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Aims: We analyzed the incidence of kidney disease in the Diabetes Prevention Program Outcomes Study (DPPOS) by originally randomized treatment group assignment: Intensive Lifestyle (ILS), Metformin (MET) or Placebo (PLB)., Methods: The current analyses used a time-to-event approach in which the primary outcome was kidney disease, ascertained as urine albumin-to-creatinine ratio (ACR) ≥ 3.39 mg/mmol (30 mg/g) or eGFR <45 mL/min/1.73m 2 , with confirmation required at the next visit, or adjudicated end-stage kidney disease (ESKD)., Results: At a median of 21 years following randomization in DPP, diabetes development was reduced in both the ILS (HR 0.73 [95%CI = 0.62, 0.85]) and MET groups (HR 0.85 [0.73, 0.99]) compared to the PLB group. Although risk for developing the primary kidney disease outcome was higher among those with incident diabetes compared to those without (HR 1.81 [1.43, 2.30]), it did not differ by intervention groups (ILS vs. PLB 1.02 (0.81, 1.29); MET vs. PLB 1.08 (0.86, 1.35). There was a non-significant metformin by age interaction (p = 0.057), with metformin being beneficial for kidney disease in the younger but potentially harmful in the older participants., Conclusions: Development of kidney disease was increased in participants who developed diabetes but did not differ by original treatment group assignment., Clinical Trial Registrations: Diabetes Prevention Program (DPP) Clinical trial reg. no. NCT00004992 DPP Outcomes Study (DPPOS) Clinical trial reg. no. NCT0038727., Competing Interests: Declaration of competing interest MEM, MTr, ASL, JPC, DD, WHH, WCK, TJO, EBS, PS, MTe, NHW and DMN report no Conflicts of Interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: We aimed to evaluate the risk of heart failure in young adults with childhood-onset type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. We also examined risk factors and microvascular disease burden associated with the incidence of heart failure., Methods: Participants in the EDC study without known baseline heart failure (n = 655) were enrolled and then followed for 25 years. "Any" heart failure comprised the underlying cause of death, primary reason for hospitalization, EDC clinic examination findings or self-report of a physician diagnosis. "Hard" heart failure was determined only by the underlying cause of death or primary reason for hospitalization. Incidence rates for heart failure were estimated using Poisson models. Cox models were constructed to examine the associations between risk factors and microvascular disease burden with incident heart failure., Results: The mean baseline age and diabetes duration were 27(8) years and 19 (8) years. Incidence for any and hard heart failure were 3.4 and 1.8/1000 person-years. Diabetes duration, ever smoking and triglycerides were significant risk factors of any heart failure; longer diabetes duration, lower estimated glomerular filtration rate and higher white blood cell count significantly predicted hard heart failure. A gradient association was observed between the number of microvascular disease (from 0 to 3) and "hard" heart failure endpoint but not "any" clinically defined heart failure., Conclusion: Young adults with long-duration type 1 diabetes had a high risk of heart failure. As microvascular disease burden increases so does the risk of heart failure independently of diabetes duration, A1c and coronary artery disease., (Copyright © 2022. Published by Elsevier Inc.)

