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Objective: To investigate the role of early infant feeding in the development of insulin-dependent diabetes mellitus (IDDM) and to determine whether an association exists in both blacks and whites., Research Design and Methods: Black and white diabetic subjects were recruited from the Allegheny County and Children's Hospital of Pittsburgh IDDM Registries. Extensive infant diet histories were obtained from the diabetic subjects and their nondiabetic siblings, who were used as nondiabetic control subjects. Each diabetic subject was matched outside his/her family to an unrelated nondiabetic control subject on birth order, birth year (+/- 2 yr), and race, which resulted in 211 case-control pairs with a mean birth year of 1967., Results: In whites, diabetic subjects were less likely to have been breast-fed than control subjects (odds ratio [OR] 0.5, 95% confidence interval [CI] 0.3, 0.9). Breast-feeding prevalence did not differ between black diabetic subjects and control subjects. Duration of overall and exclusive breast-feeding did not differ between diabetic and control subjects in the black and white cohorts. The following analyses, which examined whether the timing of the first breast milk substitute to which the infant was exposed differed between diabetic and control subjects, were conducted for exposure to any breast milk substitute and to breast milk substitutes that were cow's milk based. In whites, age at exposure to any breast milk substitutes and cow's milk-based substitutes were similar between diabetic and control subjects. In blacks, the first exposure to breast milk substitutes occurred significantly earlier for any substitute (5.1 vs. 11.9 wk, P = 0.02) and marginally earlier for cow's milk-based substitutes (3.9 vs. 8.5 wk, P = 0.07) in diabetic subjects compared with control subjects. The first exposure to breast milk substitutes was more likely to occur by 3 mo of age in black diabetic subjects compared with black control subjects (OR 3.3, 95% CI 1.1-10.0) after adjusting for maternal age at birth. The addition of breast-feeding status to the model only slightly weakened this association in blacks., Conclusions: The analyses of this study cohort suggest that the observed protective effect of breast-feeding on the risk of IDDM may be related to differences in the age at exposure to breast milk substitutes in blacks but not in whites.

The apolipoprotein (apo) E polymorphism has been related to differences in lipoprotein metabolism and lipid/lipoprotein concentrations in a number of studies. Whether these associations are seen in insulin-dependent diabetes mellitus (IDDM), which itself affects many of the same aspects of lipoprotein metabolism as does the apo E polymorphism, is unknown. The present study is an investigation into the influence of apo E phenotype on lipoprotein concentrations in a large group of IDDM patients (n = 433) participating in the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. The frequency of the three apo E alleles 2, 3, and 4 did not differ in this population from that reported in general white populations. Although the diabetic subjects show the same trends as seen in the general population, ie, apo E-2 is associated with lower and apo E-4 with higher low-density lipoprotein cholesterol (LDLc) compared with apo E3 (P less than .03), they also show relationships with glycemic control that influence the relative levels of lipid measures with respect to apo E phenotype. Results also raise the possibility that lipoprotein composition varies according to apo E phenotype in IDDM.

Objective: To determine the descriptive epidemiological patterns of the secondary attack rate of insulin-dependent diabetes mellitus (IDDM) among siblings of probands through older ages., Research Design and Methods: A family history analysis was performed on 1774 IDDM probands who were diagnosed or seen within 1 yr of diagnosis at Children's Hospital of Pittsburgh from 1 January 1950 through 31 December 1981. The probands were discharged on insulin and were diagnosed at less than 17 yr of age. The time frame permitted the risk of IDDM for siblings of probands to be calculated over a broad spectrum of age., Results: Risk estimates for the 3966 full natural siblings through 10, 20, and 30 yr of age were 1.6, 4.1, and 6.3%, respectively. Secondary attack rates were equivalent for male and female siblings through 15 yr of age (3%); however, the risk to males increased an additional 4% between 16 and 30 yr of age compared with 2.5% for females (P = 0.01). There was no evidence of an excess sex concordance among affected sibling pairs., Conclusions: Males have a greater secondary attack rate of IDDM at older ages than females. This may be due to an increased exposure to environmental agents among males or protective influences operating among females.

Objective: This project evaluated the utility of quantitative sensory techniques in predicting the development of neuropathy for subjects participating in a prospective study., Research Design and Methods: Distal symmetric polyneuropathy was evaluated in 77 insulin-dependent diabetes mellitus individuals via quantitative sensory testing, nerve conduction studies, and clinical examination., Results: Although the specificity and positive predictive value were low for the quantitative sensory techniques as predictors of neuropathy diagnosed on clinical exam approximately 2 yr later, the sensitivity for vibratory thresholds was high (100%). Variability over the 2-yr interval was shown on follow-up testing for each of the objective assessment modalities and it was not explained by differences for potential risk factors measured at baseline., Conclusion: Despite a cross-sectional relationship between the assessment modalities and clinically overt neuropathy at baseline, these follow-up data suggest that the potential for the objective modalities as predictors of clinically diagnosed neuropathy may be limited.

