Perfluoroalkyl substances and likelihood of stroke in persons with and without diabetes.

OBJECTIVE: The main objective of this study is to evaluate the relationship of perfluoroalkyl substances with stroke and any modifying influence of diabetes. METHODS: Data on 3921 adults aged ⩾20 years with and 44,285 without diabetes were drawn from the C8 Health Project. Four perfluoroalkyl substances were investigated: perfluorohexane sulphate, C8 - perfluorooctanoic acid, perfluoroctane sulfonate and perfluorononaoic acid. RESULTS: There were 238 cases of stroke among those with and 643 among those without diabetes. In analyses controlled for age, sex, race, diabetes duration, body mass index, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein, kidney function and a history of smoking, a history of stroke was significantly inversely associated with serum perfluorohexane sulphate (odds ratio = 0.75, 0.64-0.88) and perfluoroctane sulfonate (odds ratio = 0.81, 0.70-0.90), but not perfluorooctanoic acid (odds ratio = 1.04, 0.94-1.15) or perfluorononaoic acid (odds ratio = 0.89, 0.70-1.14) among those with diabetes. Perfluoroalkyl substances demonstrated no association with stroke among those without diabetes (p interaction = 0.006 and 0.01 for perfluorohexane sulphate and perfluorooctanoic acid, respectively). CONCLUSION: In this large cross-sectional study, serum levels of perfluorohexane sulphate and perfluoroctane sulfonate were inversely associated with stroke among those with diabetes. Although mechanisms and implications for this diabetes-specific inverse relationship need to be further explored, our data suggest that perfluoroalkyl substances do not increase risk of stroke among persons with or without diabetes.

Perfluoroalkyl substances are inversely associated with coronary heart disease in adults with diabetes.

AIMS: Perfluoroalkyl substances (PFAS) are environmentally and biologically persistent synthetic environmental contaminants linked to adverse health outcomes. Though null to modest inverse relationships between PFAS and coronary heart disease (CHD) have been reported, studies regarding relationships in high risk populations such as those with diabetes are sparse. We investigated the relationship of PFAS with CHD in persons with diabetes. METHODS: Data on 5270 adults, aged ≥20 years, with diabetes were obtained from the C8 Health Project. Four PFAS were investigated separately: perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA). RESULTS: In logistic regression analyses adjusting for age, sex, diabetes duration, BMI, smoking, lipids, WBC, CRP, eGFR, uric acid, hemoglobin and iron, all PFAS were inversely associated with CHD, ORs (95% CIs): PFHxS; 0.72 (0.65-0.79), PFOA; 0.90 (0.81-0.96), PFOS; 0.90 (0.81-0.99), PFNA; 0.88 (0.76-1.02). Stratification by chronic kidney disease status revealed similar inverse relationships for those with and without chronic kidney disease. CONCLUSIONS: In this cross-sectional study of over 5000 adults with diabetes, PFAS showed inverse associations with CHD. These findings may, if confirmed in future studies, provide new physiologic understanding of CHD prevention strategies.

Increased risk of respiratory diseases in adults with Type 1 and Type 2 diabetes.

AIMS: Diabetes is linked with decreases in lung elasticity and in capacity to transfer carbon monoxide. Systemic inflammation, a common concern with diabetes, may contribute to airflow obstruction. We examined the association of self-reported diabetes with self-reported respiratory diseases (RDs) among 53,146 adults from the C8 Health Project. METHODS: Participants were categorized into three groups: Type 1 (T1D, n = 781), Type 2 (T2D, n = 4277), or no diabetes (n = 48,088). ORs (95% CIs) for the association of diabetes with four RDs were computed: emphysema, chronic obstructive pulmonary disease (COPD), chronic bronchitis (CB), and asthma. Covariates controlled for were age, sex, estimated glomerular filtration rate, C-reactive protein, smoking history, BMI, and perfluorooctonaoic acid (C8). RESULTS: RDs were present in 26%, 21% and 13% of persons with T1D, T2D, and no diabetes, respectively. In multivariable analyses, persons with T1D were 62% more likely to have any RD (OR: 1.62, CI: (1.36-1.93)), while those with T2D were 1.3 times as likely (OR: 1.26, CI: 1.15-1.37)). Compared to those without diabetes, in those with T1D and T2D diabetes respectively, ORs (CIs) for COPD were 1.89 (1.38-2.57), 1.45 (1.23-1.71), asthma: 1.51 (1.21-1.87), 1.38 (1.24-1.53), CB: 1.96 (1.57-2.45), 1.35 (1.20-1.52) and emphysema: 1.25 (0.85-1.82), 1.31 (1.10-1.56). Population attributable risks for any RDs associated with a history of smoking were 19%, 30%, and 26% for those with Type 1, Type 2, and no diabetes respectively. CONCLUSIONS: Diabetes, more so in T1D, appears to increase RD risk. Smoking is an important risk factor, but not as informative in Type 1 diabetes.

