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© 2015 by the American Diabetes Association.Emerging data suggest that type 1 diabetes is a more aggressive disease in children than in adults, with important differences in pathophysiology and clinical course. Therefore, the efficacy of disease-modifying

Objective: Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications analyses demonstrated that intensive insulin therapy was inversely associated with incident hypertension. We thus sought to confirm these observations and, given sex differences in other type 1 diabetes complications and risk factors, assessed whether any such associations differ by sex.Research Design and Methods: Participants of a prospective cohort of childhood-onset type 1 diabetes, free of hypertension at study entry (baseline mean age, 28 years; diabetes duration, 19 years), were selected for study (n = 510). Hypertension incidence was defined as blood pressure >140/90 mmHg or use of hypertension medications in two consecutive visits. Intensive insulin therapy was defined as three or more injections (or pump) and four or more glucose tests daily. Baseline predictors of hypertension were examined using Cox proportional hazards models. Models with time-dependent updated means of baseline significant variables were also constructed.Results: Hypertension incidence over 18 years of follow-up was marginally higher in men than in women (43.2 vs. 35.4%, P = 0.07). A significant interaction was noted between sex and HbA(1c), and separate models were constructed by sex. Multivariably, elevated HbA(1c) was a significant predictor only in men (hazard ratio 1.48 [95% CI 1.28-1.71]). In time-dependent models, although a significant effect of HbA(1c) was also seen in women (1.21 [1.00-1.46]), the effect of glycemic control on hypertension development remained stronger in men (1.59 [1.29-1.97], P interaction <0.0001).Conclusions: Although hyperglycemia is a risk factor for hypertension, its effect is stronger in men compared with women with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Survival in type 1 diabetes has improved, but the impact on life expectancy in the U.S. type 1 diabetes population is not well established. Our objective was to estimate the life expectancy of the Pittsburgh Epidemiology of Diabetes Complications (EDC) study cohort and quantify improvements by comparing two subcohorts based on year of diabetes diagnosis (1950-1964 [n = 390] vs. 1965-1980 [n = 543]). The EDC study is a prospective cohort study of 933 participants with childhood-onset (aged <17 years) type 1 diabetes diagnosed at Children's Hospital of Pittsburgh from 1950 to 1980. Mortality ascertainment was censored 31 December 2009. Abridged cohort life tables were constructed to calculate life expectancy. Death occurred in 237 (60.8%) of the 1950-1964 subcohort compared with 88 (16.2%) of the 1965-1980 subcohort. The life expectancy at birth for those diagnosed 1965-1980 was ~15 years greater than participants diagnosed 1950-1964 (68.8 [95% CI 64.7-72.8] vs. 53.4 [50.8-56.0] years, respectively) (P < 0.0001); this difference persisted regardless of sex or pubertal status at diagnosis. This improvement in life expectancy emphasizes the need for insurance companies to update analysis of the life expectancy of those with childhood-onset type 1 diabetes because weighting of insurance premiums is based on outdated estimates. [ABSTRACT FROM AUTHOR]

Objective: Although management of type 1 diabetes improved dramatically in the 1980s, the effect on mortality is not clear.Research Design and Methods: We report trends in 30-year mortality using the Allegheny County (Pennsylvania) childhood-onset (age <18 years) type 1 diabetes registry (n = 1,075) with diagnosis from 1965-1979, by dividing the cohort into three diagnosis year cohorts (1965-1969, 1970-1974, and 1975-1979). Local (Allegheny County) mortality data were used to calculate standardized mortality ratios (SMRs).Results: As of 1 January 2008, vital status was ascertained for 97.0% of participants (n = 1,043) when mean age ± SD and duration of diabetes were 42.8 ± 8.0 and 32.0 ± 7.6 years, respectively. The 279 deaths (26.0%) observed were 7 times higher than expected (SMR 6.9 [95% CI 6.1-7.7]). An improving trend in SMR was seen by diagnosis cohort at 30 years of diabetes duration (9.3 [7.2-11.3], 7.5 [5.8-9.2], and 5.6 [4.0-7.2] for 1965-1969, 1970-1974, and 1975-1979, respectively). Although no sex difference in survival was observed (P = 0.27), female diabetic patients were 13 times more likely to die than age-matched women in the general population (SMR 13.2 [10.7-15.7]), much higher than the SMR for men (5.0 [4.0-6.0]). Conversely, whereas 30-year survival was significantly lower in African Americans than in Caucasians (57.2 vs. 82.7%, respectively; P < 0.001), no differences in SMR were seen by race.Conclusions: Although survival has clearly improved, those with diabetes diagnosed most recently (1975-1979) still had a mortality rate 5.6 times higher than that seen in the general population, revealing a continuing need for improvements in treatment and care, particularly for women and African Americans with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Although subjects with diabetes have increased risk for cardiovascular disease (CVD), the evolution of this increased risk as pre-diabetic individuals progress to diabetes is not understood. This study examines the longitudinal relationship between selected CVD risk factors (blood pressure, triglycerides, HDL and LDL cholesterol, and LDL peak particle density [PPD]) and glycemia in the three treatment groups of the Diabetes Prevention Program.Research Design and Methods: A total of 3,234 participants with impaired glucose tolerance (IGT) were followed for a mean of 3.2 years after randomization to intensive lifestyle intervention (ILS), metformin, or placebo. Using repeated-measures models, adjusted mean levels of risk factors were estimated for an annual change in glycemic status. Tests were also conducted to assess the risk factor trends with improvement or worsening of glycemic status.Results: CVD risk factor values and changes from baseline became more unfavorable as glucose tolerance status deteriorated but improved with reversion to normal glucose tolerance (NGT), especially in the ILS intervention group (trend test P < 0.001 for all risk factors except for LDL PPD [P = 0.02] in ILS and HDL cholesterol [P = 0.02] in placebo). Although there were few significant differences in the transition from IGT to diabetes, there were strong relationships between risk factors and continuous measures of glycemia.Conclusions: Progression from IGT to diabetes is associated with mild deterioration, whereas reversion to NGT is associated with improvement in risk factors. Early intervention with ILS, but less so with metformin, in participants at high risk for diabetes improves the cardiovascular risk and glucose tolerance profile simultaneously. [ABSTRACT FROM AUTHOR]