Prospective studies of the relatives of people with Type 1 diabetes can provide insights into risk factors for processes leading to the ultimate destruction of the pancreatic islet B-cells. Relatives ascertained through the Children's Hospital of Pittsburgh diabetes registry were followed and rates of conversion to diabetes were determined. We studied the role of genetic and immunological markers, and used the oral glucose tolerance test (OGTT) to study metabolic disturbances among first-degree relatives. A group of siblings was serotyped for the HLA-A and -B antigens, and the degree of HLA haplotype sharing with the diabetic sibling was established. Later, islet cell antibody (ICA) assays were performed, and subjects were followed to determine the predictive value of ICA testing for the subsequent development of diabetes. The rate of conversion to diabetes among the siblings was 14 times greater than the rate observed in the general population from which they come. This is comparable to rates observed by other centres following relatives of people with Type 1 diabetes. Impaired glucose tolerance (by National Diabetes Data Group (USA) criteria) carried a three-fold greater risk for subsequent Type 1 diabetes than did a normal OGTT. Those relatives with detectable ICA were about 50 times more likely to convert to diabetes than were those without ICA. In a group of siblings in whom HLA haplotype sharing was determined, the prevalence of detectable ICA was greater among those who were HLA-identical to the diabetic sibling (9.9%) than among those who were haplo-identical (5.3%) or completely dissimilar (2.4%) at the HLA-A and -B regions.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the role of insulin clearance in the dawn phenomenon, we studied 10 adolescents with IDDM in comparison to 10 healthy, matched control subjects reported previously. In diabetics, metabolic clearance rate of insulin was calculated during i.v. infusion of insulin from 0100 to 0430 h and from 0430 to 0800 h (0.17 and 0.33 mU/kg/min, respectively), with a Harvard pump, while maintaining nocturnal euglycemia. In controls, metabolic clearance rate of insulin was calculated from the prehepatic insulin secretion rate based on C-peptide levels. In diabetic and control subjects, plasma glucose, free insulin, and glucagon concentrations were similar and did not change during the dawn period. However, metabolic clearance rate of insulin increased during the dawn period in diabetic (9.42 +/- 0.91 to 19.89 +/- 1.52 mL/kg/min, p less than 0.0001) and control subjects (4.87 +/- 1.11 to 9.30 +/- 1.50 mL/kg/min, p = 0.008). Plasma cortisol and adrenocorticotropic hormone levels increased and growth hormone (GH) decreased significantly during the dawn period. Diabetic adolescents had significantly higher plasma GH levels than control subjects throughout the night. We conclude the 1) increased insulin clearance is responsible for the dawn phenomenon in healthy and diabetic adolescents and 2) insulin resistance due to GH is an unlikely cause for the dawn phenomenon because diabetic subjects, despite higher GH levels, maintain plasma glucose levels similar to control subjects without requiring higher plasma free insulin concentrations.

Pancreatic hypoplasia is an uncommon developmental defect that has not been well documented in association with type I diabetes mellitus. We report the case of a patient with an atypical clinical onset of type I diabetes mellitus who died following pancreas transplantation. Autopsy showed the surprising finding of hypoplasia of the native pancreas with other features indicating the concurrence of type I diabetes mellitus. These findings lead to speculation about the occurrence and interaction of these two diseases in our patient.

The role of platelet aggregation in the pathogenesis of diabetes complications remains unclear despite a number of reports suggesting associations in univariate analyses. The Pittsburgh Epidemiology of Diabetes Complications Study is a prospective study initiated in 1985 to determine risk factors for the development of complications in insulin-dependent diabetes mellitus (IDDM). This report focuses on the cross-sectional correlation between platelet count and aggregation and IDDM complications, in 563 participants aged 18 years and older seen at baseline. Spontaneous whole blood platelet aggregation (SWBPA) and other hematological variables [hematocrit, total platelet count (TPC), red blood cell count (RBC), fibrinogen and white blood cell count (WBC)] were evaluated as risk factors for IDDM complications (nephropathy, neuropathy, and retinopathy) in the baseline cross-sectional data of the Pittsburgh Epidemiology of Diabetes Complications Study. SWBPA was determined by a method based on the percentage fall in platelet count after shaking a fresh citrated blood sample kept at 37 degrees C. Subjects with chronic aspirin use or on dialysis were excluded from analysis. An increased TPC was observed in subjects with overt nephropathy (291.4 +/- 65.1 versus 261.2 +/- 64.9, p less than 0.001) compared with subjects without nephropathy. Similar results were found for proliferative retinopathy. The association with nephropathy (but not with retinopathy) persisted in multivariate analyses.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneity within insulin-dependent diabetes mellitus (IDDM) has been hypothesized, but few studies have focused on differences which may exist between familial and sporadic IDDM cases. Presenting characteristics for 330 white, newly diagnosed IDDM cases were evaluated. Familial cases were older (10.2 +/- 5.1 years vs 7.9 +/- 4.2 years, P = 0.010) and had, on average, less severe metabolic disturbances at presentation, as demonstrated by lower mean hemoglobin A1 (12.6 +/- 2.4% vs 14.4 +/- 2.6%, P = 0.001) and mean insulin dose at discharge (0.62 +/- 0.35 U/kg/day vs 0.85 +/- 0.29 U/kg/day, P less than 0.001), and higher mean plasma bicarbonate concentrations (19.3 +/- 3.9 mmol/l vs 15.8 +/- 5.9 mmol/l, P = 0.023) and mean plasma C-peptide levels (0.35 +/- 0.36 pmol/ml vs 0.14 +/- 0.15 pmol/ml, P less than 0.001). Further analyses on a subset of IDDM cases (n = 100) indicated that initial differences in metabolic indices observed at diagnosis were no longer apparent at one-year post-diagnosis. These results suggest that the etiology of familial and sporadic IDDM is similar and that the less severe presentation observed at diagnosis in the familial cases may be due to earlier identification of the disease, reflecting increased parental knowledge of diabetic symptoms and/or frequent testing for diabetes.

