Janice S. Dorman

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 (≥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 ≥30 yr duration, giving a combined prevalence of microalbuminuria and overt nephropathy at ≥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 (>30%) compared with men (11%) when determined by ankle/arm blood pressure ratio <0.8 at rest or after exercise. These results suggest that the natural history of IDDM complications varies considerably by sex and that the prevalence of complications (especially renal complications in males) may be higher than previously recognized.

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 Childrens 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% ≥30 yr old) with no difference by sex. By focusing on subjects s 18 yr old, all significant univariate variables (e.g., duration, glycosylated hemoglobin [HbAJ) were analyzed in 3 multiple logistic regression models: all subjects ≥18 yr old and separating the same subjects into two groups based on age (18-29 and 2:30 yr). Duration, HbA1, smoking status, and high-density lipoprotein cholesterol were found to be associated with neuropathy in the models for the ≥18-yr-old group and the ≥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. There was a univariate association of neuropathy with macrovascular disease, nephropathy, and retinopathy. Macrovascular disease, although borderline significant, remained in the original logistic model for the ≥18-yr-old subjects. The addition of either retinopathy or nephropathy to the original logistic model for the 18- to 29-yr-old subjects resulted in a statistically significantly improved fit (of model to data), suggesting that these complications may be a marker for something beyond the risk factors described. The results suggest that traditional cardiovascular risk factors (e.g., lipids and smoking) are important determinants of distal symmetric polyneuropathy and if confirmed in prospective follow-up, open new avenues to the prevention of diabetic neuropathy.

Contribution of Diabetes Duration Before Puberty to Development of Microvascular Complications in IDDM Subjects

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 Childrens 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.

Factors Associated With Avoidance of Severe Complications After 25 Yr of IDDM: Pittsburgh Epidemiology of Diabetes Complications Study I

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 ≥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 < 0.05), better lipid profile and blood pressure (P < 0.01), and considerably lower glycosylated hemoglobin levels (P < 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 < 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.

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 thanin 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.

Measuring Diabetic Neuropathy: Assessment and Comparison of Clinical Examination and Quantitative Sensory Testing

The need for a standardized and valid means of assessing diabetic neuropathy has been increasingly recognized. To identify potential components of such an assessment, interobserver variation (neurologist and internist) of a standard neurologic examination and the comparability of this examination with vibratory and thermal sensitivity testing was studied. The study population comprised the first 100 participants in a neuropathy substudy of 25- to 34-yr-old subjects with insulin-dependent diabetes mellitus taking part in a cohort follow-up study. Symptoms of dysesthesias, paresthesias, and burning, aching, or stabbing pain revealed good interobserver agreement. Signs of neuropathy, more prevalent in the great toe than index finger, showed poor interobserver agreement for vibration, but fair interobserver agreement for touch and pinprick. Mean quantitative sensory thresholds differed significantly by clinical category of abnormal vibratory and pinprick sensations. Threshold testing showed twice the prevalence of abnormality compared with clinical examination. It is concluded that components of the clinical examination can be identified that, along with quantitative sensory-threshold testing, may provide a satisfactory core assessment for use both in epidemiologic studies and incorporation into more in-depth protocols required for clinical research and practice. The clinical relevance of the greater prevalence of abnormalities on threshold testing will be established by long-term follow-up.

Familial resemblance of bone mineral density (BMD) and calcaneal ultrasound attenuation : The BMD in Mothers and Daughters Study

The familial resemblance in bone mineral density (BMD) and calcaneal broadband ultrasound attenuation (BUA) was examined in 207 mother‐daughter pairs. Mothers were participants in the Study of Osteoporotic Fractures. Three groups of daughters were recruited based on their maternal history of “fracture,” “low BMD” without fracture (< 0.58 g/cm2, t‐score < −2.5), and “normal BMD” without fracture (> 0.67 g/cm2, t‐score > −1.6). Data on other potentially heritable factors known to influence BMD and BUA were also collected. BMD was measured at the hip, spine, whole body, and calcaneus. Calcaneal BUA was assessed using the Walker‐Sonix UBA 575. Total hip and femoral neck BMD were significantly lower (5.0–8.0%, p < 0.017) among daughters, in particular premenopausal daughters, of mothers with established osteoporosis (“fracture” or “low BMD”) compared with daughters of mothers at lower risk of osteoporosis (“normal BMD”). BUA did not differ across daughter groups. Lifestyle characteristics (dietary calcium, smoking, physical activity) were not highly correlated in mothers and daughters. Height, weight, and body composition were significantly correlated within mother‐daughter pairs and could be a potential mechanism by which BMD is inherited. Among pre‐ and postmenopausal daughters, heritability estimates ranged from 50–63% and 34–48%, respectively. Heritability for calcaneal BUA (53%) was evident among postmenopausal daughters only. In conclusion, familial association in BMD was strongest among premenopausal daughters. Estimates of heritability suggest that maternal BMD and BUA are important independent predictors of BMD and BUA among daughters, reinforcing the importance of prevention and early intervention among women with a positive family history of osteoporosis. (J Bone Miner Res 1999;14: 102–110)

Cardiovascular disease and arterial calcification in insulin-dependent diabetes mellitus: interrelations and risk factor profiles. Pittsburgh Epidemiology of Diabetes Complications Study-V.

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.

Childhood Diabetes in China: Enormous variation by place and ethnic group

OBJECTIVE To investigate the incidence rate of IDDM in China. RESEARCH DESIGN AND METHODS The Chinese IDDM registry was established in 1991 as part of the World Health Organizations Multinational Project for Childhood Diabetes (DiaMond) project. Twenty-two centers were developed to monitor the incidence of IDDM in children <15 years of age. The population under investigation includes >20 million individuals, representing ∼7% of the children in China. Capture-recapture methods were used to estimate the ascertainment. RESULTS The overall ascertainment-corrected IDDM incidence rate in China was 0.51 per 100,000, the lowest rate ever reported. There was a 12-fold geographic variation (0.13–1.61 per 100,000). In general, the incidence rate was higher in the north and the east. There was a sixfold difference among ethnic groups (highest: Mongol group, 1.82 per 100,000; lowest: Zhuang group, 0.32 per 100,000). CONCLUSIONS China has an extremely low overall IDDM incidence rate. China also has the greatest geographic and ethnic variation seen for any country.