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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]

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: 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]

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]

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]

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]

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]

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.)

Objective: Understanding mechanisms underlying rapid estimated glomerular filtration rate (eGFR) decline is important to predict and treat kidney disease in type 1 diabetes (T1D)., Research Design and Methods: We performed a case-control study nested within four T1D cohorts to identify urinary proteins associated with rapid eGFR decline. Case and control subjects were categorized based on eGFR decline ≥3 and <1 mL/min/1.73 m2/year, respectively. We used targeted liquid chromatography-tandem mass spectrometry to measure 38 peptides from 20 proteins implicated in diabetic kidney disease. Significant proteins were investigated in complementary human cohorts and in mouse proximal tubular epithelial cell cultures., Results: The cohort study included 1,270 participants followed a median 8 years. In the discovery set, only cathepsin D peptide and protein were significant on full adjustment for clinical and laboratory variables. In the validation set, associations of cathepsin D with eGFR decline were replicated in minimally adjusted models but lost significance with adjustment for albuminuria. In a meta-analysis with combination of discovery and validation sets, the odds ratio for the association of cathepsin D with rapid eGFR decline was 1.29 per SD (95% CI 1.07-1.55). In complementary human cohorts, urine cathepsin D was associated with tubulointerstitial injury and tubulointerstitial cathepsin D expression was associated with increased cortical interstitial fractional volume. In mouse proximal tubular epithelial cell cultures, advanced glycation end product-BSA increased cathepsin D activity and inflammatory and tubular injury markers, which were further increased with cathepsin D siRNA., Conclusions: Urine cathepsin D is associated with rapid eGFR decline in T1D and reflects kidney tubulointerstitial injury., (© 2022 by the American Diabetes Association.)

Objective: We hypothesized that there is heterogeneity in long-term patterns of glycemic control with respect to cardiovascular disease (CVD) development in type 1 diabetes and that risk factors for CVD differ by glycemic control pattern. Thus, we estimated associations between data-derived latent HbA1c trajectories and 30-year CVD risk in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (<17 years old) type 1 diabetes., Research Design and Methods: Participants (n = 536 with two or more HbA1c measurements [median 6] and CVD-free at baseline; mean age 27 and diabetes duration 18 years) were followed from 1986 to 1988 to 2016 to 2018 to ascertain CVD incidence (CVD death, myocardial infarction, stroke, coronary revascularization or blockage ≥50%, ischemic electrocardiogram, or angina). Latent HbA1c trajectories and their association with time-to-CVD incidence were simultaneously assessed using joint latent class mixed models., Results: Two HbA1c trajectories with respect to differential CVD risk were identified: low (HbA1c ∼8% [64 mmol/mol] and improving over follow-up, 76% of cohort) and high (HbA1c ∼10% [86 mmol/mol] and stable, 24%). Overall, 30-year CVD incidence was 47.4% (n = 253); major adverse cardiovascular event incidence was 31.0% (n = 176). High HbA1c was associated with threefold increased CVD risk versus low HbA1c. Both groups had similar age and diabetes duration. Non-HDL cholesterol and estimated glomerular filtration rate were associated with CVD risk only in low HbA1c; albumin excretion rate was associated with CVD risk only in high HbA1c., Conclusions: These risk factor differences suggest that pathways to CVD may differ by glycemic control, potentially resulting in important implications for prognosis in type 1 diabetes., (© 2021 by the American Diabetes Association.)

Objectives: Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D., Research Design and Methods: In a case-control study, 817 patients with T1D from three large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m 2 per year decline in estimated glomerular filtration rate (eGFR), while control was defined as <1 mL/min/1.73 m 2 per year decline over a minimum 4-year follow-up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform., Results: At individual lipids, free fatty acid (FFA)20:2 was directly and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps, and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min/1.73 m 2 . A multilipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved the C-statistic of the clinical model from 0.816 to 0.841 ( P = 0.039). Observations were confirmed in the validation subset., Conclusions: Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at the sn1 carbon of the phospholipids' glycerol backbone as an independent predictor of rapid GFR decline in T1D., (© 2021 by the American Diabetes Association.)

Objective: The role of genetic factors in the risk of cardiovascular disease (CVD) for patients with type 1 diabetes (T1D) remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study., Research Design and Methods: Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1,371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or nonfatal myocardial infarction [MI] or stroke) and any CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD with adjustment for other factors (including age, lipids, blood pressure, and glycemia)., Results: CAD PRS was strongly associated with the subsequent risk of any CVD (42% and 38% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001) and with the risk of MACE (50% and 40% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001). Several individual single nucleotide polymorphisms were also nominally associated with the risk of any CVD and MACE., Conclusions: Genetic factors are associated with the risk of subsequent CVD in individuals with T1D above and beyond the effect of established risk factors such as age, lipids, blood pressure, and glycemia., (© 2021 by the American Diabetes Association.)