Epidemiological techniques have been utilized to accumulate new knowledge about insulin-dependent diabetes mellitus (IDDM), leading to important insights into the disease process and the alteration of these mechanisms when viewed from a geographic or population base. More recently, highly powerful and sophisticated techniques of molecular biology have been added to the research arsenal, extending the knowledge on the genetic basis for IDDM and the probable environmental factors involved. The development and growth of the new discipline of epidemiological genetics promises exciting new developments for the future of our field as well as that of other major medical problems having a genetic base, but significantly influenced by environmental factors. This review stresses the importance of carefully validated diabetes registries in the study of the epidemiology of IDDM. The Children's Hospital of Pittsburgh and the University of Pittsburgh Medical Center have spear-headed the development of such registries, worldwide. The first international meeting on IDDM epidemiology in 1983 gave as a result, i.e., the finding that there were truly remarkable differences in the risk of developing IDDM depending upon the geographic location of the individual. Later collaborative work via the Diabetes Epidemiology Research International (DERI) group has confirmed the previous finding and added the description of secular trends and epidemics of IDDM. It is remarkable that the incidence rate of IDDM in children below 15 years vary from 1/100,000/yr in the Orient to 35/100,000/yr in Finland. The epidemiological approach in the study of IDDM has also stimulated research into the various facets of the etiology of the disease, genetic factors, autoimmune mechanisms and environmental factors.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the extent to which cholesterol measured in childhood is predictive of values in adulthood, the investigators conducting the second follow-up of the Beaver County Lipid Study tracked the cholesterol values of 295 adults who had initially participated as children (ages 11 to 14 years) in a countywide school screening program. The follow-up study was conducted 16 years after the initial study, when the participants had reached a mean age of 28 years. The overall correlation (r) between baseline (1972-1973) total cholesterol values and the values found at the present follow-up was 0.44 (p less than 0.0001). Women had a higher correlation (r = 0.51) than men (r = 0.38). In addition, the efficacy of childhood screening for cholesterol levels was assessed by considering currently recommended borderline values (greater than 175 mg/dl (4.6 mmol/L) for children and greater than 200 mg/dl (5.2 mmol/L) for adults) as a "positive" test result. The sensitivity of screening at age 12 years for predicting elevated adult total cholesterol concentrations was 63%, specificity was 67%, and the predictive value of a positive test result was 47%. Comparison of false-positive results (above the borderline cutoff point as a child but not as an adult) and false-negative results (below the borderline cutoff point as a child but above it as an adult) showed that male subjects with false-positive results smoked significantly less than those with false-negative results (p less than 0.05) and had a greater improvement during the preceding 7 years in cholesterol-lowering dietary practices (p less than 0.01). Female subjects with false-positive results smoked significantly less than those with false-negative results (p less than 0.05), were less overweight (p less than 0.05), and had a lower prevalence of oral contraceptive use (p less than 0.01). These results support the potential value of screening for hypercholesterolemia in childhood on a population basis. Although some subjects were misclassified as a result of childhood screening, some of this misclassification was associated with adopting changes that a screening and intervention program would be designed to promote--nonsmoking, weight control, and a prudent diet.

Cardiovascular disease is a frequent complication of insulin-dependent diabetes mellitus (IDDM), but the prevalence, interrelations, and risk factors of its principal components (coronary, cerebrovascular, and lower-extremity arterial disease) and of medial arterial wall calcification are not well understood. To address these issues, data from the Epidemiology of Diabetes Complications Study (n = 657) baseline examination were examined. The term coronary heart disease (CHD) was applied to those with myocardial infarction or angina, whereas lower-extremity arterial disease (LEAD) was applied to those who had undergone amputation of a lower limb or who had an ankle to arm blood pressure ratio less than 0.8 at rest or after exercise. Calcification of the lower-extremity arteries was considered to be present if ankle pressure was more than 100 mm Hg higher than brachial pressure. Although the prevalence of CHD was low, LEAD was significantly more common in women than in men (p less than 0.01), whereas calcification was more frequent in men than in women (p less than 0.01). Ten percent of those with LEAD also had CHD, and 8% with LEAD had calcification. Modeling of potential risk factors (e.g., diabetes duration and glycosylated hemoglobin) revealed that duration, female gender, fibrinogen, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and high density lipoprotein cholesterol to apolipoprotein A-I ratio were independent predictors of LEAD, whereas for CHD only, diabetes duration and hypertension contributed to CHD. Calcification revealed a mixed pattern, with duration, hypertension, and triglyceride to apolipoprotein A-I ratio being the statistically significant associated factors. The results suggest that although LEAD, CHD, and calcification often coexist, their risk factor profiles differ.

