Tina Costacou

The 30-Year Natural History of Type 1 Diabetes Complications The Pittsburgh Epidemiology of Diabetes Complications Study Experience

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.

Type 1 diabetes and coronary artery disease.

Although the increased risk of premature heart disease in type 1 diabetes has been recognized for some time, the underlying pathogenesis is still poorly understood. The most likely factor, a priori, to account for this increased risk is hyperglycemia. However, despite recent evidence from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study that prior intensive glycemic control reduces cardiovascular disease (CVD), the epidemiologic association between glycemia and coronary heart disease (CHD) is surprisingly weak. This paradox is a focus of the current review, which also evaluates other major determinants of coronary artery disease (CAD) in type 1 diabetes, including the roles of insulin resistance, cytokines, inflammatory biomarkers, and, briefly, genetic factors. Finally, the clinical implications of this information are discussed. A high occurrence of, and mortality from, CHD in type 1 diabetes has been documented since the late 1970s (1,2). A 1984 registry reported a 10-fold or greater CHD mortality compared with that expected from U.S. national data (3). This very high relative risk, partly reflecting the extremely low CHD death rate in the general young-adult population, was subsequently confirmed by Joslin investigators (4), who reported that those with type 1 diabetes by 55 years of age experienced a sixfold greater cumulative CHD mortality compared with the rate expected using Framingham Study data. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) also reported a standardized mortality ratio (SMR) from ischemic heart disease of 9.1 (for men) and 13.5 (for women) for those with a diabetes diagnosis before 30 years of age (5). Two recent prospective epidemiologic studies, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (6) and Eurodiab (7), a multicenter, clinic-based study in Europe, confirmed these earlier reports and reported an incidence of total coronary events (including electrocardiogram [ECG] changes) …

Temporal patterns in overweight and obesity in Type 1 diabetes.

Diabet. Med. 27, 398–404 (2010)

The Prediction of Major Outcomes of Type 1 Diabetes: a 12-Year Prospective Evaluation of Three Separate Definitions of the Metabolic Syndrome and Their Components and Estimated Glucose Disposal Rate The Pittsburgh Epidemiology of Diabetes Complications Study experience

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 (≥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.

Tracing the Mediterranean diet through principal components and cluster analyses in the Greek population

Objective: To identify dietary patterns, and their socio-demographic and lifestyle correlates in a large sample of Greek adults, and assess their adherence to the traditional Mediterranean diet.Design: Principal component (PC) analysis was used to identify dietary patterns among 28 034 participants of the Greek branch of the European Prospective Investigation into Cancer and Nutrition. Dietary information was collected through a validated, semiquantitative, food-frequency questionnaire. The extracted PCs were subsequently regressed on sociodemographic and lifestyle variables. Analyses were also performed to classify individuals with similar dietary behavior into clusters.Results:Four PCs were identified: PC1 resembled the Mediterranean diet, PC2 approximated a vegetarian diet with emphasis on seed oils, PC3 reflected a preference for sweets, and PC4 reflected a Western diet. PC1 and PC2 were positively associated with age, education, physical activity, and nonsmoking status. Females, in comparison to males, scored higher on PC1 but lower on PC2. Males, younger, more educated individuals, nonsmokers and residents of Greater Athens (Attica) scored higher on PC3. PC4 was associated with younger age, less education, and current smoking. In cluster analyses, cluster A contrasted clusters B and C in having much higher mean PC1- and PC2-scores and substantially lower PC3- and PC4-scores. PC1 and PC4 were, respectively, positively and inversely correlated with an a priori Mediterranean-diet score; PC2 and PC3 were unrelated to it.Conclusion: The Mediterranean-like PC1-score as well as the vegetarian-like PC2 were higher among older, more educated people, and were associated with a healthier lifestyle than PC4, which reflected a Western-type diet. PC1 was strongly positively associated with an a priori Mediterranean-diet score.Sponsorship: The European Prospective Investigation into Cancer and Nutrition (EPIC) is coordinated by the International Agency for Research on Cancer and supported by the Europe Against Cancer Programme of the European Commission. The Greek segment of the EPIC study is also supported by the Greek Ministry of Health and the Greek Ministry of Education.

Haptoglobin Genotype : A Determinant of Cardiovascular Complication Risk in Type 1 Diabetes

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.

Disparities in food habits across Europe.

