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)

The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate ('neutral'), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 ¼ *0401 ¼ *0402 > *0404 > *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that metaanalyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels.

Women with type 1 diabetes have a delayed menarche and a greater prevalence of menstrual disorders than women without diabetes. However, little is known about the menopause transition among type 1 diabetic women. The Familial Autoimmune and Diabetes (FAD) Study recruited both adult individuals who were identified from the Children's Hospital of Pittsburgh Type 1 Diabetes Registry for the years 1950 -1964 and their family members. Unrelated nondiabetic control probands and their relatives were also evaluated. Women with type 1 diabetes (n ‫؍‬ 143) compared with nondiabetic sisters (n ‫؍‬ 186) or unrelated control subjects (n ‫؍‬ 160) were more likely to have an older age at menarche (13.5, 12.5, and 12.6 years, respectively, P < 0.001), more menstrual irregularities before 30 years of age (45.7, 33.3, and 33.1%, respectively, P ‫؍‬ 0.04), and a younger age at menopause (41.6, 49.9, and 48.0 years, respectively, P ‫؍‬ 0.05). This resulted in a 6-year reduction in the number of reproductive years (30.0, 37.0, and 35.2 years, respectively, P ‫؍‬ 0.05) for women with type 1 diabetes. Risk factors univariately associated with earlier menopause included type 1 diabetes (hazard ratio [HR] 1.99, P ‫؍‬ 0.04), menstrual irregularities before 30 years of age (HR 1.87, P ‫؍‬ 0.04), nulliparity (HR 2.14, P ‫؍‬ 0.01), and unilateral oophorectomy (HR 6.51, P < 0.0001). Multivariate analysis confirmed that type 1 diabetes (HR 1.98, P ‫؍‬ 0.056), menstrual irregularities by 30 years of age (HR 2.36, P ‫؍‬ 0.01), and unilateral oophorectomy (HR 9.76, P < 0.0001) were independent determinants of earlier menopause in our cohort. We hypothesize that an earlier menopause, which resulted in a 17% decrease in reproductive years, is a major unstudied complication of type 1 diabetes.

OBJECTIVE -To determine whether middle-aged premenopausal women with type 1 diabetes had more self-reported fractures and lower bone mineral density (BMD) compared with nondiabetic women.RESEARCH DESIGN AND METHODS -Participants were premenopausal women aged 35-55 years with type 1 diabetes (n ϭ 67; 32.2 Ϯ 5.3 years duration) and without diabetes (n ϭ 237). Total hip, femoral neck, whole-body, and spine BMD were measured by dual X-ray absorptiometry. Calcaneal broadband ultrasound attenuation (BUA) was assessed with quantitative ultrasound.RESULTS -Women with type 1 diabetes were more likely to report a fracture after age 20 years compared with nondiabetic women (33.3 vs. 22.6%; age-adjusted odds ratio 1.89 [95% CI 1.02-3.49]). Type 1 diabetes was associated with lower total hip BMD (0.890 vs. 0.961 g/cm 2 ; P Ͻ 0.001), femoral neck BMD (0.797 vs. 0.847 g/cm 2 ; P ϭ 0.001), whole-body BMD (1.132 vs. 1.165 g/cm 2 ; P Ͻ 0.01), and lower calcaneal BUA (71.6 vs. 84.9 dB/MHz; P Ͻ 0.001) after multivariate adjustment. BMD was 3-8% lower in type 1 diabetic compared with control women and calcaneal BUA was 15% lower. Spine BMD and biomarkers of bone remodeling were not significantly different between groups. In the type 1 diabetic women, reduced monofilament detection and blindness were both associated with lower BMD.CONCLUSIONS -Lower BMD in premenopausal women with type 1 diabetes may substantially increase their risk of developing osteoporosis after menopause. Type 1 diabetic women should be targeted for osteoporosis screening and possible fracture prevention as they transition through menopause. Diabetes Care 29:306 -311, 2006T he impact of the menopause transition on osteoporosis in type 1 diabetes is not well established. The Nord-Trodelag Health Survey (1) and the Iowa Women's Health Survey (2) found a 7-and 12-fold increase in hip fractures, respectively, in older type 1 diabetic women. Type 1 diabetes was associated with ϳ10% lower bone mineral density (BMD) compared with nondiabetic adults (3-10) in most but not all studies (11-13), though many include only small numbers of cases and lack adjustment for traditional osteoporosis risk factors (e.g., lower body weight and smoking). Few investigations (3,5,13) of type 1 diabetes and BMD focus exclusively on middleaged and postmenopausal women, those at highest risk for osteoporosis and fractures.Evidence exists for the role of diabetes complications of peripheral neuropathy (6,12,14,15), retinopathy (14,16 -18), and nephropathy (14,17,19) in osteoporosis. Peripheral measures of bone, such as calcaneal quantitative ultrasound (QUS) (20,21), could be more affected by peripheral vascular disease or peripheral neuropathy (15). Worse glycemic control in type 1 diabetes was generally not related to lower BMD (4 -12,17,22). Genetic variants in the vitamin D receptor (8) or collagen type 1 ␣-1 (9) are possibly associated with low BMD in type 1 diabetes. Decreased BMD in middle-aged type 1 diabetic women could be due to increased bone turnover (16,23,24), but recent studie...

OBJECTIVE -To evaluate menstrual cycle histories among women with type 1 diabetes, their sisters, and unrelated control subjects without diabetes across all reproductive ages.RESEARCH DESIGN AND METHODS -Menstrual and reproductive histories were obtained by questionnaire from 143 women with type 1 diabetes, 186 sisters without diabetes, and 158 unrelated control subjects without diabetes participating in the Familial Autoimmune and Diabetes study.RESULTS -Women with type 1 diabetes had more menstrual problems (long cycles, long menstruation, and heavy menstruation) before age 30 years than sisters and control subjects. These differences were all statistically significant, except for heavy menstruation at age Ͻ20 years. No differences were observed after age 30 years. Women with type 1 diabetes experienced later menarche, earlier natural menopause, fewer pregnancies, and more stillbirths than women without diabetes. Multiple regression analyses revealed that type 1 diabetes caused an approximate twofold increased risk of any menstrual problem before age 30 years. These were primarily related to long cycles and long menstruation in women aged Ͻ20 and 20 -29 years, as well as with heavy menstruation from 20 to 29 years. Oral contraceptives were protective for any menstrual problem and heavy menstruation from 30 to 39 years of age. With history of pregnancy from 20 to 40 years of age, any menstrual problem and long menstruation were more likely.CONCLUSIONS -The results suggest that type 1 diabetes is an independent risk factor for menstrual disturbances in young adults. Future studies may determine whether addressing menstrual disturbances improves quality of life and health for these women.