Recently, concern has arisen that human (as opposed to beef or pork) insulin may cause more frequent and/or severe hypoglycaemia in association with reduced warning symptoms. This question was examined from questionnaire data of 628 Type 1 diabetic patients (mean age 28 years and duration of diabetes 19 years) participating in the baseline examination of a follow-up study of diabetes complications. Those using human insulin (n = 73) reported an insignificantly higher frequency of hypoglycaemic reactions in the last year than those using animal insulin (66 vs 55% with reactions at least monthly) and only a weak trend was seen overall for the prevalence of human insulin use to increase with increasing frequency of hypoglycaemia (p = 0.06). Hypoglycaemic reactions resulting in unconsciousness were too rare to permit analysis by type of insulin used. The prevalence of reduced awareness of hypoglycaemia was similar among human insulin users to that seen in animal insulin users (25 vs 19%, NS). However, prevalence of reduced awareness showed a strong relationship to current blood glucose in the animal (r = -0.18, p less than 0.001) but not human (r = -0.06, NS) insulin users. Excluding patients with autonomic symptoms or neuropathy did not alter the results, nor did excluding the 34 individuals taking more than three insulin injections per day. It is concluded that human insulin use is not associated with either any substantial increased frequency of hypoglycaemia or reduction in awareness of hypoglycaemia. However, human insulin use does appear to be associated with reduced awareness of hypoglycaemia in those whose blood glucose control is relatively poor.

Sex-related differences in insulin sensitivity were evaluated in male and female adolescents with insulin-dependent diabetes mellitus (IDDM). They were matched for age, pubertal staging, body mass index, and glycohemoglobin levels. During a 1.7 mU/kg.min hyperinsulinemic-euglycemic clamp, the insulin-mediated glucose disposal rate was lower (26.9 +/- 2.1 vs. 47.1 +/- 3.7 mumol/kg.min; P less than 0.001), and GH levels were higher (6.5 +/- 1.2 vs. 2.9 +/- 0.8 micrograms/L; P = 0.03) in females than in males. Plasma glucagon, cortisol, epinephrine, and norepinephrine levels during the clamp were similar in the two sexes, except for pancreatic polypeptide, which showed a tendency to be higher in females (19 +/- 4 vs. 11 +/- 1 pmol/L; P = 0.07). During insulin-induced hypoglycemia, the rate of drop in plasma glucose was faster (0.16 +/- 0.01 vs. 0.11 +/- 0.01 mmol/L.min; P = 0.001), and the rate of glucose recovery was slower in males than in females (0.04 +/- 0.01 vs. 0.06 +/- 0.01 mmol/L.min; P = 0.05). Plasma glucose concentrations were lower in males than in females (glucose nadir, 2.3 +/- 0.2 vs. 3.3 +/- 0.2 mmol/L; P = 0.002; glucose peak, 3.7 +/- 0.2 vs. 5.3 +/- 0.4 mmol/L; P = 0.002), with similar plasma free insulin concentrations. Despite a greater degree of hypoglycemia, GH responses were lower in males than in females. The remaining counterregulatory hormone responses were similar in both sexes. We conclude that there is a distinct sexual dimorphism in insulin sensitivity in adolescents with IDDM. This is likely to be due to sex-related differences in GH levels. Furthermore, male patients with IDDM are apt to develop greater degrees of hypoglycemia accompanied by lower GH responses.

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.

The roles of potential risk factors for background and proliferative retinopathy were evaluated in cross-sectional analyses from the Epidemiology of Diabetes Complications Study, Pittsburgh, Pennsylvania. This report presents results from the 657 insulin-dependent diabetic participants seen at the baseline examination (1986-1988). The presence of and severity of retinopathy were judged from stereoscopic photographs of three views of the ocular fundus using the modified Airlie House classification system. Fifty-three percent of the participants had background retinopathy, and 31% had proliferative retinopathy. Logistic regression analyses showed that among participants aged less than 18 years, those with background retinopathy were older and had higher levels of glycosylated hemoglobin compared with those without retinopathy. In the 18-29-year age group, participants with background retinopathy had a longer duration of diabetes, higher low density lipoprotein (LDL) cholesterol levels, and lower high density lipoprotein cholesterol levels and were more likely to have microalbuminuria compared with those without retinopathy. Participants aged 18-29 years with proliferative retinopathy had a longer duration of diabetes, higher diastolic blood pressure, and higher fibrinogen and LDL cholesterol levels than those with background retinopathy. In the age group greater than or equal to 30 years, diabetes duration, diastolic blood pressure, and fibrinogen, LDL cholesterol, and triglyceride levels were increased in participants with proliferative retinopathy versus those with background retinopathy. In a multivariate model of proliferative retinopathy, controlling for concurrent renal disease weakened the influence of blood pressure, fibrinogen, triglycerides, and LDL cholesterol and improved the overall fit of the model. These results suggest that diabetic nephropathy may contribute to the development of proliferative (but not background) retinopathy by increasing blood pressure and fibrinogen, by altering the lipoprotein profile, and possibly through other mechanisms.