The obesity epidemic and rising diabetes incidence in a low-income racially diverse southern US cohort.

BACKGROUND: Obesity is known to be a major risk factor for diabetes, but the magnitude of risk and variation between blacks and whites are less well documented in populations heavily affected by obesity. Herein we assess rates and risks of incident diabetes in a diverse southern population where obesity is common. METHODS: A total of 24,000 black and 14,064 white adults aged 40-79 in the Southern Community Cohort Study with no self-reported diabetes at study enrollment during 2002-2009 was followed for up to 10 (median 4.5) years. Incidence rates, odds ratios (OR) and accompanying 95% confidence intervals (CI) for medication-treated incident diabetes were determined according to body mass index (BMI) and other characteristics, including tobacco and alcohol consumption, healthy eating and physical activity indices, and socioeconomic status (SES). RESULTS: Risk of incident diabetes rose monotonically with increasing BMI, but the trends differed between blacks and whites (pinteraction < .0001). Adjusted ORs (CIs) for diabetes among those with BMI≥40 vs 20-25 kg/m2 were 11.9 (8.4-16.8) for whites and 4.0 (3.3-4.8) for blacks. Diabetes incidence was more than twice as high among blacks than whites of normal BMI, but the racial difference became attenuated as BMI rose, with estimated 5-year probabilities of developing diabetes approaching 20% for both blacks and whites with BMI≥40 kg/m2. Diabetes risk was also associated with low SES, significantly (pinteraction≤.02) more so for whites, current cigarette smoking, and lower healthy eating and physical activity indices, although high BMI remained the predominant risk factor among both blacks and whites. From baseline prevalence and 20-year projections of the incidence trends, we estimate that the large majority of surviving cohort participants with BMI≥40 kg/m2 will be diagnosed with diabetes. CONCLUSIONS: Even using conservative criteria to ascertain diabetes incidence (i.e., requiring diabetes medication use and ignoring undiagnosed cases), rates of obesity-associated diabetes were exceptionally high in this low-income adult population. The findings indicate that effective strategies to halt the rising prevalence of obesity are needed to avoid substantial increases in diabetes in coming years.

Effect of high density lipoprotein cholesterol on the relationship of serum iron and hemoglobin with kidney function in diabetes.

Findings of increased hemoglobin inside the HDL proteome among persons with diabetes who have haptoglobin 2-2 genotype suggest that iron-induced lipid peroxidation may be involved in diabetic kidney disease. We investigated the relationships of serum hemoglobin and iron with kidney function, and whether this varied by level of HDLc, in 5296 adults with and 49,161 without diabetes. Estimated eGFR was our marker of kidney function. Hemoglobin was positively associated with eGFR among those with diabetes and inversely among those without diabetes (interaction p-value <0.0001). Iron was inversely associated with eGFR regardless of diabetes status. When stratified by median HDLc and median hemoglobin, among persons with diabetes mean eGFR was highest in those with high hemoglobin and low HDLc and lowest in those with both low hemoglobin and low HDLc. This divergent relationship was not observed in the non-diabetic population. In contrast to hemoglobin, high iron and low HDLc were associated with a lower mean eGFR regardless of diabetes status. Our data suggest that among persons with diabetes, both hemoglobin and iron are harmful to kidney function at high levels. Our data also suggest that HDLc may play a role in the relationship of high hemoglobin in kidney function in diabetes.