Objective: Individuals with diabetes have higher resting heart rate compared with those without, which may be predictive of long-term cardiovascular disease (CVD) risk. Using data from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, we evaluated whether the beneficial effect of intensive versus conventional diabetes therapy on heart rate persisted, the factors mediating the differences in heart rate between treatment groups, and the effects of heart rate on future CVD risk., Research Design and Methods: Longitudinal changes in heart rate, from annual electrocardiograms over 22 years of EDIC follow-up, were evaluated in 1,402 participants with type 1 diabetes. Linear mixed models were used to assess the effect of DCCT treatment group on mean heart rate over time, and Cox proportional hazards models were used to estimate the effect of heart rate on CVD risk during DCCT/EDIC., Results: At DCCT closeout, 52% of participants were male and mean ± SD age was 33 ± 7 years, diabetes duration 12 ± 5 years, and HbA 1c 7.4 ± 1.2% (intensive) and 9.1 ± 1.6% (conventional). Through EDIC, participants in the intensive group had significantly lower heart rate in comparison with the conventional group. While significant group differences in heart rate were fully attenuated by DCCT/EDIC mean HbA 1c , higher heart rate predicted CVD and major adverse cardiovascular events independent of other risk factors., Conclusions: After 22 years of follow-up, former intensive versus conventional therapy remained significantly associated with lower heart rate, consistent with the long-term beneficial effects of intensive therapy on CVD. DCCT treatment group effects on heart rate were explained by differences in DCCT/EDIC mean HbA 1c ., (© 2021 by the American Diabetes Association.)

Objective: High-sensitivity cardiac troponin-T (hs-cTnT) and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), biomarkers of cardiovascular disease (CVD) and heart failure, respectively, have not been widely studied in type 1 diabetes (T1D). We evaluated whether their assessment in T1D enhances the prediction of CVD and major adverse cardiovascular events (MACE)., Research Design and Methods: hs-cTnT and NT-proBNP were analyzed on the Roche Cobas E601 using the first available stored specimen ( n = 581; mean age 29 years and diabetes duration 21 years). CVD was defined as CVD death, myocardial infarction, coronary revascularization, angina, ischemia, or stroke, and MACE as CVD death, myocardial infarction, or stroke., Results: Median hs-cTnT (5.0 ng/L; interquartile range <3.0, 10.0) was higher among men ( P < 0.0001), whereas median NT-proBNP (22.0 ng/L; 7.0, 61.0) did not differ by sex. In Cox models, log hs-cTnT (hazard ratio [HR] 1.38, P = 0.0006) and log NT-proBNP (HR 1.24, P = 0.0001) independently predicted CVD during 21 years of follow-up. However, their addition to models, singly or together, did not significantly improve CVD prediction. Furthermore, a marginally significant sex interaction was observed ( P = 0.06), indicating that the hs-cTnT prediction was limited to men. hs-cTnT and NT-proBNP also predicted MACE, although only NT-proBNP remained significant (HR 1.27, P = 0.0009) when the biomarkers were included in a model simultaneously. Nonetheless, their addition to multivariable models did not enhance MACE prediction., Conclusions: Sex differences were observed in the concentration and predictive ability of hs-cTnT and NT-proBNP in T1D. Overall, their addition to traditional risk factor models increased the area under the curve for neither CVD nor MACE., (© 2020 by the American Diabetes Association.)

Objective: We aimed to determine optimal blood pressure (BP) thresholds for minimizing coronary artery disease (CAD) risk in people with childhood-onset type 1 diabetes., Research Design and Methods: The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study participants without known CAD at baseline ( n = 605) were included and followed for 25 years. The associations of time-weighted BP measures (systolic BP [SBP], diastolic BP [DBP], and mean arterial pressure) with incident CAD were examined by using Cox models. Areas under the receiver operating characteristic curve (AUC) were summarized by different cut points of time-weighted BPs. Risk stratification analyses were then performed on the basis of BP (<120/80 vs. ≥120/80 mmHg) and HbA 1c (<8% vs. ≥8%)., Results: Baseline mean age was 27 years. Half of the cohort were women and 98% were white. A dose-gradient association was observed for categorized time-weighted BPs and CAD. According to AUC, the optimal cut point for SBP was 120 mmHg and for DBP was 80 mmHg. BP ≥120/80 mmHg was associated with a 1.9 times (95% CI 1.4, 2.6) greater risk of developing CAD than that for BP <120/80 mmHg. Participants with good control of both BP and HbA 1c had BP <120/80 mmHg and HbA 1c <8%. Those with only high BP (hazard ratio [HR] 2.0 [95% CI 1.1, 3.9]) carried a similar risk of developing CAD as those with only high HbA 1c (HR 1.6 [95% CI 0.97, 2.8])., Conclusions: The optimal BP threshold associated with minimal CAD risk is 120/80 mmHg in young adults with childhood-onset type 1 diabetes., (© 2019 by the American Diabetes Association.)