Aims: We aimed to determine if neuroimaging characteristics of gray and white matter are associated with gait speed in middle-aged individuals with childhood-onset type 1 diabetes (T1D), and whether associations are independent of diabetic peripheral neuropathy (DPN) status., Methods: In a cohort of 100 middle-aged adults with childhood-onset T1D (aged 49.2 ± 7.0 years, 50F/50M), we assessed cross-sectional associations of DPN, severity of white matter hyperintensities (WMH; Fazekas score), and regional gray matter volume (GMV) with gait speed. Associations were tested separately and combined in linear regression models adjusted for diabetes duration and locomotor risk factors., Results: Average gait speed was 1.3 m/s, with 52% of participants walking below the age-appropriate range of 1.3-1.5 m/s. In separate models, higher WMH severity (β = -0.27, p = 0.01) and smaller caudate GMV (β = -0.21, p = 0.04), but not DPN (β = -0.20, p = 0.08) were associated with slower gait speed. When combined, only WMH severity remained significant (β = -0.22, p = 0.04)., Conclusions: More than half of participants walked more slowly than expected based on age. Gait speed was slower among those with more severe WMH independent of locomotor risk factors. Gait slowing in middle-aged persons with T1D may reflect brain changes, and thus, deserve further attention., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Dietary intake provides a potential intervention target to reduce the high risk for coronary artery disease (CAD) in type 1 diabetes. This effort aimed to identify patterns of nutrient intake in young/middle-aged adults with type 1 diabetes and to examine associations between those patterns and development of CAD., Methods: Principal component analysis was used to derive nutrient intake patterns among 514 individuals with childhood-onset (<17 years old) type 1 diabetes aged 18+ years and free of CAD (defined as CAD death, myocardial infarction, revascularization, ischemia, or study physician diagnosed angina). Cox models were used to assess the association between nutrient patterns and CAD incidence over 30-years of follow-up., Results: Three nutrient principal components (PC) were identified: PC1 (high caffeine and saccharin intake), PC2 (high alcohol and caffeine, lower intake of essential nutrients) and PC3 (higher fiber/micronutrients, low alcohol). In unadjusted Cox models, only PC1 (negatively) and PC2 (positively) were associated with CAD risk. These associations were no longer significant after adjusting for diabetes duration., Conclusions: Important dietary components underlying the three patterns identified may have been influenced by diabetes duration or age. Future research can continue to explore patterns of nutrient intake over time and CAD development in type 1 diabetes., (Copyright © 2021. Published by Elsevier Inc.)

Aims: To examine candidate insulin resistance single nucleotide polymorphisms (SNPs) for associations with glycemic control, insulin resistance, BMI, and complications in an observational type 1 diabetes (T1D) cohort: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study., Methods: In 422 European-ancestry participants, we assessed associations using additive models between 15 candidate SNPs and 25-year mortality, cardiovascular disease, microalbuminuria, overt nephropathy and proliferative retinopathy, and 25-year mean HbA1c, estimated glucose disposal rate (eGDR, inverse measure of insulin resistance), and BMI., Results: The A allele of rs12970134 was associated with higher mean HbA1c (β = +0.34 ± 0.09, p = 0.00009) and nominally associated with worse eGDR (p = 0.02). Further analyses suggest the HbA1c association may be modified by diabetes therapy regimen: rs12970134 AA genotype was associated with higher HbA1c under non-intensive therapy conditions (<3 insulin injections/day or monitoring blood glucose<3 times/day [p = 0.004]), but not under intensive therapy (≥3 injections/day or insulin pump and monitoring glucose≥3 times/day [p = 0.71]). There were no significant associations between any SNPs and BMI or complications., Conclusions: rs12970134, near MC4R, is strongly associated with HbA1c in this cohort. Further exploration of this genomic region is warranted, as it may hold promise for discovering new therapeutic targets to improve glycemic control in T1D., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Vascular damage is thought to have a role in premature ovarian aging. We thus assessed the association between the presence, and age at onset of, vascular diabetes complications and age at natural menopause in women with