Objective: Haptoglobin is a plasma protein that binds free hemoglobin, thereby inhibiting hemoglobin-induced oxidative damage. We investigated the association between the haptoglobin genotype and the incidence of coronary artery disease (CAD) in a cohort of individuals with childhood-onset type 1 diabetes.Research Design and Methods: Participants from the Epidemiology of Diabetes Complications Study who were free of CAD at study entry and had DNA available were selected (n = 453, mean age 27.1 years, and diabetes duration 18.8 years). CAD was defined as angina, ischemic electrocardiogram, myocardial infarction confirmed by Q-waves on electrocardiogram or hospital records, angiographic stenosis >50%, or revascularization.Results: The proportions of the cohort with the haptoglobin 1/1, 2/1, and 2/2 genotypes were 11.5, 41.3, and 47.2%, respectively. During 18 years of follow-up, there were 135 (29.8%) incident CAD events. Univariately, the proportion of CAD events increased from 15.4 to 28.3 and 34.6% for haptoglobin 1/1, 2/1, and 2/2, respectively (P = 0.02, P-trend = 0.007). Cumulative incidence (including 33 baseline prevalent cases) also increased from 24.1 to 32.3 and 39.1%, respectively (P = 0.07, P-trend = 0.02). In Cox proportional hazards models adjusting for traditional CAD risk factors, the haptoglobin 2/2 genotype was associated with increased CAD incidence compared with the haptoglobin 1/1 genotype (hazard ratio [HR] 2.21, 95% CI 1.05-4.65, P = 0.04). Although the risk associated with the haptoglobin 2/1 genotype did not reach significance (1.78, 0.84-3.79, P = 0.13), there remained a significant trend across the three groups (P = 0.03).Conclusions: These data support the hypothesis that the haptoglobin genotype influences cardiovascular risk in type 1 diabetes. [ABSTRACT FROM AUTHOR]

BACKGROUND: The sensitivity of albuminuria in predicting loss of kidney function has been questioned. We determined the sequence of kidney disease stages (microalbuminuria, macroalbuminuria, low estimated glomerular filtration rate [eGFR], and end-stage renal disease [ESRD]) and characterized those without albuminuria before a low eGFR. STUDY DESIGN: The Pittsburgh Epidemiology of Diabetes Complications Study is a prospective cohort investigation of childhood-onset type 1 diabetes. SETTING & PARTICIPANTS: 480 study participants with eGFR greater than 60 mL/min/1.73 m(2) (mean age, 27 years; diabetes duration, 19 years at study entry) were prospectively followed up for 16 years. OUTCOMES & MEASUREMENTS: Low eGFR was defined as creatinine clearance less than 60 mL/min/1.73 m(2) from timed urine collections; microalbuminuria, as albumin excretion rate between 20 to 200 microg/min (30 to 300 mg/24 h); macroalbuminuria, as albumin excretion rate greater than 200 microg/min (>300 mg/24 h); and ESRD, as dialysis or renal transplantation. RESULTS: The 33 of 480 individuals (7%) who developed ESRD had prior albuminuria. 71 of 480 (15%) individuals developed low eGFR. 66 of 71 (93%) had prior/concurrent albuminuria, and 5 of 71 (7%) did not. Incident low eGFR values in the 5 patients were: (1) 54, (2) 58, (3) 59, (4) 59.7, and (5) 59.8 mL/min/1.73 m(2). 3 of 5 (60%; patients 1, 4, and 5) subsequently developed albuminuria. Final eGFRs in the 5 patients were: (1) 94, (2) 86, (3) 60, (4) 65, and (5) 54 mL/min/1.73 m(2), respectively. LIMITATIONS: GFR and insulin sensitivity were not measured, but estimated. Incident decreased eGFR in patients without preceding/concurrent albuminuria may be caused by misclassification or a temporary eGFR decrease. CONCLUSIONS: Moderately decreased eGFR may occur rarely in patients with type 1 diabetes without preceding albuminuria. Copyright © 2007 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The metabolic syndrome has been shown to confer an increased risk of cardiovascular disease in both the general and type 2 diabetic populations, but few studies have assessed the metabolic syndrome in type 1 diabetic patients. In a type 1 diabetic cohort, we assessed the prevalence and value of the metabolic syndrome in improving the prediction of major complication outcomes compared with its components and a surrogate measure of insulin resistance, estimated glucose disposal rate (eGDR). RESEARCH DESIGN AND METHODS: A total of 514 (78%) subjects participating in the Pittsburgh Epidemiology of Diabetes Complications Study with complete 12-year follow-up clinical data were classified by baseline metabolic syndrome status according to three definitions: those of the National Cholesterol Education Program Adult Treatment Panel III (modified by the American Heart Association), the International Diabetes Federation (IDF), and the World Health Organization (WHO). The complication outcomes included coronary artery disease, renal failure, diabetes-related death, and the aggregate of these three major outcomes of diabetes (MOD). RESULTS: Metabolic syndrome prevalence ranged from 8% (IDF) to 21% (WHO). All definitions showed reasonable specificity (> or = 83%) for each outcome, while the WHO definition had the highest sensitivity for all outcomes except renal failure, for which eGDR was most sensitive. However, the components of each definition predicted better than the overall syndrome. Microalbuminuria was clearly the strongest predictor of all individual measures, yielding hazard ratios of 9 and 6 for mortality and MOD, respectively. CONCLUSIONS: Though the three metabolic syndrome classifications predict major complication outcomes in type 1 diabetes, their individual components predict better. Of the variables studied, including HbA1, microalbuminuria appears to be the best single predictor of MOD. [ABSTRACT FROM AUTHOR]