Polycyclic aromatic hydrocarbon biomarkers and serum markers of inflammation. A positive association that is more evident in men.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are potent atmospheric pollutants, occurring from anthropogenic and natural sources. Several animal studies have reported a positive association of PAHs with inflammation. However, it is not clear if lower background exposure to PAHs is associated with inflammation in humans, independent of smoking, a major source of PAHs. METHODS: We examined participants from the National Health and Nutrition Examination Survey 2001-2002, 2003-2004, and 2005-2006. Our exposures of interest were eight urinary monohydroxy polycyclic aromatic hydrocarbon biomarkers. Our outcomes were serum markers of inflammation; C-reactive protein (CRP) (≤10 mg/L) and total white blood cell (WBC) count (4000-12,000 cells/µL). RESULTS: Compared to participants with summed biomarkers of low-molecular weight (LMW) PAHs in the lowest quartile, the multivariable odds ratios (95% confidence interval) of high serum CRP (≥3 mg/L) and high total WBC count (defined as at or above the 95 percentile of total WBC distribution) among participants in the highest exposure quartile were 1.77 (1.13, 2.76) and 1.34 (1.12, 1.60) respectively. Urinary 1-hydroxypyrene, the biomarker of the higher molecular weight pyrene, was positively associated with total WBC count, and to lesser extent with serum CRP. In subsequent analyses, the positive association between LMW PAHs and serum CRP and total WBC count was found to be present within the stratified subgroups, independent of smoking and other potential confounders. The positive association was more evident among adult males when compared to females. CONCLUSIONS: Urinary PAH biomarkers were found to be positively associated with serum CRP and total WBC count independent of smoking and other potential confounders. The association was more evident in men.

Cross-sectional evaluation of noninvasively detected skin intrinsic fluorescence and mean hemoglobin a1c in type 1 diabetes.

BACKGROUND: This study evaluated the relationship between skin intrinsic fluorescence (SIF) and long-term mean hemoglobin A1c (HbA1c) in individuals with type 1 diabetes. SUBJECTS AND METHODS: We undertook a cross-sectional analysis of 172 individuals with type 1 diabetes followed longitudinally with HbA1c data available over an average of 16.6 years. SIF was evaluated cross-sectionally using the SCOUT DS device (VeraLight Inc., Albuquerque, NM) and correlated with most recent HbA1c and long-term mean HbA1c. Potential determinants of this relationship, including age, gender, smoking status, duration of diabetes, and renal function, were also evaluated. RESULTS: Age-adjusted skin intrinsic fluorescence significantly correlated with long-term mean HbA1c (R=0.44, P<0.0001). In contrast, there was no significant relationship between SIF and most recent HbA1c (R=0.14, P=0.075). The best-fit model describing the relationship between SIF and mean HbA1c controlled for factors of age, duration of disease, renal function, and site of study conduct. Controlling for these factors was also important in understanding the relationship between most recent HbA1c and SIF. Evaluating longer-term HbA1c data also strengthened the relationship between SIF and mean HbA1c. In the presence of renal dysfunction or damage, as indicated by an estimated glomerular filtration rate of <60 mL/min/1.73 m2 or presence of gross proteinuria, there was no significant correlation between SIF and mean HbA1c. CONCLUSIONS: Noninvasive detection of SIF significantly correlates with long-term mean HbA1c, providing insight into long-term glycemic exposure. Age, duration of diabetes, and renal function are potential contributors to this relationship.

Skin fluorescence correlates strongly with coronary artery calcification severity in type 1 diabetes.