Objective: The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the major role of hyperglycemia as a risk factor for clinical cardiovascular outcomes in type 1 diabetes (T1D). We assessed whether and to what extent the effect of glycemia is mediated by other established cardiovascular disease (CVD) risk factors., Research Design and Methods: In the DCCT, 1,441 participants were randomized to receive either intensive or conventional diabetes therapy. The EDIC observational follow-up study enrolled 96% of the surviving DCCT cohort with 94% of the survivors still actively participating after more than 27 years of follow-up. Mediation of the effect of glycemia, as captured by HbA 1c , on the subsequent CVD risk was quantified using the relative change in the CVD risk associated with HbA 1c between models without and with the potential mediator., Results: Adjusted for age, only a few factors (e.g., pulse, triglycerides, albumin excretion rate) explained more than 10% of the effect of glycemia on CVD risk when considered individually. In multivariable models, these traditional risk factors together mediated up to ∼50% of the effect of glycemia on the risk of CVD. However, the association between HbA 1c and the risk of CVD remained highly significant even after adjustment for these risk factors., Conclusions: While HbA 1c is associated with many traditional CVD risk factors, its association with these factors alone cannot explain its effects on risk of CVD. Consequently, aggressive management of traditional nonglycemic CVD risk factors, coupled with aggressive glycemic management, is indicated for individuals with type 1 diabetes., (© 2019 by the American Diabetes Association.)

Objective: The implementation of the Chronic Care Model (CCM) improves health care quality. We examined the sustained effectiveness of multicomponent integrated care in type 2 diabetes., Research Design and Methods: We searched PubMed and Ovid MEDLINE (January 2000-August 2016) and identified randomized controlled trials comprising two or more quality improvement strategies from two or more domains (health system, health care providers, or patients) lasting ≥12 months with one or more clinical outcomes. Two reviewers extracted data and appraised the reporting quality., Results: In a meta-analysis of 181 trials ( N = 135,112), random-effects modeling revealed pooled mean differences in HbA 1c of -0.28% (95% CI -0.35 to -0.21) (-3.1 mmol/mol [-3.9 to -2.3]), in systolic blood pressure (SBP) of -2.3 mmHg (-3.1 to -1.4), in diastolic blood pressure (DBP) of -1.1 mmHg (-1.5 to -0.6), and in LDL cholesterol (LDL-C) of -0.14 mmol/L (-0.21 to -0.07), with greater effects in patients with LDL-C ≥3.4 mmol/L (-0.31 vs. -0.10 mmol/L for <3.4 mmol/L; P difference = 0.013), studies from Asia (HbA 1c -0.51% vs. -0.23% for North America [-5.5 vs. -2.5 mmol/mol]; P difference = 0.046), and studies lasting >12 months (SBP -3.4 vs. -1.4 mmHg, P difference = 0.034; DBP -1.7 vs. -0.7 mmHg, P difference = 0.047; LDL-C -0.21 vs. -0.07 mmol/L for 12-month studies, P difference = 0.049). Patients with median age <60 years had greater HbA 1c reduction (-0.35% vs. -0.18% for ≥60 years [-3.8 vs. -2.0 mmol/mol]; P difference = 0.029). Team change, patient education/self-management, and improved patient-provider communication had the largest effect sizes (0.28-0.36% [3.0-3.9 mmol/mol])., Conclusions: Despite the small effect size of multicomponent integrated care (in part attenuated by good background care), team-based care with better information flow may improve patient-provider communication and self-management in patients who are young, with suboptimal control, and in low-resource settings., (© 2018 by the American Diabetes Association.)

Objective: A common belief is that only a minority of patients with type 1 diabetes (T1D) develop advanced kidney disease and that incidence is higher among men and lower in those diagnosed at a younger age. However, because few patients with T1D survived to older ages until recently, long-term risks have been unclear., Research Design and Methods: We examined the 50-year cumulative kidney complication risk in a childhood-onset T1D cohort diagnosed during 1950-80 ( n = 932; mean baseline age 29 years, duration 19 years). Participants comprised 144 who died prior to baseline, 130 followed with periodic surveys, and 658 followed with biennial surveys and a maximum of nine examinations for 25 years. Micro- and macroalbuminuria were defined as an albumin excretion rate of 20-199 and ≥200 μg/min, respectively, and end-stage renal disease (ESRD) was defined as dialysis or kidney transplantation. Cumulative incidence was estimated at 10-year intervals between 20 and 50 years , duration and compared by calendar year of diabetes onset., Results: By 50 years , T1D duration, ESRD affected 60% of the cohort; macroalbuminuria, 72%; and microalbuminuria, 88%. Little evidence existed for declines in cumulative incidence in recent cohorts, except for ESRD (microalbuminuria 3% increase, macroalbuminuria no change; ESRD 45% decrease by 40 years of T1D duration). Onset before age 6 years was associated with the lowest risk; incidence generally did not differ by sex., Conclusions: Some degree of kidney disease in T1D is virtually universal at long durations and not declining, which has major implications for formulating health care and research strategies. ESRD has declined, but continues to affect >25% of the population by 40 years , duration., (© 2017 by the American Diabetes Association.)