Declining incidences in Europe of overt nephropathy, proliferative retinopathy, and mortality in type 1 diabetes have recently been reported. However, comparable data for the U.S. and trend data for neuropathy and macrovascular complications are lacking. These issues are addressed using the prospective observational Pittsburgh Epidemiology of Childhood-Onset Diabetes Complications Study. Participants were stratified into five cohorts by diagnosis year: 1950-1959, 1960-1964, 1965-1969, 1970-1974, and 1975-1980. Mortality, renal failure, and coronary artery disease (CAD) status were determined on the complete cohort (n = 906) at 20, 25, and 30 years. Overt nephropathy, proliferative retinopathy, and neuropathy were assessed at 20 and 25 years on the subset of participants with a clinical examination. There was a decreasing trend by diagnosis year for mortality, renal failure, and neuropathy across all time intervals (P < 0.05), with the 1950-1959 cohort having a fivefold higher mortality at 25 years than the 1970s' cohorts. Proliferative retinopathy and overt nephropathy showed nonsignificant declines at 20 years (P < 0.16 and P < 0.13, respectively) and no change at 25 years. CAD event rates, which were lower than the other complications, also showed no trend. Although some type 1 diabetes complications (mortality, renal failure, and neuropathy) are declining, others (CAD, overt nephropathy, and proliferative retinopathy) show less favorable changes by 30 years. [ABSTRACT FROM AUTHOR]

Objective: To determine whether using the chronic care model (CCM) in an underserved community leads to improved clinical and behavioral outcomes for people with diabetes.Research Design and Methods: This multilevel, cluster-design, randomized controlled trial examined the effectiveness of a CCM-based intervention in an underserved urban community. Eleven primary care practices, along with their patients, were randomized to three groups: CCM intervention (n = 30 patients), provider education only (PROV group) (n = 38), and usual care (UC group) (n = 51).Results: A marked decline in HbA(1c) was observed in the CCM group (-0.6%, P = 0.008) but not in the other groups. The magnitude of the association remained strong after adjustment for clustering (P = 0.01). The same pattern was observed for a decline in non-HDL cholesterol and for the proportion of participants who self-monitor blood glucose in the CCM group (non-HDL cholesterol: -10.4 mg/dl, P = 0.24; self-monitor blood glucose: +22.2%, P < 0.0001), with statistically significant between-group differences in improvement (non-HDL cholesterol: P = 0.05; self-monitor blood glucose: P = 0.03) after adjustment. The CCM group also showed improvement in HDL cholesterol (+5.5 mg/dl, P = 0.0004), diabetes knowledge test scores (+6.7%, P = 0.07), and empowerment scores (+2, P = 0.02).Conclusions: These results suggest that implementing the CCM in the community is effective in improving clinical and behavioral outcomes in patients with diabetes. [ABSTRACT FROM AUTHOR]