type 1 diabetes., Methods: Female participants of the Epidemiology of Diabetes Complications study with type 1 diabetes who experienced natural menopause and who never received hormone therapy during their menopausal transition were included in the analysis (n=105). Microalbuminuria (MA), overt nephropathy, proliferative retinopathy, confirmed distal symmetric polyneuropathy, and coronary artery disease, were assessed during biennial clinical exanimations for the first 10 years of follow-up and at year 18, 25 and 30. Menopausal status was determined via self-report and sex hormone data. For each complication, separate linear regression models were used to assess whether, compared with women without the complication of interest, an earlier age at complication development (i.e., <30 years of age) was associated with an earlier age at natural menopause., Results: Although results from multivariable linear regression models suggested a similar age at menopause between women with normo-albuminuria and those diagnosed with MA after 30 years of age, menopause occurred 2.06 years earlier (β±SE=-2.06±1.08) among women diagnosed with MA before age 30 (p=0.06). No significant association was observed for other complications., Conclusion: Among women with type 1 diabetes, menopause appears to occur earlier in those diagnosed with MA before age 30 compared to those with normo-albuminuria, suggesting that vascular dysfunction associated with early microvascular disease may affect ovarian aging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: We assessed the association of skin intrinsic fluorescence (SIF) scores, as a measure of advanced glycation end-products (AGE), with all-cause mortality in type 1 diabetes (T1D)., Methods: This is an observational retrospective study of a convenience sample from the Epidemiology of Diabetes Complications (EDC) study. AGEs were measured with a SIF score between 2007 and 2014; vital status was assessed in 2020., Results: Among 245 participants, mean age was 48.6 ± 7.4 years, median diabetes duration was 39.5 years (IQR: 34.2, 44.9), and 53.5% were female. Compared to survivors, the deceased (n = 20) were older, with higher SIF scores, longer diabetes duration, lower body mass index (BMI), and an adverse risk factor profile (all p≤0.05). Univariate Cox regression showed a marginal association between SIF score and mortality (HR: 1.1, 95% CI 0.9-1.2, p = 0.06), which persisted after adjustment for multiple daily insulin shots/pump (MDI) use (HR: 1.1, 95% CI 1.0-1.2, p = 0.04). This association was attenuated after adjustment for T1D duration, A 1c months, or estimated glomerular filtration rate (eGFR)., Conclusions: In individuals with long duration T1D, SIF scores adjusted for MDI predicted all-cause mortality, although this association was attenuated after adjustments. Given the nature of sampling and small number of events, our findings require replication., Competing Interests: Declaration of competing interest Dr. Orchard reports grants from the NIDDK/NIH during the conduct of the study; Dr. Costacou reports grants from NIDDK during the conduct of the study; E.L. Tomaszewski reports grants from the NIH during the conduct of the study and employment by AstraZeneca outside the submitted work. No competing financial interests are reported for Dr. Songer, Dr. Hawkins, Dr. Conway, Dr. Buchanich, and Mr. Maynard., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To assess the role of periodontal disease (PD) as a predictor of coronary artery disease (CAD) and mortality in a prospective type 1 diabetes (T1D) cohort and to evaluate the role of smoking in this relationship., Methods: Data were based on 320 participants of the Pittsburgh Epidemiology of Diabetes Complications study of T1D who, during 1992-94, received a partial mouth periodontal exam, and who were followed for up to 19 years to ascertain complication incidence. PD was defined as clinical attachment loss of ≥4 mm for at least 10% of the examined sites. Predictors of all-cause mortality; Hard CAD (CAD death, myocardial infarction or revascularization), and Total CAD (Hard CAD, angina, ischemic ECG) were assessed using Cox models., Results: During 19 years of follow-up, 33.7% (97/288) developed CAD, 27.3% (83/304) developed Hard CAD, and 16.9% (54/320) died. Among current smokers, 46.4% (26/56) developed CAD, 42.7% (24/56) developed Hard CAD and 29.5% (18/61) died. PD was not associated with all-cause mortality, although it was a significant predictor of both CAD (HR = 1.12, CI = 1.01-1.23) and Hard CAD (HR = 1.30, CI = 1.11-1.51). As smoking modified the PD-CAD and PD-Hard