Objective: We examined the association between the prevalence and incidence of electrocardiographic (ECG) abnormalities and the development of cardiovascular disease (CVD) in patients with type 1 diabetes, among whom these ECG abnormalities are common., Research Design and Methods: We conducted a longitudinal cohort study involving 1,306 patients with type 1 diabetes (mean age 35.5 ± 6.9 years; 47.7% female) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. ECG abnormalities were defined by the Minnesota Code ECG classification as major, minor, or no abnormality. CVD events were defined as the first occurrence of myocardial infarction, stroke, confirmed angina, coronary artery revascularization, congestive heart failure, or death from any CVD., Results: During a median follow-up of 19 years, 155 participants (11.9%) developed CVD events. In multivariable Cox proportional hazard models adjusted for demographics and potential confounders, the presence of any major ECG abnormalities as a time-varying covariate was associated with a more than twofold increased risk of CVD events (hazard ratio [HR] 2.10 [95% CI 1.26, 3.48] vs. no abnormality/normal ECG, and 2.19 [1.46, 3.29] vs. no major abnormality). Also, each visit (year) at which the diagnosis of major ECG abnormality was retained was associated with a 30% increased risk of CVD (HR 1.30 [95% CI 1.14, 1.48]). The presence of minor ECG abnormalities was not associated with a significant increase in CVD risk., Conclusions: The presence of major ECG abnormalities is associated with an increased risk of CVD in patients with type 1 diabetes. This suggests a potential role for ECG screening in patients with type 1 diabetes to identify individuals at risk for CVD., (© 2017 by the American Diabetes Association.)