Objective: Diabetes is associated with increased urinary incontinence risk. Weight loss improves incontinence, but exercise may worsen this condition. We examined whether an intensive lifestyle intervention or metformin therapy among overweight pre-diabetic women was associated with a lower prevalence of incontinence.Research Design and Methods: We analyzed data from the Diabetes Prevention Program, a randomized controlled trial in 27 U.S. centers. Of the 1,957 women included in this analysis, 660 (34%) were randomized to intensive lifestyle therapy, 636 (32%) to metformin, and 661 (34%) to placebo with standard lifestyle advice. The main outcome measure was incontinence symptoms by frequency and type by a validated questionnaire completed at the end-of-trial visit (mean 2.9 years).Results: The prevalence of total (stress or urge) weekly incontinence was lower among women in the intensive lifestyle group (38.3%) than those randomized to metformin (48.1%) or placebo (45.7%). This difference was most apparent among women with stress incontinence (31.3% for intensive lifestyle group vs. 39.7% for metformin vs. 36.7% for placebo, P = 0.006). Changes in weight accounted for most of the protective effect of the intensive lifestyle intervention on stress incontinence.Conclusions: Less-frequent urinary incontinence may be a powerful motivator for women to choose lifestyle modification to prevent diabetes. [ABSTRACT FROM AUTHOR]

Aims Excess mortality in Type 1 diabetes has previously been found among Black individuals. The aim of the present study was therefore to determine underlying causes.Methods A longitudinal study of 1261 [1184 White (93.9%) and 76 Black (6.0%)] individuals diagnosed with Type 1 diabetes between 1965 and 1979, at age < 17 years from the Allegheny County, Pennsylvania and Children's Hospital of Pittsburgh registries. Subjects were contacted in 1999 to determine living status and, where appropriate, cause of death. Living status was determined in 1183 participants (93.8%).Results Of the 200 deaths overall, cause of death was determined in 157 subjects (79%); 31 dying from acute and 101 from chronic complications, and 25 from non-diabetes related causes. Seven deaths were investigated but no cause determined. Black participants had a significantly higher mortality rate compared with White participants for acute complications (hazard ratio = 4.9, 95% confidence interval: 2.0, 11.6), but not for any other cause. There was a temporal decline in the 20-year mortality rates in both racial groups across the three cohorts diagnosed in 1965-69, 1970-74 and 1975-79.Conclusions These results show that the excess mortality in Black people was attributed to acute complications which therefore should be a focus for prevention. [ABSTRACT FROM AUTHOR]

Background: The metabolic syndrome is a high-risk state for diabetes and cardiovascular disease. Little is known about its prevalence and prevention in those with impaired glucose tolerance.Objective: To determine the prevalence of the metabolic syndrome at baseline in the Diabetes Prevention Program and the effect of intensive lifestyle intervention and metformin therapy on the syndrome's incidence and resolution.Design: Randomized, controlled clinical trial.Setting: Research and community-based centers.Participants: Participants had impaired glucose tolerance (World Health Organization criteria plus fasting plasma glucose level >or=5.3 mmol/L [>or=95 mg/dL]) and were followed for a mean of 3.2 years after random assignment to intensive lifestyle intervention, metformin therapy, or placebo.Interventions: Metformin, 850 mg twice daily, or intensive lifestyle intervention designed to achieve and maintain a 7% weight loss and 150 minutes of exercise per week.Measurements: The metabolic syndrome was defined as having 3 or more characteristics (waist circumference; blood pressure; and levels of high-density lipoprotein cholesterol, triglycerides, and fasting plasma glucose) that met criteria from the National Cholesterol Education Program Adult Treatment Panel III.Results: Fifty-three percent of participants (n = 1711) had the metabolic syndrome at baseline; incidence did not vary substantially by age. However, low levels of high-density lipoprotein cholesterol predominated in younger participants (age 25 to 44 years), and high blood pressure predominated in older participants (age 60 to 82 years). In life-table analyses (log-rank test), incidence of the metabolic syndrome was reduced by 41% in the lifestyle group (P < 0.001) and by 17% in the metformin group (P = 0.03) compared with placebo. Three-year cumulative incidences were 51%, 45%, and 34% in the placebo, metformin, and lifestyle groups, respectively. There was no significant heterogeneity by ethnic group.Limitations: The study involved a volunteer group with impaired glucose tolerance, which limits generalizability.Conclusions: The metabolic syndrome affected approximately half of the participants in the Diabetes Prevention Program at baseline. Both lifestyle intervention and metformin therapy reduced the development of the syndrome in the remaining participants. [ABSTRACT FROM AUTHOR]