The BB rat is the experimental analogue of human juvenile diabetes mellitus. From 30 through 120 days after birth, 59 BB rats were treated with water (n = 20), or FK 506 in daily intragastric doses of 1 mg/kg (n = 19) or 2 mg/kg (n = 20). Diabetes developed in 75%, 15%, and 0% of the three groups. Animals protected from diabetes by FK 506, and killed in the nondiabetic state at 120 days had normal intraperitoneal glucose tolerance tests, virtual absence histopathologically of autoimmune insulitis, normal pancreatic insulin content, and immunocytochemical confirmation of islet insulin and glucagon content. Forty five to 75 days after stopping FK 506, about 3/4 of the animals who were diabetes free at 120 days have remained so. These results provide support for a clinical trial of FK 506 for recent onset diabetes.

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.

We report results from 120 (25- to 34-year-old) participants in a neuropathy substudy of subjects with insulin-dependent diabetes mellitus (IDDM) taking part in a cohort follow-up study. Diabetic neuropathy was evaluated by quantitative sensory testing, nerve conduction studies, and clinical examination. Mean quantitative sensory thresholds differed significantly by clinical category of abnormal sensation and ankle reflex activity. Mean sural and peroneal amplitudes and conduction velocities were also significantly lower for subjects classified as having abnormal ankle reflex activity. Modeling potential correlates in logistic analyses showed glycemic control, triglyceride levels, and hypertension status to be independently associated with clinically overt neuropathy. Similar lipid and hemodynamic parameters were associated with abnormality by any single assessment method used to define neuropathy. Although follow-up is needed to resolve the best assessment methods for determining neuropathy, these results suggest that good glycemic control as well as control of blood pressure and lipids is advisible.

Proportional hazards models measuring the effect of age at onset of insulin-dependent diabetes mellitus on mortality risk are presented. The study population consisted of 924 insulin-dependent diabetic patients who were seen within 1 year of diagnosis at Children's Hospital of Pittsburgh between 1950 and 1981 and were more than 20 years old at follow-up. Age at diabetes onset was categorized as prepubertal or pubertal, defined by age. Individuals with pubertal onset of diabetes had a significantly higher risk of mortality compared with those with prepubertal onset by diabetes duration but not by attained age. It is proposed that age at onset is an independent determinant of mortality in diabetic individuals and may represent either heterogeneity within insulin-dependent diabetes mellitus with respect to long-term prognosis or an interactive effect of diabetes duration and puberty on prognosis.

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)

To identify characteristics associated with long-term avoidance of insulin-dependent diabetes mellitus (IDDM) complications, subjects taking part in an epidemiologic natural history study of childhood-onset IDDM, with a duration of disease greater than or equal to 25 yr, were studied. Nineteen percent of 175 subjects had avoided overt nephropathy, definite cardiovascular and peripheral vascular disease, clinical neuropathy, and proliferative retinopathy. Approximately half of the nonrenal complications occurred in the absence of renal disease. Subjects free of these advanced complications were characterized by a longer duration of disease (P less than 0.05), better lipid profile and blood pressure (P less than 0.01), and considerably lower glycosylated hemoglobin levels (P less than 0.001). Health-related behaviors, including recent medical contact, regular glucose monitoring, physical activity in youth, and avoidance of cigarette smoking, did not relate to complication status, although regular (at least weekly) alcohol consumption was more prevalent (P less than 0.05) in those without complications. We conclude that a lower mean glycosylated hemoglobin level is strongly related to the avoidance of all IDDM complications.

There was a need to design a questionnaire that could accurately assess the activity patterns of Native Americans to evaluate the relationship between physical activity and diabetes. Such a questionnaire was developed and implemented into the data collection scheme of the prospective Pima Indian Study of Arizona. The questionnaire, which assesses historical, past-year, and past-week leisure and occupational activity, was examined in 29 Pima individuals aged 21-36 yr and was shown to be reliable with test-retest correlations (rank-order correlations ranged from 0.62 to 0.96 for leisure and occupational activity). Reproducibility of the past-year leisure physical-activity estimate was determined in 69 participants aged 10-59 yr and was found to be reliable in all age-groups with the exception of the 10- to 14-yr-old age-group (rank-order correlations were 0.31 in the 10- to 14-yr-old age-group compared to 0.88 to 0.92 in those greater than 20 yr of age). Validity of the current-activity section of the questionnaire was demonstrated indirectly through comparisons with activity monitors. The past-week leisure-activity estimate was related to the Caltrac activity monitor counts per hour (rho = 0.62, P less than 0.05, n = 17). In summary, a physical-activity questionnaire has been developed that is both reliable and feasible to use in the Pima Indian population to evaluate the relationship of physical activity to non-insulin-dependent diabetes mellitus.

Noninsulin dependent diabetes mellitus (NIDDM) is associated with an entirely different set of genetic alterations from insulin-dependent diabetes mellitus (IDDM). Over 90% of IDDM carry HLA type DR3, DR4 or both. Several theories have been proposed to explain how the genetic alterations are translated into a beta cell destructive process. All involve the elaboration of a beta cell autoantigen. A major current research focus is on the development of pharmacologic approaches to the control of the beta cell destructive process (cyclosporine A). This has led to a shift in interest to the early identification of individuals at risk for IDDM. Many questions remain to be answered. In our paper emphasis is placed on epidemiological research. In Allegheny County, Pennsylvania, we have found an incidence of 1.73 cases/1000 (incidence rate of 15/100,000/year). There were marked geographical variations (incidence rate of 1/100,000/year in Asian countries, of 40/100,000/year in Finland). This suggests that there are major environmental determinants leading to expression of disease in genetically susceptible individuals. There are no geographical differences in the main age of onset, the sex ratio and the clinical patterns in the initial course of newly detected IDDM. In all parts of the world islet cell antibodies are positive in 60-80% of newly diagnosed IDDM. Migration of children from their native homeland with a low incidence rate to a country with high incidence rate was accompanied by an increase of incidence. The following potential environmental factors have been considered: viral infections, environmental toxins, nutrients, and stress. In our view IDDM occurs in genetically susceptible individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