Objective: The degree to which mortality and cardiovascular disease (CVD) incidence remains elevated in young U.S. adults with type 1 diabetes (T1DM) is unclear. We determined contemporary rates for adults <45 years old with long-standing, childhood-onset T1DM from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study., Research Design and Methods: Members of the EDC Study cohort <45 years old during the 1996-2012 follow-up period (n = 502) were studied. Mortality and CVD rates were calculated for those aged 30-39 and 40-44 years. Data from the background Allegheny County, Pennsylvania, population were used to calculate age- and sex-matched standardized mortality (SMR) and incidence rate ratios (IRR)., Results: In both age groups, the SMR for total mortality was ∼5 (95% CIs: 30-39-year-olds, 2.8, 7.2; 40-44-year-olds, 3.4, 7.8). CVD mortality SMRs ranged from 19 (95% CI 11, 32) to 33 (95% CI 17, 59). Hospitalized CVD IRR was ∼8 (95% CIs: 30-39-year-olds, 2.5, 18.9; 40-44-year-olds, 4.5, 12.8); revascularization procedures account for much of the increased risk. For all outcomes, the relative risk was larger in women. Participants aged 30-39 years had 6.3% (95% CI 3.8, 9.8) absolute 10-year CVD risk, approaching the American College of Cardiology/American Heart Association-recommended cut point of 7.5% for initiation of statin therapy in older adults., Conclusions: Total and CVD mortality and hospitalized CVD are all significantly increased in this contemporary U.S. cohort of young adults with long-standing T1DM. These findings support more aggressive risk factor management in T1DM, especially among women., (© 2016 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 therapies may be different in the two populations. Understanding the developmental and regulatory pathways for type 1 diabetes-modifying therapies in children will enable industry, academia, funders, advocacy groups, and regulators to translate new science to clinical care. This consensus report characterizes the fundamental differences in type 1 diabetes between children and adults and proposes a thoughtful approach to better understand the development and regulatory pathways for type 1 diabetes therapies., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: The aim of this study was to investigate the presence and correlates of clinically relevant cognitive impairment in middle-aged adults with childhood-onset type 1 diabetes (T1D)., Research Design and Methods: During 2010-2013, 97 adults diagnosed with T1D and aged <18 years (age and duration 49 ± 7 and 41 ± 6 years, respectively; 51% female) and 138 similarly aged adults without T1D (age 49 ± 7 years; 55% female) completed extensive neuropsychological testing. Biomedical data on participants with T1D were collected periodically since 1986-1988. Cognitive impairment status was based on the number of test scores ≥1.5 SD worse than demographically appropriate published norms: none, mild (only one test), or clinically relevant (two or more tests)., Results: The prevalence of clinically relevant cognitive impairment was five times higher among participants with than without T1D (28% vs. 5%; P < 0.0001), independent of education, age, or blood pressure. Effect sizes were large (Cohen d 0.6-0.9; P < 0.0001) for psychomotor speed and visuoconstruction tasks and were modest (d 0.3-0.6; P < 0.05) for measures of executive function. Among participants with T1D, prevalent cognitive impairment was related to 14-year average A1c >7.5% (58 mmol/mol) (odds ratio [OR] 3.0; P = 0.009), proliferative retinopathy (OR 2.8; P = 0.01), and distal symmetric polyneuropathy (OR 2.6; P = 0.03) measured 5 years earlier; higher BMI (OR 1.1; P = 0.03); and ankle-brachial index ≥1.3 (OR 4.2; P = 0.01) measured 20 years earlier, independent of education., Conclusions: Clinically relevant cognitive impairment is highly prevalent among these middle-aged adults with childhood-onset T1D. In this aging cohort, chronic hyperglycemia and prevalent microvascular disease were associated with cognitive impairment, relationships shown previously in younger populations with T1D. Two additional potentially modifiable risk factors for T1D-related cognitive impairment, vascular health and BMI, deserve further study., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: Restoration of normal glucose regulation (NGR) in people with prediabetes significantly decreases the risk of future diabetes. We sought to examine whether regression to NGR is also associated with a long-term decrease in cardiovascular disease (CVD) risk., Research Design and Methods: The Framingham (2008) score (as an estimate of the global 10-year CVD risk) and individual CVD risk factors were calculated annually for the Diabetes Prevention Program Outcomes Study years 1-10 among those patients who returned to NGR at least once during the Diabetes Prevention Program (DPP) compared with those who remained with prediabetes or those in whom diabetes developed during DPP (N = 2,775)., Results: The Framingham scores by glycemic exposure did not differ among the treatment groups; therefore, pooled estimates were stratified by glycemic status and were adjusted for differences in risk factors at DPP baseline and in the treatment arm. During 10 years of follow-up, the mean Framingham 10-year CVD risk scores were highest in the prediabetes group (16.2%), intermediate in the NGR group (15.5%), and 14.4% in people with diabetes (all pairwise comparisons P < 0.05), but scores decreased over time for those people with prediabetes (18.6% in year 1 vs. 15.9% in year 10, P < 0.01). The lower score in the diabetes group versus other groups, a declining score in the prediabetes group, and favorable changes in each individual risk factor in all groups were explained, in part, by higher or increasing medication use for lipids and blood pressure., Conclusions: Prediabetes represents a high-risk state for CVD. Restoration of NGR and/or medical treatment of CVD risk factors can significantly reduce the estimated CVD risk in people with prediabetes., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: We evaluate whether lifestyle and metformin interventions used to prevent diabetes have durable effects on markers of inflammation and coagulation and whether the effects are influenced by the development of diabetes., Research Design and Methods: The Diabetes Prevention Program was a controlled clinical trial of 3,234 subjects at high risk for diabetes who were randomized to lifestyle, metformin, or placebo interventions for 3.4 years. Diabetes was diagnosed semiannually by fasting glucose and annually by oral glucose tolerance testing. In addition to baseline testing, anthropometry was performed every 6 months; fasting insulin yearly; and hs-CRP, tissue plasminogen activator (tPA), and fibrinogen at 1 year and end of study (EOS)., Results: CRP and tPA levels were unchanged in the placebo group but fell in the lifestyle and metformin groups at 1 year and remained lower at EOS. These reductions were not seen in those who developed diabetes over the course of the study despite intervention. Fibrinogen was lower at 1 year in the lifestyle group. Differences in weight and weight change explained most of the influence of diabetes on the CRP response in the lifestyle group, but only partly in the placebo and metformin groups. Weight, insulin sensitivity, and hyperglycemia differences each accounted for the influence of diabetes on the tPA response., Conclusions: Lifestyle and metformin interventions have durable effects to lower hs-CRP and tPA. Incident diabetes prevented these improvements, and this was accounted for by differences in weight, insulin resistance, and glucose levels., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