BACKGROUND: Coronary artery calcification (CAC) is more severe and occurs at an earlier age in type 1 diabetes. Risk factors for this subclinical marker of atherosclerotic burden, like coronary artery disease (CAD) itself, are not fully identified. One postulated mechanism for the increased CAC observed in type 1 diabetes is the accumulation of advanced glycation end products (AGEs). As certain collagen AGEs fluoresce, skin intrinsic fluorescence (SIF) can act as a novel marker of levels of collagen AGEs. We thus sought to determine the relationship between skin intrinsic fluorescence and CAC in type 1 diabetes. METHODS: One hundred five participants in the Pittsburgh Epidemiology of Diabetes Complications study of childhood-onset (age <17 years) type 1 diabetes who had previously undergone electron beam tomography scanning for CAC (80 of whom had follow-up data) had SIF measurements taken using the SCOUT DM (VeraLight, Inc., Albuquerque, NM). Mean age and diabetes' duration were 49 and 40 years, respectively, at the time of SIF measurement. RESULTS: Seventy-one percent of the study participants had some measurable CAC that was univariately (but not after age adjustment) cross-sectionally associated with SIF (odds ratio = 2.51, 1.37-4.59). However, for CAC severity using natural logarithmically transformed scores, SIF was both univariately (P < 0.0001) and multivariably (P = 0.03) associated with CAC. This relationship was independent of age, a history of CAD, renal function, or renal damage. Receiver operator characteristic analyses revealed that the discriminative ability of SIF to detect CAC went from an area under the curve of 71% for the presence of any CAC to 85% for those with a CAC score >400. CONCLUSIONS: The relationship between SIF and CAC appears stronger with more severe calcification. Given the strong relationship of CAC with CAD this finding has important implications and suggests that SIF maybe a useful marker of CAC/CAD risk and potentially a therapeutic target.

Double-edged relationship between adiposity and coronary artery calcification in type 1 diabetes.

Coronary artery disease (CAD), a leading cause of death in type 1 diabetes (T1D), often occurs two or more decades earlier in this population compared to the population without diabetes. Although CAD generally increases with adiposity, this association is unclear in T1D. In this study, we examined associations of adiposity with coronary artery calcium (CAC) in 315 individuals with T1D. Mean age and diabetes duration were 42 and 34 years, respectively, at study entry. CAC, visceral adiposity (VAT) and subcutaneous adiposity (SAT) were determined by electron beam tomography; and BMI and waist circumference (WC) were determined. The presence of CAC was positively associated with VAT, SAT and BMI in men (p<0.05) and with all four adiposity measures in women (p<0.05) after adjustment for age and other traditional cardiovascular risk factors. However, after adjustment, the degree of CAC was not associated with any of the four adiposity measures, with the exception of SAT in women. Women in the lowest tertile of SAT had more CAC than those in the second tertile (p<0.016). Adiposity was positively associated with the presence of CAC, but the relationship with its severity was either inverse or non-existent. This double-edged association emphasises the complex relationship between adiposity and cardiovascular risk in diabetes.

Progression of coronary artery calcium in type 1 diabetes mellitus.

Coronary artery calcium (CAC) has been previously associated with atherosclerotic plaque disease and coronary events. Thus, identifying predictors of CAC progression may provide new insights for early risk-factor intervention and subsequent reduction of the rates of more severe atherosclerotic disease. The aim of this study was to identify risk factors for CAC progression and evaluate whether risk-factor change was related to CAC progression in a cohort of patients with type 1 diabetes mellitus (DM). Participants in the Pittsburgh EDC Study, a prospective investigation of childhood-onset type 1 DM, who underwent 2 electron beam tomographic screenings 4 years apart were selected for study (n = 222). CAC was calculated using the Agatston method of scoring, and progression was defined as an increase >2.5 in the square root-transformed CAC score. Adjusting for DM duration and initial CAC score, body mass index (BMI; odds ratio [OR] 1.13, 95% confidence interval [CI] 1.01 to 1.26), non-high-density lipoprotein cholesterol (OR 1.01, 95% CI 1.003 to 1.03), and albumin excretion rate (OR 1.30, 95% CI 1.03 to 1.63) were associated with CAC progression. When considering change in risk factors, an increase in BMI (OR 1.38, 95% CI 1.10 to 1.72) was also associated with CAC progression after adjustment. In conclusion, in this cohort with type 1 DM, in addition to baseline BMI, non-high-density lipoprotein cholesterol, albumin excretion rate, and all known coronary artery disease risk factors, weight gain further added to the prediction of CAC progression. Thus, weight control, in addition to lipid and renal management, may help retard atherosclerosis progression in persons with type 1 DM.