Objective: To quantify total diabetes care received (generalist or specialist) from diagnosis onward and its association with the incidence of diabetes complications in a representative cohort of patients with type 1 diabetes.Research Design and Methods: A total of 429 subjects from the Pittsburgh Epidemiology of Diabetes Complications Study, a prospective follow-up study of childhood-onset type 1 diabetic subjects first seen between 1986 and 1988 (mean age 28 years, mean duration 19 years), followed biennially for up to 10 years were studied. Specialist care was defined as care received from a board-certified endocrinologist, diabetologist, or diabetes clinic and quantified as the percent of diabetes duration spent in specialist care.Results: There was a significant trend for a higher incidence of neuropathy, overt nephropathy, and coronary artery disease with lower use of specialist care. Multivariate analyses controlling for diabetes duration, demographic characteristics, health care practices, and physiological risk factors demonstrated that higher past use of specialist care was found to be significantly protective against the development of overt nephropathy (risk ratio 0.43, 95% CI 0.21-0.88) and neuropathy (0.54, 0.35-0.83) and weakly protective against coronary artery disease (0.65, 0.37-1.1).Conclusions: A higher proportion of diabetes duration spent in specialist care may result in delayed development of certain diabetes complications independent of other risk factors. This study thus supports the concept that the benefits of specialist care should be available to all patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Subjects with type 1 diabetes are at high risk for many long-term complications, including early mortality and coronary artery disease (CAD). Few data are available on which to base goal levels for two major risk factors, namely blood pressure and lipid/lipoproteins. The objective of this study was to determine at which levels of LDL and HDL cholesterol, triglycerides, and blood pressure the relative risks of type 1 diabetic complications increase significantly.Research Design and Methods: Observational prospective study of 589 patients with childhood-onset type 1 diabetes (<17 years) aged > or =18 years at baseline; 10-year incidence of mortality, CAD, lower-extremity arterial disease, proliferative retinopathy, distal symmetric polyneuropathy, and overt nephropathy. Relative risks were determined using traditional groupings of blood pressure and lipid/lipoproteins, measured at baseline, using the lowest groupings (<100 mg/dl [2.6 mmol/l] LDL cholesterol, <45 mg/dl [1.1 mmol/l] HDL cholesterol, <100 mg/dl [1.1 mmol/l] triglycerides, <110 mmHg systolic blood pressure, and <80 mmHg diastolic blood pressure) as reference. Adjustments for age, sex, and glycemic control were examined.Results: Driven mainly by strong relationships (RR range 1.8-12.1) with mortality, CAD, and overt nephropathy, suggested goal levels are as follows: LDL cholesterol <100 mg/dl (2.6 mmol/l), HDL cholesterol >45 mg/dl (1.1 mmol/l), triglycerides <150 mg/dl (1.7 mmol/l), systolic blood pressure <120 mmHg, and diastolic blood pressure <80 mmHG: Age, sex, and glycemic control had little influence on these goals.Conclusions: Although observational in nature, these data strongly support the case for vigorous control of lipid levels and blood pressure in patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

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 <18 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 +/- 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 = 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.Conclusions: An improvement in long-term survival was observed in the more recently diagnosed cohort. This improvement is consistent with the introduction of HbA1 testing, home blood glucose monitoring, and improved blood pressure therapy in the 1980s. [ABSTRACT FROM AUTHOR]

We studied the relationship of coronary artery calcification (CAC), a marker of coronary atherosclerosis, with prevalent clinical coronary artery disease (CAD) and established cardiovascular disease (CVD) risk factors in a type 1 diabetic population. At the 10-year follow-up examination of the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study cohort, 302 adults (mean age 38.1 +/- 7.8 years) received electron beam tomography (EBT) scanning of the heart and a clinical examination. Clinical CAD was defined as a confirmed history of myocardial infarction (MI), angiographic stenosis > or =50%, Pittsburgh EDC Study physician-diagnosed angina, or ischemic electrocardiogram (ECG). CAC correlated with most CVD risk factors. CAC had 84 and 71% sensitivity for clinical CAD in men and women, respectively, and 100% sensitivity for MI or obstructive CAD. A CACS cut point of 400 was the most efficient coronary calcium correlate of CAD. In subjects with angina only, CAC sensitivity was 83% in men and 46% in women. In logistic regression, CAC, ECG R-R variation, peripheral vascular disease, and Beck Depression Inventory independently correlated with prevalent CAD in men and overall. Except for CAC, the same variables independently correlated with CAD in women, and age also entered the model. CAC was an independent correlate of MI or obstructive CAD in both sexes and was the strongest independent correlate in men, but CAC was not independently associated with angina and ischemic ECG in either sex. It is concluded that EBT-detected CAC is strongly correlated with CAD in type 1 diabetes-particularly in men. [ABSTRACT FROM AUTHOR]

Objective: To determine whether diabetes care characteristics and glycemic control differ by use of specialist care in a representative cohort of patients with type 1 diabetes.Research Design and Methods: Health care, sociodemographic characteristics, and glycemic control were compared between participants in the Pittsburgh Epidemiology of Diabetes Complications Study who reported receiving specialist care (n = 212) and those who did not (n = 217). Specialist care was defined as having received care from an endocrinologist or diabetologist or diabetes clinic attendance during the last year.Results: Patients who reported receiving specialist care were more likely to be female, to have an education level beyond high school, to have an annual household income >$20,000, and to have health insurance. Additionally, patients receiving specialist care were more likely to have received diabetes education during the previous 3 years, to have knowledge of HbAlc testing and to have received that test during the previous 6 months, to have knowledge of the Diabetes Control and Complications Trial results, to self-monitor blood glucose, and to inject insulin more than twice daily. A lower HbA1 level was associated with specialist care versus generalist care (9.7 vs. 10.3%; P = 0.0006) as were higher education and income levels. Multivariate analyses suggest that the lower HbA1 levels observed in patients receiving specialist care were restricted to patients with an annual income >$20,000.Conclusions: Specialist care was associated with higher levels of participation in diabetes self-care practices and a lower HbA1 level. Future efforts should research and address the failure of patients with low incomes to benefit from specialist care. [ABSTRACT FROM AUTHOR]