OBJECTIVE To describe the beneficial long-term effects of an average of 6.5 years of intensive diabetes therapy (INT) in type 1 diabetes on measures of atherosclerosis, cardiac structure and function, and clinical cardiovascular events observed in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS The DCCT was a randomized clinical trial of 1,441 participants assigned to receive INT or conventional therapy (CON). It was conducted between 1983-1993 with an average follow-up of 6.5 years. EDIC (1994-present) is an observational follow-up of the DCCT cohort. Cardiovascular events have been recorded throughout. During EDIC common carotid intima-media thickness (IMT) was measured with ultrasound, coronary artery calcification with computed tomography, and cardiac structure and function with cardiac magnetic resonance imaging. RESULTS DCCT INT and lower levels of HbA1c during DCCT/EDIC were associated with thinner carotid IMT, less coronary calcification, and a lower incidence of clinical cardiovascular events including myocardial infarction, stroke, and cardiac death. While there were no significant differences in cardiac structure and function between the former INT and CON groups, they were significantly associated with higher HbA1c during DCCT/EDIC. CONCLUSIONS DCCT INT and the attendant 6.5 years of lower HbA1c had long-term salutary effects on the development and progression of atherosclerosis and cardiovascular disease during the subsequent follow-up during EDIC.

Objective: The incidence of type 1 diabetes complications appears to be decreasing, but relative contributions of risk factors are unclear. We thus estimated the effect of modifiable risk factors on the incidence of a composite end point, major outcomes of diabetes (MOD)., Research Design and Methods: The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study was used to derive two cohorts based on diabetes diagnosis year (1960-1969 and 1970-1980). Baseline exam data in the current analysis for the 1960s group were collected in 1986-1988 and for the 1970s in 1996-1998. Each group was followed for 8 years for MOD incidence (diabetes-related death, myocardial infarction, revascularization procedure/blockage ≥50%, stroke, end-stage renal disease, blindness, and amputation). Assessed risk factors include the following: HbA1c, hypertension, microalbuminuria, BMI, hypercholesterolemia, and smoking. Accelerated failure time models were used to estimate the acceleration factor., Results: MOD incidence decreased in the 1970s cohort (15.8% [95% CI 11.6-21.4]) compared with the 1960s (22.6% [17.0-29.1]) over the 8-year follow-up (P = 0.06). Hypertension and microalbuminuria were associated with significantly accelerated MOD incidence in both cohorts (P < 0.01 for both). High HbA1c (P = 0.0005), hypercholesterolemia (P = 0.01), and current smoking (P = 0.003) significantly accelerated the incidence of MOD in the 1960s but not 1970s cohort. BMI was not associated with MOD in either cohort., Conclusions: These results suggest that hypertension and microalbuminuria remain important predictors of complications that are not being adequately addressed.

Objective: Although oxidative stress (OxS) is thought to contribute to atherosclerosis and coronary artery disease (CAD), little is known about the variability in an individual's ability to respond to OxS. Therefore, we assessed potential indices of response to OxS and evaluated whether they modify the association between OxS and CAD., Research Design and Methods: We evaluated plasma α- and γ-tocopherol per unit cholesterol (potential response markers); urinary 15-isoprostane F2t per milligram creatinine (isoprostane [IsoP], a potential stress marker); and the α-tocopherol-to-IsoP ratio (as a measure of response to stress), measured three times during 20 years of follow-up, in relation to CAD incidence in a cohort with childhood-onset type 1 diabetes (n = 658; mean age at baseline, 28 years; duration of diabetes, 19 years). Participants with three samples (blood and either 24-h or overnight urine) available before the onset of CAD or the end of follow-up (n = 356) were selected for study., Results: In multivariable mixed models, α-tocopherol over time was inversely associated with CAD (β = -0.27; P = 0.02), whereas a direct association was observed for IsoP (β = 0.0008; P = 0.06). Moreover, the α-tocopherol-to-IsoP ratio was strongly and inversely related to CAD incidence (β = -0.72; P = 0.003), whereas in a separate model including α-tocopherol and IsoP, both biomarkers maintained statistical significance. No association was observed for γ-tocopherol (β = -0.22; P = 0.54)., Conclusions: These data suggest that a greater potential capability (α-tocopherol) to respond to OxS (urinary IsoP) relates to CAD incidence.

Objective: To determine whether type A behavior predicts all-cause mortality and incident coronary artery disease (CAD) in a type 1 diabetic population., Research Design and Methods: Follow-up data (22 years) from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset type 1 diabetes were analyzed for the 506 participants who completed the Bortner Rating Scale (measuring type A behavior) and Beck Depression Inventory (BDI) at baseline (1986-1988). CAD comprised myocardial infarction as determined by hospital records/Q waves on electrocardiogram (ECG), CAD death (determined by a mortality classification committee), angiographic stenosis, ischemic ECG, and angina., Results: There were 128 deaths (25.3%) during follow-up. Univariate analysis showed an inverse relationship between Bortner scores and all-cause mortality (P=0.01), which remained significant after allowing for age, sex, duration, HbA1c, education, smoking, BMI, and physical activity (P=0.03). However, the addition of BDI scores attenuated the relationship (P=0.11) with a significant interaction (P=0.03) such that any protective effect against mortality was limited among individuals with lower BDI scores (bottom three quintiles) (P=0.07), whereas no effect was seen in those with higher BDI scores (P=0.97). Bortner scores showed only a borderline association with incident CAD (P=0.09)., Conclusions: Those with higher type A behavior have lower all-cause mortality in our type 1 diabetic population, an effect that interacts with depressive symptomatology such that it is only operative in those with low BDI scores. Further research should focus on understanding this interaction.