To ascertain whether the dawn phenomenon occurs in normal adolescents and, if so, to determine its mechanism, we measured nocturnal plasma glucose, insulin, glucagon, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH) levels between 01.00 and 08.00 h in 10 healthy adolescents. The prehepatic insulin secretion rate was calculated based on C peptide levels. The metabolic clearance rate of insulin (MCRI) was calculated as the ratio of mean insulin secretion rate to mean insulin concentration. There was no change in plasma glucose, insulin, and glucagon between 01.00-04.00 and 05.00-08.00 h (paired t test). The MCRI was higher at 05.00-08.00 h compared to 01.00-04.00 h (9.30 +/- 1.50 vs. 4.87 +/- 1.11 ml.kg-1.min-1; p = 0.008). The prehepatic insulin secretion increased at 05.00-08.00 h relative to 01.00-04.00 h (1.1 +/- 0.2 vs. 0.6 +/- 0.1 pmol.kg-1.min-1; p = 0.013). Similarly, cortisol and ACTH levels were higher at 05.00-08.00 versus 01.00-04.00 h (323 +/- 33 vs. 102 +/- 22 nmol/l, p less than 0.001; 3.6 +/- 0.5 vs. 1.8 +/- 0.4 pmol/l, p = 0.006, respectively). Growth hormone was higher at 01.00-04.00 versus 05.00-08.00 h (7.6 +/- 1.2 and 3.0 +/- 0.9 microgram/l; p = 0.019). ACTH correlated with MCRI (r = 0.66; p = 0.002) and prehepatic insulin secretion (r = 0.75; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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)

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.

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.

Ten male subjects underwent exercise testing in three modes, arms (A), legs (L), and arms + legs (A + L), after ingesting 0.3 g X kg-1 body weight of either NaHCO3 to induce alkalosis or CaCO3 as a placebo (i.e., six exercise trials). Ratings of perceived exertion (RPE: Borg, 15-pt scale) for the arms (RPE-A), legs (RPE-L), chest (REP-C), and overall body (RPE-O) did not differ between acid-base conditions at 20, 40, or 60% VO2max for all three exercise modes. At 80% VO2max, 1) RPE-A was lower (P less than 0.01) during A; 2) RPE-L was lower (P less than 0.01) during L; and 3) RPE-A and RPE-L were lower (P less than 0.01) during A + L under the NaHCO3 as compared to the CaCO3 condition. Differences were not found for RPE-L during A or for RPE-A during L. RPE-C and RPE-O were lower (P less than 0.01) under NaHCO3 during A, L, and A + L. Blood acid-base, VO2, and cardiorespiratory responses were not differentially influenced by exercise mode. Blood pH was significantly higher under NaHCO3 than CaCO3 at pre-exercise and 80% VO2max. VO2, heart rate, and tidal volume did not differ between acid-base conditions at any exercise intensity. VE and respiratory rate did not differ between acid-base conditions at 20, 40, or 60% VO2max but were significantly lower under NaHCO3 at 80% VO2max. RPE-A and L were positively related to blood [H+], and RPE-C was positively related to VE for all exercise modes.

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)

To assess the immunologic differences related to histocompatibility leukocyte antigen (HLA) haplotypes in patients with type 1 diabetes, trivalent killed influenza virus vaccine was given in the fall, when no influenza occurred, to 59 patients with diabetes (mean age 16 years) and 64 siblings without diabetes (mean age 36 years). All subjects had normal hemagglutination inhibition antibody responses at days 14 and 42 after vaccination, with no significant differences noted between patients with diabetes and those without diabetes. However, subjects with HLA haplotypes DR 3, DR 4, or both had lower antibody responses to influenza A/Chile and B/USSR at 14 days after vaccination (p less than 0.02) than DR x/x controls (who lacked 3 or 4). Lymphocyte transformation (LT) responses before and after vaccination were similar for patients with diabetes and those without diabetes. Of significance was that subjects with HLA haplotypes DR 3, DR 4, or both had 41.1% LT responders at 42 days after vaccination, compared with subjects with HLA-DR x/x (lacking 3 or 4) who had 22.6% responders (p less than 0.03), when influenza A/Chile was used as an antigen. Although not significant, influenza antigens A/Philippines and B/USSR each showed similar trends with increased postvaccine LT responses. The HLA associations were independent of sex, age, and the presence of diabetes. These studies suggest that HLA haplotypes DR 3 and DR 4, which were clearly linked to type 1 diabetes mellitus, were also associated with altered immune responsiveness to influenza viral proteins.