The pathogenesis of excess cardiovascular risk in type 1 diabetes is unclear. LDL cholesterol is only weakly predictive, and its concentration is often normal in type 1 diabetes. We therefore examined whether markers of LDL oxidation such as antibodies to oxidized LDL (Ab-OxLDL) and LDL-containing immune complexes, rather than LDL concentration, were predictive of coronary artery disease (CAD) in type 1 diabetes. This nested case-control study from an epidemiologic cohort study included 49 incident cases of myocardial infarction (MI), angina, or CAD death and 49 age-, sex-, and duration-matched control subjects. Ab-OxLDL was measured by enzyme immunoassay and the apolipoprotein B (ApoB) content of immune complexes (ApoB-IC) precipitated by polyethylene glycol by immunoelectrophoresis in baseline stored samples. Ab-OxLDL was inversely, and ApoB-IC directly, related to subsequent CAD. In multivariate analyses, Ab-OxLDL remained a significant independent predictor along with previously recognized predictors, hypertension and Beck depression score. In conclusion, oxidation of LDL and the immune response it elicits may play a role in predicting the development of CAD in type 1 diabetes and explain at least some of the enhanced CAD risk in type I diabetes. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) in insulin dependent diabetes mellitus (IDDM) has been linked to renal disease. However, little is known concerning international variation in the correlations with hyperglycaemia and standard CVD risk factors.Methods: A cross-sectional comparison was made of prevalence rates and risk factor associations in two large studies of IDDM subjects: the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) and the EURODIAB IDDM Complications Study from 31 centres in Europe. Subgroups of each were chosen to be comparable by age and duration of diabetes. The EDC population comprises 286 men (mean duration 20.1 years) and 281 women (mean duration 19.9 years); EURODIAB 608 men (mean duration 18.1 years) and 607 women (mean duration 18.9 years). The mean age of both populations was 28 years. Cardiovascular disease was defined by a past medical history of myocardial infarction, angina, and/or the Minnesota ECG codes (1.1-1.3, 4.1-4.3, 5.1-5.3, 7.1).Results: Overall prevalence of CVD was similar in the two populations (i.e. men 8.6% versus 8.0%, women 7.4% versus 8.5%, EURODIAB versus EDC respectively), although EDC women had a higher prevalence of angina (3.9% versus 0.5%, P < 0.001). Multivariate modelling suggests that glycaemic control (HbA1c) is not related to CVD in men. Age and high density lipoprotein cholesterol predict CVD in EURODIAB, while triglycerides and hypertension predict CVD in EDC. For women in both populations, age and hypertension (or renal disease) are independent predictors. HbA1c is also an independent predictor-inversely in EURODIAB women (P < 0.008) and positively in EDC women (P = 0.03). Renal disease was more strongly linked to CVD in EDC than in EURODIAB.Conclusions: Despite a similar prevalence of CVD, risk factor associations appear to differ in the two study populations. Glycaemic control (HbA1c) does not show a consistent or strong relationship to CVD. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the prevalence and incidence of being overweight in type 1 diabetes, to identify factors associated with weight gain and improved glycemic control, and to examine relationships among weight gain, glycemic control, and cardiovascular risk factors. RESEARCH DESIGN AND METHODS: The prevalence and incidence of being overweight in the Pittsburgh Epidemiology of Diabetes Complications (EDC) cohort (n = 441) were compared with the general population (National Health and Nutrition Examination Survey [NHANES]). Factors associated with weight gain and improved glycemic control were identified, and relationships among weight gain, glycemic control, and cardiovascular risk factors were examined over a 6.9 +/- 2.2-year period. RESULTS: At baseline, the prevalence of being overweight (BMI > 27.8 kg/m2 for men and > 27.3 kg/m2 for women) was 10.4 and 11.4%, respectively, and was lower than the age- and sex-specific estimate for the general population (P < 0.05). The incidence of being overweight was comparable in men (12.6%) and women (11.8%) and did not differ from the general population (P = 0.98). Weight gain correlated with improvements in HbA1c (r = -0.21, P < 0.001). Patients with the highest baseline HbA1c levels gained the most weight and had the greatest improvement in glycemic control. A lower baseline BMI was also associated with a greater improvement in glycemic control. Weight gain favorably influenced the lipid profile in the setting of improved glycemic control, but adversely influenced the lipid profile in the absence of improved glycemic control. Weight change was directly associated with blood pressure change, but the incidence of hypertension was more strongly influenced by the development of nephropathy. CONCLUSIONS: The prevalence of being overweight in type 1 diabetes remains lower than that in the general population. Moderate weight gain did not adversely affect the cardiovascular risk profile in the setting of improved glycemic control. [ABSTRACT FROM AUTHOR]