Objective: To determine whether skin intrinsic fluorescence (SIF) is associated with long-term complications of type 1 diabetes (T1D) and, if so, whether it is independent of chronic glycemic exposure and previous intensive therapy., Research Design and Methods: We studied 1,185 (92%) of 1,289 active Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) participants from 2010 to 2011. SIF was determined using a fluorescence spectrometer and related cross-sectionally to recently determined measures of retinopathy (stereo fundus photography), cardiac autonomic neuropathy (CAN; R-R interval), confirmed clinical neuropathy, nephropathy (albumin excretion rate [AER]), and coronary artery calcification (CAC)., Results: Overall, moderately strong associations were seen with all complications, before adjustment for mean HbA1c over time, which rendered these associations nonsignificant with the exception of sustained AER>30 mg/24 h and CAC, which were largely unaffected by adjustment. However, when examined within the former DCCT treatment group, associations were generally weaker in the intensive group and nonsignificant after adjustment, while in the conventional group, associations remained significant for CAN, sustained AER>30 mg/24 h, and CAC even after mean HbA1c adjustment., Conclusions: SIF is associated with T1D complications in DCCT\EDIC. Much of this association appears to be related to historical glycemic exposure, particularly in the previously intensively treated participants, in whom adjustment for HbA1c eliminates statistical significance.

Objective: Skin intrinsic fluorescence (SIF) reflects many factors, including the presence of certain advanced glycation end products. We investigated whether SIF was associated with coronary artery disease (CAD) in type 1 diabetes and whether this relationship was independent of renal disease., Research Design and Methods: SIF was measured in 112 subjects from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study and 60 from MedStar Health Research Institute when mean age and diabetes duration were 48 and 36 years, respectively. Cumulative glycemic exposure (updated mean A1C) represented a mean of 18 years' follow-up in EDC and 10.3 in MedStar., Results: Of the 172 participants, 30 had CAD (15 male and 15 female). SIF levels were higher in those with CAD (P < 0.0001). SIF was strongly associated with CAD (odds ratio [OR] 3.5 [95% CI 2.1-6.1]). After age, duration, and updated mean A1C were controlled for, SIF remained associated with CAD (2.4 [1.3-4.4]), more strongly in men (5.6 [2.1-14.6]) than in women (1.4 [0.61-3.3]). As there was no significant sex interaction, further analyses were conducted combining the sexes. Further accounting for sex and nephropathy status did not improve the model fit, though with nephropathy in the model, the OR for SIF was reduced to 1.7 (95% CI 0.89-3.4)., Conclusions: SIF has a significant cross-sectional association with CAD. This association is strongly linked to age and duration and, to a lesser degree, to mean A1C and renal disease. SIF therefore may be a useful overall marker of CAD risk in type 1 diabetes.

Objective: To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes., Research Design and Methods: A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20-79 years., Results: A total of 35 studies (1980-2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5-34.8) for any DR, 6.96% (6.87-7.04) for proliferative DR, 6.81% (6.74-6.89) for diabetic macular edema, and 10.2% (10.1-10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A(1c), and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes., Conclusions: There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

Objective: To determine whether skin intrinsic fluorescence (SIF) was associated with autonomic neuropathy and confirmed distal symmetrical polyneuropathy (CDSP) in 111 individuals with type 1 diabetes (mean age 49 years, mean diabetes duration 40 years)., Research Design and Methods: SIF was measured using the SCOUT DM device. Autonomic neuropathy was defined as an electrocardiographic abnormal heart rate response to deep breathing (expiration-to-inspiration ratio <1.1). CDSP was defined using the Diabetes Control and Complications Trial clinical exam protocol (the presence of two or more of the following: symptoms, sensory and/or motor signs, and/or reduced/absent tendon reflexes consistent with DSP) confirmed by the presence of an abnormal age-specific vibratory threshold (using a Vibratron II tester)., Results: The prevalence of autonomic neuropathy and CDSP were 61 and 66%, respectively. SIF was higher in those with autonomic neuropathy (P < 0.0001). In multivariable analyses controlling for age and updated mean (18-year average) HbA(1c), and allowing for other univariately and clinically significant correlates of autonomic neuropathy, each SD change in SIF was associated with a 2.6-greater likelihood of autonomic neuropathy (P = 0.006). Receiver operating characteristic (ROC) analyses revealed that SIF and updated mean HbA(1c) accounted for 80 and 57%, respectively, of the area under the curve (AUC) for autonomic neuropathy. SIF also was higher in those with CDSP (P < 0.0001) and remained so in multivariable analyses (odds ratio 2.70; P = 0.005). ROC analyses revealed that SIF and updated mean HbA(1c) accounted for 78 and 59%, respectively, of the AUC for CDSP., Conclusions: SIF, a marker of dermal advanced glycation end products, appears to be more strongly associated with the presence of both CDSP and autonomic neuropathy than mean HbA(1c).

