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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)

One hundred seventy-two members from 27 randomly selected multiple case Caucasian families of patients with insulin-dependent diabetes mellitus (IDDM) were studied at the DNA level to ascertain the reliability of codon 57 of the HLA-DQ beta-chain gene as a disease protection/susceptibility marker. The analysis was carried out by polymerase chain reaction amplification of DNA encoding the first domain of the DQ beta chain and by dot blot analysis of the amplified material with allele-specific oligonucleotide probes. One hundred twenty-three randomly selected healthy Caucasian donors were also tested. The results demonstrated that haplotypes carrying an aspartic acid in position 57 (Asp-57) of their DQ beta chain were significantly increased in frequency among nondiabetic haplotypes (23/38), while non-Asp-57 haplotypes were significantly increased in frequency among diabetic haplotypes (65/69). Ninety-six percent of the diabetic probands in our study were homozygous non-Asp/non-Asp as compared to 19.5% of healthy unrelated controls. This conferred a relative risk of 107 (chi 2 = 54.97; P = 0.00003) for non-Asp-57 homozygous individuals. Even though the inheritance and genetic features of IDDM are complex and are not necessarily fully explained by DQ beta chain polymorphism, this approach is much more sensitive than HLA serolog in assessing risk for IDDM.

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 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.

OBJECTIVES -To investigate long-term mortality and its temporal trends as of 1 January 1999 among the 1,075 patients with type 1 diabetes (onset age Ͻ18 years, diagnosed between 1965 and 1979) who comprise the Allegheny County population-based registry.RESEARCH DESIGN AND METHODS -Overall, sex-and race-specific mortality rates per person-year of follow-up were determined. Standardized mortality ratios were also calculated. Survival analyses and Cox proportional hazard model were also used. Temporal trends were examined by dividing the cohort into three groups by year of diagnosis (1965-1969, 1970 -1974, and 1975-1979).RESULTS -Living status of 972 cases was ascertained as of January 1, 1999 (ascertainment rate 90.4%). The mean duration of diabetes was 25.2 Ϯ 5.8 (SD) years. Overall, 170 deaths were observed. The crude mortality rate was 627 per 100,000 person-years (95% CI 532-728) and standardized mortality ratio was 519 (440 -602). Life-table analyses by the Kaplan-Meier method indicated cumulative survival rates of 98.0% at 10 years, 92.1% at 20 years, and 79.6% at 30 years duration of diabetes. There was a significant improvement in the survival rate between the cohort diagnosed during 1965-1969 and that diagnosed during 1975-1979 by the log-rank test (P ϭ 0.03). Mortality was higher in African-Americans than in Caucasians, but there were no differences seen by sex. The improvement in recent years was seen in both ethnic groups and sexes.

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.

The presence of an amino acid other than aspartic acid at position 57 of the HLA-DQ (3 chain (non-Asp-57) is highly associated with susceptibility to insulin-dependent diabetes mellitus (IDDM), whereas an aspartic acid at this position (Asp-57) appears to confer resistance to the disease. We hypothesize that the 30-fold difference in IDDM incidence across racial groups and countries is related to variability in the frequency of these alleles. Diabetic and nondiabetic individuals were evaluated in five populations, including those at low, moderate, and high risk. HLA-DQ (3 genotype distributions among the IDDM case groups were markedly different (P < 0.001), as were those among nondiabetic controls (P < 0.001).Non-Asp-57 alleles were signiflcantly associated with IDDM in all areas; population-specific odds ratios for non-Asp-57 homozygotes relative to Asp-57 homozygotes ranged from 14 to 111. Relative risk information from the case-control study and population incidence data were combined to estimate genotypespecific incidence rates for the Allegheny County, PA, Caucasians. These rates were used to predict the overall incidence rates in the remaining populations, which were within the 95% confidence intervals of the actual rates established from incidence registries. These results are consistent with the hypothesis that population variation in the distribution of non-Asp-57 alleles may explain much of the geographic variation in IDDM incidence.Many chronic diseases exhibit marked geographic variation in incidence (1). Insulin-dependent (type I) diabetes mellitus (IDDM) is one such disorder for which the worldwide patterns of incidence have been well documented (2-4). Ageadjusted IDDM incidence rates are very high in the Scandinavian countries, such as Finland (29.5/100,000 per year) (4), but are extraordinarily low in the Oriental populations, such as China (5) and Japan (4) (0.7/100,000 per year) (Fig. 1). Although the causes of the geographic variation in IDDM incidence are unknown, differences in the distribution of genetic or environmental factors are likely to be related to the variations in disease incidence across populations.In humans, the HLA region of the short arm of chromosome 6 contains genes of the major histocompatibility complex (MHC), which are highly associated with susceptibility to IDDM (6). We now know that the outer domains of MHC molecules form a cleft in which polypeptides from processed antigens can bind. The shape of the MHC molecule's cleft is determined by critical amino acid segments. Variation in these crucial sequences directly affects the peptide-binding ability ofthe molecule and permits the proper lodging of some antigens, whereas others are not efficiently bound (7). When properly presented, the helper T-cell recognizes the MHC molecule/polypeptide complex by means of its a/f, receptor and becomes activated. The MHC molecule/polypeptide complex is also known to restrict the T-cell clone repertoire of an individual (8). It appears that variation in those critical amino ac...