Background: Intensive diabetes therapy aimed at achieving near normoglycemia reduces the risk of microvascular and neurologic complications of type 1 diabetes. We studied whether the use of intensive therapy as compared with conventional therapy during the Diabetes Control and Complications Trial (DCCT) affected the long-term incidence of cardiovascular disease.Methods: The DCCT randomly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy, treating them for a mean of 6.5 years between 1983 and 1993. Ninety-three percent were subsequently followed until February 1, 2005, during the observational Epidemiology of Diabetes Interventions and Complications study. Cardiovascular disease (defined as nonfatal myocardial infarction, stroke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization) was assessed with standardized measures and classified by an independent committee.Results: During the mean 17 years of follow-up, 46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT, as compared with 98 events in 52 patients who had received conventional treatment. Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent (95 percent confidence interval, 9 to 63 percent; P=0.02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57 percent (95 percent confidence interval, 12 to 79 percent; P=0.02). The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease, but differences between treatment groups remained significant (P< or =0.05) after adjusting for these factors.Conclusions: Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the usefulness of ischemic resting electrocardiogram (ECG), ankle brachial index (ABI) <0.8, ankle brachial difference (ABD) > or = 75 mm Hg (a marker of peripheral medial arterial wall calcification), and estimated glucose disposal rate (eGDR) (a marker for insulin resistance) for predicting mortality risk in the context of standard risk factors.Methods: Data are from participants in the Pittsburgh Epidemiology of Diabetes Complications Study of 658 subjects with childhood onset Type 1 diabetes of mean age 28 years (range 8-48) and duration of diabetes 19 years (range 7-37) at baseline. Deaths were confirmed by death certificates.Results: There were 68 deaths from all causes during 10 years follow-up. In univariate analysis, the mortality hazard ratios and 95% confidence intervals associated with ischemic ECG (6.7, 3.7-12.1), the lowest quintile of eGDR (i.e., the most insulin resistant) (6.7, 4.1-10.9), ABI <0.8 (2.5, 1.1-5.9), and ABD > or = 75 mm Hg (6.7) were only marginally less than those conveyed by pre-existing coronary artery disease (8.4, 4.7-15.2) or overt nephropathy (7.6, 4.5-12.9). Ischemic ECG and eGDR were independent mortality predictors, together with duration of diabetes, coronary artery disease, overt nephropathy, nonhigh density lipoprotein cholesterol, and smoking history. If serum creatinine was available, it entered, and glycosylated hemoglobin replaced eGDR.Conclusions: Estimated GDR and ECG ischemia are strong predictors of mortality in type 1 diabetes and may be useful in the identification of those at risk. [ABSTRACT FROM AUTHOR]

Objective: Diabetic peripheral neuropathy (DPN) is common; however, the features and burden of neuropathic pain (NP) in type 1 diabetes (T1D) are poorly understood. We evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for NP during long-term follow-up of participants with T1D., Research Design and Methods: The Michigan Neuropathy Screening Instrument (MNSI) was administered annually (1994-2020) for 1,324 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. NP with clinical signs of DPN (NP DPN+) was defined according to self-reported NP plus an examination score >2, while NP without clinical signs of DPN (NP DPN-) was defined according to self-reported NP and an examination score ≤2., Results: At EDIC year 1, median age for participants was 36 years (interquartile range 30, 41), diabetes duration 13 years (10, 18), and HbA1c 7.9% (7.2, 8.9). At year 26 (median diabetes duration 39 years), cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs. 46% NP DPN-). NP prevalence was 20% at 26 years (11% NP DPN+ and 9% NP DPN-), suggesting frequent remission. Annualized remission rates were similar regardless of pain medication use. In addition to HbA1c, female sex was associated with NP DPN-., Conclusions: NP incidence in T1D was high and frequently occurred in the absence of clinical signs of neuropathy, as assessed with the MNSI. Pain remission was not explained by pain medication use. Effective clinical strategies for identification and management are needed., (© 2024 by the American Diabetes Association.)

Background: The cholesterol efflux capacity of high density lipoprotein (HDL) is negatively associated with cardiovascular risk. Small HDL particles account almost quantitatively for cholesterol efflux capacity, perhaps mediated through efflux of cholesterol and outer leaflet plasma membrane phospholipids by ABCA1 (ATP binding cassette subfamily A member 1). People with type 1 diabetes are at increased coronary artery disease (CAD) risk despite normal HDL-cholesterol concentrations. We therefore tested the hypothesis that small HDL particles (HDL-P)-rather than HDL-cholesterol-predict incident CAD in type 1 diabetes., Methods and Results: Incident CAD (CAD death, myocardial infarction, or coronary revascularization) was determined in 550 individuals with childhood-onset type 1 diabetes. HDL-P was quantified by calibrated ion mobility analysis and cholesterol efflux capacity was quantified with validated assays. During a median follow-up of 26 years, 36.5% of the participants developed incident CAD, for an incidence density of 181.3 per 10 000 person-years. In multivariable Cox models, neither HDL-cholesterol nor apolipoprotein A1 concentration was significantly associated with CAD risk. In contrast, higher extra-small HDL-P concentrations were significantly associated with decreased CAD risk (hazard ratio [HR], 0.26 [95% CI, 0.14-0.50]). Weaker associations were observed for total HDL-P (HR, 0.88 [95% CI, 0.83-0.93]), small HDL (HR, 0.83 [95% CI, 0.68-1.02]), medium HDL (HR, 0.79 [95% CI, 0.71-0.89]), and large HDL (HR, 0.72 [95% CI, 0.59-0.89]). Although cholesterol efflux capacity was negatively associated with incident CAD, this association was no longer significant after adjustment for total HDL-P., Conclusions: Lower concentrations of total HDL-P and HDL subpopulations were positively associated with incident CAD independently of HDL-cholesterol, apolipoprotein A1, and other common CVD risk factors. Extra-small HDL was a much stronger predictor of risk than the other HDLs. Our data are consistent with the proposal that extra-small HDL plays a critical role in cardioprotection in type 1 diabetes, mediated by macrophage cholesterol efflux by the ABCA1 pathway.