OBJECTIVE To examine the relationship between cardiovascular autonomic neuropathy and pulse waveform analysis (PWA) measures of arterial stiffness in a childhood-onset type 1 diabetes population. RESEARCH DESIGN AND METHODS Cardiac autonomic nerve function was measured in the baseline examination of the Pittsburgh Epidemiology of Diabetes Complications Study of childhood-onset type 1 diabetes by heart rate variability (R-R interval) during deep breathing and expressed as expiration-to-inspiration (E/I) ratio. Other cardiovascular and diabetes factors were also assessed. PWA was performed using SphgymoCor Px on 144 participants at the 18-year follow-up examination. Univariate and multivariate analyses for associations between baseline nerve function and other cardiovascular and diabetes-related factors were performed for augmentation index (AIx), augmentation pressure (AP), and subendocardial viability ratio (SEVR), a surrogate marker of myocardial perfusion. RESULTS E/I ratio correlated negatively with both AIx (r = -0.18, P = 0.03) and AP (r = -0.32, P < 0.001) and positively with SEVR (r = 0.47, P < 0.001) univariately. Lower baseline E/I ratio, HDL cholesterol, and a history of smoking were associated with higher follow-up (18 years later) AIx and AP and lower SEVR in multivariate analyses. Higher baseline HbA(1) was also associated with higher AP and lower SEVR multivariately. CONCLUSIONS Cardiovascular autonomic neuropathy is associated with increased arterial stiffness measures and decreased estimated myocardial perfusion in those with type 1 diabetes some 18 years later. This association persists after adjustment for potential confounders as well as for baseline HbA(1), HDL cholesterol, and smoking history, which were also associated with these PWA measures.

Objective: While lower hemoglobin is generally associated with adverse events in diabetes, we have recently observed in type 1 diabetes that those with overt nephropathy had hemoglobin levels as high as 18.8 g/dl. We thus explored whether hemoglobin concentrations are generally higher in type 1 diabetes., Research Design and Methods: Baseline (1986-1988) hemoglobin levels from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) of type 1 diabetes were compared with general population data from the National Health and Nutrition Examination Survey (NHANES) III in the same age range as the EDC population (aged 8-48 years)., Results: Both male and female EDC study participants had significantly higher hemoglobin levels than their NHANES III counterparts (men: 16.0 vs. 15.1 g/dl, P < 0.0001; women: 14.1 vs. 13.3 g/dl, P < 0.0001). The difference between the two populations was greatest in adolescent female subjects., Conclusions: Hemoglobin levels may be higher in type 1 diabetes than in the general population, which may have important clinical implications.

Objective: Cardiovascular risk prediction models are available for the general population (Framingham) and for type 2 diabetes (U.K. Prospective Diabetes Study [UKPDS] Risk Engine) but may not be appropriate in type 1 diabetes, as risk factors including younger age at diabetes onset and presence of diabetes complications are not considered. Therefore, our objective was to examine the accuracy of Framingham and UKPDS models for predicting coronary heart disease (CHD) in a type 1 diabetic cohort., Research Design and Methods: Ten-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, a prospective cohort study of 658 subjects with childhood-onset type 1 diabetes diagnosed between 1950 and 1980 first seen in 1986-1988, were analyzed. EDC study data were used to calculate the 10-year probability of CHD (fatal CHD, nonfatal myocardial infarction, or Q-waves) applying to the Framingham and UKPDS equations., Results: Mean age at CHD onset was 39 years. When fatal/nonfatal myocardial infarction and CHD death were modeled, both the UKPDS and Framingham models showed significant lack of calibration (P < 0.0001) but moderate discrimination (0.76 UKPDS, 0.77 Framingham men, and 0.88 Framingham women). Both the UKPDS and Framingham models underestimated probability of events in highest risk deciles., Conclusions: Currently available CHD models poorly predict events in type 1 diabetes. Future research should focus on determining the risk factors accounting for the lack of fit and developing prediction models specific to this high-risk group.