The venous plasma glucose and insulin concentrations recorded during oral glucose tolerance testing of over 300 1st degree relatives (parents and siblings) of insulin dependent diabetics are presented. Men had higher glucose concentrations than women, the difference increasing with age, while insulin responses appeared greater in adolescent girls and young women than their male counterparts. The possible relationship between the different insulin responses in the two sexes and the sex difference in cardiovascular risk factors is discussed. It is suggested that the absence of a marked sex differential in heart disease mortality amongst diabetics may partly result from the loss by diabetic women of their greater insulin production relative to men in young adult life.

Genetic, immunological and viral factors have been implicated in pathogenesis of Type 1 diabetes mellitus. The development of Type 1 diabetes in two siblings of patients with Type 1 diabetes studied as part of a large epidemiological study, is described. One case, a 13-year-old male not sharing either HLA haplotype with his diabetic sister, had virtually normal glucose tolerance 80 days before symptomatic presentation. He showed serological evidence of infection by Coxsackie CB4 (at diagnosis) and influenza A virus (soon after diagnosis). The other case, a 15-year-old male, had impaired glucose tolerance for over 500 days (i.e., since the diagnosis of diabetes in his HLA-identical brother) before symptomatic presentation which was not associated with serological evidence of acute viral infection. The former case was negative for islet cell antibody (cytoplasmic) when first seen though positive at diagnosis, while the latter was positive throughout. These two cases suggest contrasting interactions of the main pathogenetic factors associated with Type 1 diabetes.

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.

In this report, we present an analysis of glucose and insulin responses during oral glucose tolerance tests in 369 siblings of Type 1 diabetic patients. All have been HLA typed at the A, B and C loci. Though most had normal glucose tolerance by National Diabetes Data Group criteria (92% of the males and 95% of the females), siblings who shared both HLA haplotypes with the diabetic patient in the family had higher mean 3-hour glucose areas than those who shared one or neither HLA haplotype (p less than 0.01). This difference was more marked in males and older siblings. Insulin concentrations did not differ significantly between the two groups except that, for those aged less than 16 years, the group sharing both haplotypes had lower fasting insulin concentrations (p = 0.05); for 16-29 year olds, the corresponding group had marginally higher 3-hour insulin areas than the remainder of siblings (p = 0.17). Little association with specific haplotypes (A1B8 or A2B15) was seen. Multivariate analyses, adjusting for age and obesity, eliminated the 3-h glucose difference in females by HLA sharing status (p = 0.37) although in males it remained significant (p less than 0.001). Failure to account for age, sex and obesity may explain some of the conflicts in the reported literature. The glucose tolerance differences seen by HLA haplotype sharing status did not correlate with the presence of anti-islet cell antibodies. These results are consistent with the hypothesis that the HLA identical siblings, particularly males, have different (i.e. worse) glucose tolerance than their haploidentical and non-HLA identical siblings.

We report four children aged 11-18 1/2 yr first seen 7-14 yr after the diagnosis of insulin-dependent diabetes. At presentation, all had marked short stature, two had hepatomegaly, and the older three had delayed adolescence. They had been severely underinsulinized. Initial funduscopy demonstrated only occasion microaneurysms in two children and a single intraretinal hemorrhage in another. The youngest was normal. Improved control required large increases in insulin dosage. Growth rate improved significantly and hepatomegaly regressed. Puberty progressed rapidly in two older patients with poor final height. Paradoxically, with improved control, retinopathy progressed rapidly with appearance of multiple microaneurysms, nerve fiber layer infarctions, intraretinal microangiopathic changes, hemorrhages, exudates, and macular edema in all the patients and severe proliferation changes in three. One child with proliferative retinopathy in both eyes developed vitreous hemorrhage and blindness in one eye. Two required panretinal photocoagulation with no further progression of their retinopathy. These rapidly progressive retinal changes remain unexplained. We advise caution when correcting metabolic derangements of diabetic patients who have been poorly controlled for a prolonged period.

We implemented a three-phase, 32-wk program to improve both self-regulation of adherence behaviors and insulin delivery in children with diabetes. Twenty children, aged 8-12 yr (mean duration 3.6 yr), enrolled. Phase 1 (wk 1-12) used behavior modification to improve diet, exercise, urine testing, and insulin adjustment, targeting an increased percentage negative urines. Feedback training and parent checks were used to improve reliability; adherence was measured using Clinitest placebos. Phase 2 (wk 13-20) was a stabilization period. Phase 3 (wk 21-32) studied the effect of insulin dose adjustment, comparing once-versus twice-daily shots in 10 pairs of children matched for %GHb. GHb, fasting plasma glucose, and lipids were measured at baseline and at the end of each phase. Results revealed a significant and sustained increase in negative urine tests, but no change in % GHb or FBG. Reliability of and adherence to urine tests were 83% and 76%, respectively. During phase 3, no significant differences were noted between groups receiving once- or twice-daily insulin injections. Thus, behavior modification resulted in increased reliability and adherence to routines, associated with a reliable increase in negative urines. This did not, however, produce changes in other control measures. Furthermore, no differences between those receiving 1 or 2 daily shots were evident.