CAD associations, analyses were stratified by smoking status. PD was associated with an increased risk of CAD (HR = 1.25, CI = 1.03-1.50) and Hard CAD (HR = 1.85, CI = 1.17-2.93) only among smokers., Conclusion: PD was a significant predictor of CAD and Hard CAD among current smokers with T1D., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: The aim was to determine if persistent c-peptide in long duration childhood onset (<17 years) type 1 diabetes (T1D) related to microvascular complications., Methods: Pittsburgh Epidemiology of Diabetes Complications (EDC) participants (n = 185) had serum c-peptide levels measured by Mercodia ultra-sensitive ELISA at the 25-year follow-up exam. Microvascular complications between those with and without detectable c-peptide were compared., Results: Eighteen (9.7%) participants had detectable median c-peptide levels of 3.8 (2.6, 12.2) pmol/L and did not differ from those without detectable levels. No differences in microalbuminuria, confirmed distal symmetric polyneuropathy, renal failure, or between those with one or more complications were found between the two groups. Proliferative retinopathy (PR) was marginally lower in those with detectable c-peptide (33.3% vs 55.1%, p = 0.08). However, those with c-peptide were somewhat less likely to have fasted for a full 8-h (66.7% vs. 84.9%, p = 0.09). Excluding those not fully fasted, PR no longer approached significance but macroalbuminuria became marginally lower in those with detectable levels (23.4% vs 0%, p = 0.07)., Conclusions: Low levels of c-peptide in T1D patients of long duration were detected but were not strongly related to microvascular complications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: DCCT showed that intensive type 1 diabetes management reduces complication incidence but did not focus on other cardiovascular disease risk factors, whose control in type 1 diabetes has not been well-studied. We assessed trends in cardiovascular risk factors in type 1 diabetes and attainment of concurrent American Diabetes Association (ADA) guidelines/recommendations (for HbA1c, blood pressure, LDL cholesterol, triglycerides) for complication prevention., Methods: Individuals with childhood-onset type 1 diabetes (n = 658; 49.4% women; baseline (1986-1988) median age 27 and duration 19 years) were followed biennially for up to 25 years, with surveys and/or examinations., Results: At the latest recorded follow-up, achievement of concurrent ADA recommendations increased for HbA 1c (from 9.7 to 25.6%, p < .0001); was unchanged for blood pressure (from 89.7% to 87.4%, p = .36); and decreased for LDL cholesterol (from 62.3 to 39.7%, p < .0001). Adoption of intensive insulin therapy (from 5.9 to 64.4%, p < .0001) and hypercholesterolemia (from 67.3 to 78.9%, p = .0006) also increased. Overall, the proportion meeting all four recommendations was essentially unaltered (from 6.8% to 7.6%) (p = .69). Results were similar by gender., Conclusions: Although the adoption of intensive insulin therapy and obtaining ADA HbA 1c recommendations are increasing, overall cardiovascular risk factor compliance remains low and merits further intervention., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: We aimed to assess association between abnormal LVEF, in the absence of coronary artery disease (CAD), and 25-year incidence of major outcomes of diabetes (MOD) in a cardiology substudy of the Pittsburgh Epidemiology of Diabetes Complications cohort of childhood-onset type 1 diabetes., Methods: 115 normotensive type 1 diabetes individuals without known CAD, underwent a baseline exercise radionuclide ventriculography. Abnormal LVEF was defined as a resting ejection fraction <50% or a failure to increase ejection fraction with exercise by >5% (men) or a fall in ejection fraction with exercise (women). Cox proportional hazards models were used to predict the composite endpoint of MOD (first instance of major CAD, stroke, end-stage renal disease, blindness, amputation or diabetes-related death)., Results: Mean baseline age was 28 and diabetes duration 19 years. In a mean follow-up of 19 years, 50 MOD events were identified. Allowing for established risk factors at baseline, abnormal LVEF (n = 22) independently predicted MOD incidence (HR = 2.12, 95% CI: 1.12-4.00, p = 0.022) but not major CAD (HR = 1.33, 95% CI: 0.53-3.33, p = 0.539)., Conclusions: An abnormal LVEF may identify diabetic cardiomyopathy and predict long term risk of MOD (but not CAD alone) in type 1 diabetes individuals, consistent with it reflecting microvascular disease., (Copyright © 2017. Published by Elsevier Inc.)