Socially-and culturally-patterned differences in food habits exist both between and within European populations. Daily individual food availability data, collected through the national household budget surveys (HBS) and harmonized in the context of the Data Food Networking (DAFNE) project, were used to assess disparities in food habits of seven European populations and to evaluate dietary changes within a 10-year interval. The availability of selected food items was further estimated according to the educational level of the household head and, based only on the Greek HBS data, according to quintiles of the households food purchasing capacity. Results for overall food availability support the north-south differentiation in food habits. Generally, the availability of most food items, including foods such as vegetable fats, animal lipids and sugar products, has decreased over the 10 years. Households in which the head was in the higher education categories reported lower availability for most food items, with the exception of low-fat milk, fresh fruit, animal lipids and soft drinks; the latter showing a sharp increase even within southern European households. The households food purchasing capacity can be used as an indicator of socio-economic status, with higher values being associated with lower status. Greek households of lower social class follow a healthier diet in terms of greater availability of vegetable oils, fresh vegetables, legumes, fish and seafood. Data from the DAFNE databank may serve as a tool for identifying and quantifying variation in food habits in Europe, as well as for providing information on the socio-economic determinants of food preferences.

Adiposity and mortality in type 1 diabetes.

Background:In the general population, adiposity exhibits a J- or U-shaped relationship with mortality; however, in catabolic states this relationship is often inversely linear. We have recently documented an age-independent increase in overweight/obesity in the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) of type 1 diabetes (T1D). As intensified insulin therapy (IIT) may promote weight gain, the impact of weight gain in T1D is of importance. We therefore assessed the association of adiposity with mortality in 655 EDC participants during 20 years of follow-up.Methods:Individuals were categorized as underweight (body mass index (BMI)<20), normal (20⩽ BMI <25), overweight (25⩽ BMI <30), or obese (BMI ⩾30). Cox models were constructed using BMI and covariates at baseline, updated means during follow-up, time variation (reflecting most recent status), and change during adulthood as predictors of mortality.Results:The prevalence of IIT (3+ insulin shots daily and/or pump) increased from 7 to 82%. Overweight increased by 47% and obesity increased sevenfold. There were 146 deaths. In unadjusted models, BMI (modeled continuously) showed a quadratic relationship with mortality (P=0.002, <0.0001 <0.0001 for baseline, updated mean and time-varying models, respectively). However, only in the time-varying model were the obese significantly different from the normal weight, whereas the baseline model showed no differences by BMI category. In both the updated mean and time-varying models, the underweight were at greater risk than were the normal weight (P<0.0001 both models). The nonlinear relationship of adiposity with mortality remained after adjustment for diabetes complications and for biological or socioeconomic/lifestyle risk factors, with the exception of baseline socioeconomic/lifestyle risk factors, in which a linear association emerged. Adjustment for waist circumference eliminated risk in the obese. Finally, weight gain during follow-up was protective.Conclusion:The relationship of adiposity with mortality in T1D now seems to resemble that of the general population, albeit with a marked increased risk in those who are underweight.

Clinically Relevant Cognitive Impairment in Middle-Aged Adults With Childhood-Onset Type 1 Diabetes

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.

Haptoglobin Genotype and Renal Function Decline in Type 1 Diabetes

OBJECTIVE Haptoglobin (Hp) binds free Hb, inhibiting Hb-induced oxidative damage. As oxidative stress has been associated with microvascular complications, we evaluated the relationship between Hp genotype and microalbuminuria, macroalbuminuria, end-stage renal disease (ESRD), and early renal function decline in type 1 diabetes. RESEARCH DESIGN AND METHODS Participants from the Epidemiology of Diabetes Complications Study with DNA available were studied for the incidence of microalbuminuria (albumin excretion rate [AER] 20–200 μg/min), macroalbuminuria (AER >200 μg/min), ESRD (renal dialysis or transplantation), and renal function decline (a decline ≥30 ml/min per 1.73 m2 from baseline estimated [by the Cockcroft-Gault equation] glomerular filtration rate [eGFR] in those with baseline eGFR >60 ml/min per 1.73 m2). RESULTS The proportions with the Hp 2/2, 2/1, and 1/1 genotype were 43.4, 44.4, and 12.1%, respectively. During 18 years of follow-up, the incidence of eGFR decline, microalbuminuria, macroalbuminuria, and ESRD was 42.0, 40.5, 16.7, and 12.2%, respectively. No significant univariate differences were observed by Hp genotype. However, in multivariable Cox models, an ∼twofold increased risk was observed for the Hp 2/2 compared with the Hp 1/1 genotype for eGFR decline (hazard ratio 1.79 [95% CI 1.06–3.00]) and ESRD (2.74 [1.17–6.45]); no significant associations were observed for microalbuminuria or macroalbuminuria. CONCLUSIONS These data suggest that although Hp genotype is not associated with albuminuria per se, it may be an independent determinant of early renal function decline and progression to ESRD. Understanding these apparent contradictory findings may provide further insight into the pathogenesis of renal disease in type 1 diabetes.