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 contribution of diabetes duration, both pre- and postpuberty, to the development of microvascular complications and mortality in diabetic subjects was investigated in three study populations from the Children's Hospital of Pittsburgh Insulin-Dependent Diabetes Mellitus (IDDM) Registry. Life-table analyses by total and postpubertal IDDM duration were used to evaluate differences in the prevalence of microvascular complications and diabetes-related mortality in subjects diagnosed before and during puberty, as defined by an age at IDDM onset marker of 11 yr for girls and 12 yr for boys. The prevalence of retinopathy and overt nephropathy in 552 White adult diabetic subjects (population 1, mean IDDM duration 20.8 yr was significantly greater in subjects diagnosed during puberty compared with those diagnosed before puberty. However, similar analyses by postpubertal duration showed no difference in microvascular complication prevalence between the two groups. These findings did not appear to be due to a confounding effect of age. Additional analyses of 239 adolescent diabetic subjects (population 2, mean duration 8.3 yr) revealed the same trend for the prevalence of retinopathy. Finally, results concerning the risk of diabetes-related mortality in a cohort of 1582 subjects (population 3, mean duration 12.9 yr) indicated that postpubertal duration of IDDM may be a more accurate determinant of the development of microvascular complications and diabetes-related mortality than total duration, and it is suggested that the contribution of the prepubertal years of diabetes to long-term prognosis may be minimal.

A series of patients having onset of Type I (insulin-dependent) diabetes mellitus before age 17 years was identified from consecutive admissions to the Children's Hospital of Pittsburgh. Family history data were obtained yielding 1006 families (1085 cases) with complete information. The prevalence of diabetes among the children differed by birth order, with a greater number than expected among first born. There was also an increased prevalence among children born to mothers older than 35 years, as well as an increased prevalence among children of very young mothers. The increased prevalence of diabetes among offspring of older mothers was apparent even after life table age corrections were made. However, both the increased prevalence among first born children and the increased prevalence among children of very young mothers could be attributed to an older attained age of these children in this particular population. This indicated that the maternal age effect was present but a birth order effect was absent when age was taken into account.

Epidemiologic studies are providing important new insights into the etiology and clinical course of IDDM as well as providing critically needed data on the magnitude of the problem in different parts of the world. The development of national IDDM registries have documented extraordinary differences in diabetes incidence and prevalence, with the highest incidence figures in Finland (greater than 30/100,000/yr) and the lowest in the Orient with Korea reporting incidence rates below 1 and Japan between 1.0-2.4/100,000/yr. The great geographic variation in expression of diabetes in childhood is strongly supportive of environmental factors playing a major role in the etiology of disease. Our studies document a linear correlation between IDDM incidence and distance from the equator and a similar but inverse correlation with mean annual environmental temperature. Other workers find a direct correlation with dairy product consumption. Factors that may play a role in beta cell damage include viral infections, environmental toxins, nutrients and stress factors. Because of the low incidence of IDDM among children living in Asia it is most important to expand the current national registries in the Asian countries and begin a careful study of the environmental differences within Asian countries as well as comparison of studies between countries with very high incidence rates and those with the lowest rates.

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.

Occupational issues in 158 insulin-dependent diabetes mellitus (IDDM) individuals and 158 matched nondiabetic siblings were examined in a case-control design to evaluate the role of diabetes in the employability of people with IDDM. Overall, the IDDM cases were more likely to report refusal for a job at some point in their lives (56 vs. 42%, P = .02) than were the nondiabetic control siblings. Surprisingly, individuals who told job interviewers about their diabetes were more likely to report job refusal than their siblings (64 vs. 42%, P = .005), whereas individuals who did not mention their diabetes reported rates of refusal similar to their siblings (44 vs. 41%). IDDM cases were also less likely to be employed full time compared with siblings (55 vs. 73%, P = .001). Reduced employment in IDDM respondents was related to work disability. Reported work disability was more than seven times greater in the IDDM than the sibling group. The presence of diabetic complications was the primary factor related to work disability. Although 13% of IDDM respondents were unable to work because of disability, absenteeism among IDDM cases currently working did not differ from that of the nondiabetic siblings. Diabetes was not significantly associated with career levels or household income levels reported by the IDDM group. Disability, however, had a strong detrimental influence on these variables. The results suggest that hiring practices by employers may still be discriminatory toward individuals with IDDM. Once hired, the employment experiences of the IDDM population appear to be similar to the experiences of the nondiabetic population, provided the development of disabling diabetic complications has not taken place.

The relationships between HLA antigens, sex, age at diagnosis, season of onset and insulin-dependent diabetes mellitus (IDDM) were studied in a consecutive admissions series of newly-diagnosed IDDM patients at Children's Hospital of Pittsburgh. In agreement with the findings of others, the strongest positive associations between IDDM and HLA antigens were seen with DR3 and DR4 (odds ratios (OR) of 3.5 and 4.4, respectively), while a very strong negative association was observed with DR2 (OR of 0.1). Male patients were significantly more likely than female patients to possess DR3 while female patients were significantly more likely to be DR4+. No consistent relationships were found between HLA antigens and either age at diagnosis or season of onset. Using a life table approach, the cumulative risk of IDDM by age 24 in HLA-identical siblings of IDDM patients was estimated to be 10.3%. This risk was significantly greater than the risks to either HLA-haploidentical siblings (2.2%) or to HLA-nonidentical siblings (1.0%), whose risks were not significantly different. B7 + HLA-identical siblings of patients appeared to be protected from the effects of HLA-identicality--their cumulative risk by age 24 was estimated to be only 2.3%.