Aims/hypothesis: Haptoglobin(Hp) 2-2 genotype has been shown to increase coronary artery disease (CAD) risk in numerous type 2 diabetes studies but in only one type 1 diabetes cohort. We assessed the association of Hp2-2 with incident CAD over 26years of follow-up in 1303 Caucasian participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study., Methods: DCCT randomized volunteers with type 1 diabetes to intensive versus conventional therapy within two cohorts: 'primary prevention' with 1-5years diabetes duration and 'secondary intervention' with 1-15years diabetes duration and early retinopathy, with or without albuminuria, but no advanced complications. CAD was defined as myocardial infarction (MI) or death judged to be from CAD, silent MI, angina, coronary revascularization, or congestive heart failure due to CAD., Results: In the entire DCCTcohort, Hp2-2 was not significantly associated with incident CAD or MI. However, in pre-specified exploratory subgroup analyses, an increased MI risk was suggested in the secondary cohort for those with Hp2-2., Conclusions/interpretation: The analysis does not statistically confirm an overall association between Hp 2-2 and incident CAD, however, some suggestions of associations were observed in secondary analyses., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: The Haptoglobin (HP) 2-2 genotype increases cardiovascular diabetes complication incidence. In type 1 diabetes, HP 2-2 also predicts declining kidney function and end-stage renal disease. We investigated whether HP 2-2 predisposes to cardio-renal mortality, while considering other causes of death as competing risks., Methods: Individuals with type 1 diabetes and HP data available (n=486; mean baseline age, 27 and duration, 19 years) were selected for study. Vital status was assessed as of 8/31/2014. The underlying cause of death was determined and classified based on standardized procedures., Results: During 25 years of follow-up, 79 (16.3%) cardio-renal deaths and 43 (8.8%) deaths related to other causes occurred. Although total mortality did not differ by HP (25.4% with HP 1 versus 24.6% with HP 2-2, p=0.84), a greater proportion of HP 2-2 carriers exhibited a cardio-renal death (19.0 versus 14.2, p=0.05). In time-to-event analyses, HP 2-2 was associated with a statistically significant increase of the sub-distribution hazard ratio for cardio-renal mortality (HR=1.64, p=0.03), although this effect was somewhat attenuated after multivariable adjustment (HR=1.58, p=0.05)., Conclusions: Our results suggest that in addition to predicting the incidence of cardio-renal complications, HP 2-2 also increases susceptibility for cardio-renal mortality in type 1 diabetes. These findings require validation in other cohorts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: To determine if regional gray matter volume (GMV) differences in middle-aged adults with and without type-1 diabetes (T1D) are localized in areas most vulnerable to aging, e.g. fronto-subcortical networks; and if these differences are explained by cardiovascular risk factors and diabetes complications., Methods: Regional GMV was computed using 3T MRI of 104 adults with a childhood onset of T1D (mean age: 49±7 and duration: 41±6years) and 151 adults without diabetes (mean age: 40±6). A Bonferroni threshold (n=45, p≤0.001) was applied to account for multiple between-group comparisons and analyses were repeated in an age- and gender-matched subset of participants with T1D and controls (n=44 in each group, mean age [SD] and range: 44.0, [4.3], 17.4 and 44.6 [4.3], 17.0, respectively)., Results: Compared to controls, T1D patients had smaller GMV in the frontal lobe (6% to 19% smaller) and adjacent supramarginal and postcentral gyri (8% to 13% smaller). Between-group differences were independent of age, waist circumference, systolic blood pressure, fasting total cholesterol and smoking status and were similar in sensitivity analyses restricted to age- and gender-matched participants. Associations between GMV and diabetes complications were not significant., Conclusions: These findings extend the notion of accelerated brain aging in T1D to middle-aged adults. The pathophysiology of frontal gray matter atrophy and its impact on future development of disability and dementia need further study, especially as middle-aged T1D patients progress to older age., (© 2013.)

