality.

Although children with IDDM are at a sevenfold increased risk of dying when compared with nondiabetic individuals of the same age, the factors associated with the excess in mortality remain unclear. To investigate potential determinants of mortality among IDDM patients, a case-control study was conducted. These retrospectively obtained data indicated that shorter relative height at onset, frequent diabetes-related readmissions, the presence of diabetes complications, a family history of diabetes, premature familial mortality, no participation in school team sports, and a lower level of education were related to subsequent mortality among males. Among females, however, a shorter duration of diabetes clinic attendance and the presence of diabetes complications were the only significant associations to mortality.