Background: In type 1 diabetes, women lose their relative protection (compared to men) against coronary artery disease (CAD), while high-density lipoprotein cholesterol (HDL-C) is less strongly associated with lower CAD risk in women., Objective: We aimed to assess whether sex differences in the HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC) association with CAD may explain these findings., Methods: HDL-P (calibrated differential ion mobility analysis) and total and ATP binding cassette transporter A1 (ABCA1)-specific CEC were quantified among 279 men and 271 women with type 1 diabetes (baseline mean age 27·8 years; diabetes duration, 19·6 years). Clinical CAD was defined as CAD death, myocardial infarction and/or coronary revascularization., Results: Women had higher large HDL-P levels and marginally lower concentrations of small HDL-P and ABCA1-specific CEC than men. No sex differences were observed in extra-small HDL-P, medium HDL-P and total CEC. During a median follow-up of 26 years, 37·6 % of men and 35·8 % of women developed CAD (p = 0·72). In multivariable Cox models stratified by sex (p Total HDL-P x sex interaction =0·01), HDL-P was negatively associated with CAD incidence in both sexes. However, associations were stronger in men, particularly for extra-small HDL-P (hazard ratio (HR) men =0·11, 95 % confidence interval (CI): 0·04-0·30; HR women =0·68, 95 % CI: 0·28-1·66; p interaction =0·001). CEC did not independently predict CAD in either sex., Conclusion: Despite few absolute differences in HDL-P concentrations by sex, the HDL-P - CAD association was weaker in women, particularly for extra-small HDL-P, suggesting that HDL-P may be less efficient in providing atheroprotection in women and perhaps explaining the lack of a sex difference in CAD in type 1 diabetes., Competing Interests: Declaration of competing interest T.C., R.G.M., J.W.H., T.J.O. and T.V. have no relevant conflicts of interest to disclose. K.E.B. serves on the Scientific Advisory Board of Esperion Therapeutics., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To perform a prospective epigenome-wide association study of DNA methylation (DNAm) and 28-year proliferative diabetic retinopathy (PDR) incidence in type 1 diabetes (T1D)., Design: Prospective observational cohort study., Participants: The Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (< 17 years) T1D., Methods: Stereoscopic fundus photographs were taken in fields 1, 2, and 4 at baseline, 2, 4, 6, 8, 16, 23, and 28 years after DNAm measurements. The photos were graded using the modified Airlie House System. In those free of PDR at baseline (n = 265; mean T1D duration of 18 years at baseline), whole blood DNAm (EPIC array) at 683 597 CpGs was analyzed in Cox models for time to event. Associations between significant CpGs and clinical risk factors were assessed; genetic variants associated with DNAm were identified (methylation quantitative trait loci [meQTLs]). Mendelian randomization was used to examine evidence of causal associations between DNAm and PDR. Post hoc regional and functional analyses were performed., Main Outcome Measures: Proliferative diabetic retinopathy was defined as the first instance of a grade of ≥ 60 in at least 1 eye or pan-retinal photocoagulation for PDR. Follow-up time was calculated from the study visit at which DNAm data were available (baseline) until PDR incidence or censoring (December 31, 2018 or last follow-up)., Results: PDR incidence was 53% over 28-years' follow-up. Greater DNAm of cg27512687 ( KIF16B ) was associated with reduced PDR incidence ( P  = 6.3 × 10 -9 ; false discovery rate [FDR]: < 0.01); 113 cis-meQTLs ( P  < 5 × 10 -8 ) were identified. Mendelian randomization analysis using the sentinel meQTL as the instrumental variable supported a potentially causal association between cg27512687 and PDR. Cg27512687 was also associated with lower pulse rate and albumin excretion rate and higher estimated glomerular filtration rate, but its association with PDR remained independently significant after adjustment for those factors. In regional analyses, DNAm of FUT4 , FKBP1A , and RIN2 was also associated with PDR incidence., Conclusions: DNA methylation of KIF16B, FUT4, FKBP1A , and RIN2 was associated with PDR incidence, supporting roles for epigenetic regulation of iron clearance, developmental pathways, and autophagy in PDR pathogenesis. Further study of those loci may provide insight into novel targets for interventions to prevent or delay PDR in T1D., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)