Objective: Oxidative stress has been implicated in the development of diabetes and cardiovascular disease. We evaluated the effect of serum antioxidants and total antioxidant reserve (TAR) on coronary artery disease (CAD) incidence in type 1 diabetes., Methods: Subjects were identified from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) cohort, a 10-year prospective study of childhood-onset type 1 diabetes. Mean age at baseline was 28 and diabetes duration 19 years. Coronary artery disease was defined as physician-diagnosed angina, confirmed MI, stenosis >or=50%, ischemic electrocardiogram (ECG), or revascularization. Controls were gender, age, and diabetes duration (+/-3 years) matched with cases. Samples and risk factors used in analyses were identified from the earliest exam prior to incidence in cases (54 cases, 67 controls)., Results: None of the antioxidant measures (alpha-tocopherol, gamma-tocopherol, retinol, TAR) showed protection against incident CAD overall. However, a protective effect of alpha-tocopherol against CAD was observed among antioxidant supplement users (HR=0.22, 95% CI=0.10-0.49) and in renal disease (HR=0.46, 95% CI=0.23-0.91). Despite similar alpha-tocopherol concentration, there was no protective effect among nonusers of antioxidant supplements., Conclusions: High alpha-tocopherol levels among patients with renal disease and in those using vitamin supplements were associated with lower CAD risk in type 1 diabetes. The specificity of these effects merits further investigation.

Low-density lipoprotein (LDL) oxidation, the immune response it provokes, and lipoprotein subclasses measured by nuclear magnetic resonance (NMR) spectroscopy have explained some of the enhanced coronary artery disease (CAD) risks in Type 1 diabetes. We examined whether cellular adhesion molecules further improve CAD prediction. Participants were identified from the Epidemiology of Diabetes Complications (EDC) cohort, a 10-year prospective study of childhood-onset Type 1 diabetes. Mean age at baseline was 28 years, and diabetes duration was 19 years. CAD incidence was determined by EDC physician-diagnosed angina, confirmed myocardial infarction (MI), stenosis > or =50%, ischemic ECG, or revascularization. Cases were gender, age, and diabetes duration (+/-3 years) matched with the controls. The samples and risk factors used in the analyses were identified from the earliest exam prior to incidence in the cases. Sixty cases and 72 controls (including 43 pairs) had complete information on all covariates. Cox proportional hazard models with backward elimination and conditional logistic regression (for paired analyses) were conducted. Separate analyses were conducted to examine whether E-selectin related differently to soft (ischemic ECG and angina; n=68) or hard (revascularization, MI, and fatal events; n=37) CAD endpoints. Mean E-selectin concentration was elevated among cases (P=.0009) compared to controls. Adjusting for previously established CAD risk factors, E-selectin remained an independent predictor of CAD (HR=1.07, 95% Cl=1.01-1.15). Multivariable models confirmed the importance of E-selectin as a risk factor of soft (HR=1.13, 95% Cl=1.03-1.24; HRs are per standard deviation increase) but not hard CAD. Study results suggest that E-selectin may enhance CAD prediction beyond traditional risk factors or markers of oxidative stress in Type 1 diabetes.

Although hyperlipidemia is associated with the development of diabetes complications, the effect of lipid reduction on microvascular complications is unknown. We initiated a 2-year, randomized, double-blinded placebo-controlled pilot trial of simvastatin/diet vs. diet alone in Type 1 diabetic patients without overt nephropathy. Thirty-nine patients with LDL cholesterol 100-160 mg/dl, >10 year duration of diabetes and an albumin excretion rate (AER) <200 microg/min were recruited for study. The primary end-point was change in AER. Secondary end-points were change in ankle-brachial index, progression of retinopathy status, change in vibratory threshold, and development of new clinical neuropathy. Nineteen patients were treated with simvastatin and twenty with placebo. However, because of the lowering of drug initiation levels by the American Diabetes Association, the trial was terminated early with 2 subjects reaching 2 years, 17 reaching 18 months, 36 reaching 1 year, and all 6 months. Simvastatin significantly reduced total cholesterol (mean on treatment 173.4 vs. 191.4, P=.020) and LDL cholesterol (mean on treatment 105.0 vs. 127.7, P<.001). Simvastatin therapy was associated with a slower rise in AER compared to placebo, though the result was not statistically significant (median rate of change/month 0.004 vs. 0.029). There was a trend towards slower progression of neuropathy as measured by vibratory threshold (median change at 1 year 0.03 simvastatin vs. 0.94, P=.07). There was no difference in change in ankle-brachial index, clinical neuropathy status, or retinopathy status. In conclusion, treatment with simvastatin may have a beneficial effect on early nephropathy and diabetic neuropathy, justifying a fully powered trial. However, this would be difficult under current treatment guidelines.

The pathogenesis of diabetic neuropathy is poorly understood. In this prospective study, we investigated the incidence rate and potential predictors for cardiovascular autonomic neuropathy (CAN) in a cohort of childhood-onset type 1 diabetic patients. Subjects from the Epidemiology of Diabetes Complications Study were examined at baseline and then biennially. CAN was diagnosed by abnormal (200 ug/min) (RR=2.46, p=0.0001) to be significant independent predictors. Hypertension was, however, predictive if nephropathy was not included in the model. We conclude that beyond age and poor glycemic control, nephropathy is a significant risk factor for CAN and this association may explain some of the increased mortality seen in CAN.

The purpose of this study was to examine the potential relationship of tissue plasminogen activator-plasminogen activator inhibitor-1 (tPA-PAI-1) complexes and diabetic complications in individuals with insulin-dependent diabetes mellitus (IDDM). To address this issue, data from the third follow-up visit of participants in the Epidemiology of Diabetes Complications (EDC) study were examined. There were 454 participants, aged 32 +/- 8 years, with duration of IDDM of 23 +/- 8 years. Higher levels of tPA-PAI-1 complexes were seen for both men and women with IDDM complications. Specifically, statistically significant differences were seen in men with neuropathy (1.81 +/- 0.9 versus 1.42 +/- 0.8 ng/mL, p < 0.01), microalbuminuria (1.77 +/- 1.1 versus 1.35 +/- 0.6 ng/mL, p < 0.01), retinopathy (1.67 +/- 0.9 versus 1.43 +/- 0.8 ng/mL, p < 0.05), and lower extremity arterial disease (1.93 +/- 0.7 versus 1.50 +/- 0.9 ng/mL, p < 0.05) versus men without the particular complication. In women, higher complex levels were shown for those with retinopathy (1.51 +/- 0.8 versus 1.29 +/- 1.1 ng/mL, p < 0.01). Potential mechanisms for the relationship of higher complex levels and diabetic complications include an altered fibrinolytic response and/or insulin resistance. Because the results are cross sectional, it cannot be established whether the higher concentration of complexes is a result of the presence of complications or are antecedent. Prospective follow-up will be required to determine if tPA-PAI-1 complexes are predictive of the development of IDDM complications.

This study examined potential risk factors for the incidence and progression of retinopathy in a large representative cohort of childhood onset insulin-dependent diabetic patients. Participants in the Epidemiology of Diabetes Complications (EDC) Study underwent a full clinical examination at baseline and again at a 2-year follow-up. Retinopathy status was ascertained using stereo fundus photographs graded according to the modified Airlie House System. The study population is based on a large cohort of childhood-onset insulin-dependent diabetic patients, seen within 1 year of diagnosis at the Children's Hospital of Pittsburgh between January 1950 and May 1980. A total of 657 subjects participated at baseline (1986-1988), with 80% of eligible survivors taking part in the follow-up examination. This report concerns risk factors associated with the progression of diabetic retinopathy over a 2-year period, and the interaction of these factors with the presence of nephropathy. Analyses showed that baseline diastolic blood pressure was significantly associated with the incidence of any retinopathy, while glycosylated hemoglobin, baseline severity of retinopathy, serum triglycerides, and, to a lesser extent, higher levels of low-density lipoprotein (LDL) cholesterol and fibrinogen were associated with the progression of retinopathy. Progression to proliferative retinopathy was related to higher LDL cholesterol, fibrinogen, serum triglycerides, albumin excretion rate, and glycosylated hemoglobin (GHb). Risk factors varied with the presence of nephropathy. In the absence of nephropathy, GHb was a significant predictor of progression, whilst this was not the case in the presence of nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

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)