High plasma concentrations of acyl-coenzyme A binding protein (ACBP) predispose to cardiovascular disease: Evidence for a phylogenetically conserved proaging function of ACBP.

Autophagy defects accelerate aging, while stimulation of autophagy decelerates aging. Acyl-coenzyme A binding protein (ACBP), which is encoded by a diazepam-binding inhibitor (DBI), acts as an extracellular feedback regulator of autophagy. As shown here, knockout of the gene coding for the yeast orthologue of ACBP/DBI (ACB1) improves chronological aging, and this effect is reversed by knockout of essential autophagy genes (ATG5, ATG7) but less so by knockout of an essential mitophagy gene (ATG32). In humans, ACBP/DBI levels independently correlate with body mass index (BMI) as well as with chronological age. In still-healthy individuals, we find that high ACBP/DBI levels correlate with future cardiovascular events (such as heart surgery, myocardial infarction, and stroke), an association that is independent of BMI and chronological age, suggesting that ACBP/DBI is indeed a biomarker of "biological" aging. Concurringly, ACBP/DBI plasma concentrations correlate with established cardiovascular risk factors (fasting glucose levels, systolic blood pressure, total free cholesterol, triglycerides), but are inversely correlated with atheroprotective high-density lipoprotein (HDL). In mice, neutralization of ACBP/DBI through a monoclonal antibody attenuates anthracycline-induced cardiotoxicity, which is a model of accelerated heart aging. In conclusion, plasma elevation of ACBP/DBI constitutes a novel biomarker of chronological aging and facets of biological aging with a prognostic value in cardiovascular disease.

Effects of acyl-coenzyme A binding protein (ACBP)/diazepam-binding inhibitor (DBI) on body mass index.

In mice, the plasma concentrations of the appetite-stimulatory and autophagy-inhibitory factor acyl-coenzyme A binding protein (ACBP, also called diazepam-binding inhibitor, DBI) acutely increase in response to starvation, but also do so upon chronic overnutrition leading to obesity. Here, we show that knockout of Acbp/Dbi in adipose tissue is sufficient to prevent high-fat diet-induced weight gain in mice. We investigated ACBP/DBI plasma concentrations in several patient cohorts to discover a similar dual pattern of regulation. In relatively healthy subjects, ACBP/DBI concentrations independently correlated with body mass index (BMI) and age. The association between ACBP/DBI and BMI was lost in subjects that underwent major weight gain in the subsequent 3-9 years, as well as in advanced cancer patients. Voluntary fasting, undernutrition in the context of advanced cancer, as well as chemotherapy were associated with an increase in circulating ACBP/DBI levels. Altogether, these results support the conclusion that ACBP/DBI may play an important role in body mass homeostasis as well as in its failure.

Plasma copeptin, kidney disease, and risk for cardiovascular morbidity and mortality in two cohorts of type 2 diabetes.

BACKGROUND: Cardiovascular disease and kidney damage are tightly associated in people with type 2 diabetes. Experimental evidence supports a causal role for vasopressin (or antidiuretic hormone) in the development of diabetic kidney disease (DKD). Plasma copeptin, the COOH-terminal portion of pre-provasopressin and a surrogate marker of vasopressin, was shown to be positively associated with the development and progression of DKD. Here we assessed the association of plasma copeptin with the risk of cardiovascular events during follow-up in two prospective cohorts of type 2 diabetic patients, and we examined if this association could be mediated by deleterious effects of vasopressin on the kidney. METHODS: We studied 3098 and 1407 type 2 diabetic patients from the French cohorts DIABHYCAR and SURDIAGENE, respectively. We considered the incidence during follow-up (median: 5 years) of a combined end point composed of myocardial infarction, coronary revascularization, hospitalization for congestive heart failure, or cardiovascular death. Copeptin concentration was measured in baseline plasma samples by an immunoluminometric assay. RESULTS: The cumulative incidence of cardiovascular events during follow-up by sex-specific tertiles of baseline plasma copeptin was 15.6% (T1), 18.7% (T2) and 21.7% (T3) in DIABHYCAR (p = 0.002), and 27.7% (T1), 34.1% (T2) and 47.6% (T3) in SURDIAGENE (p < 0.0001). Cox proportional hazards survival regression analyses confirmed the association of copeptin with cardiovascular events in both cohorts: hazard ratio with 95% confidence interval for T3 vs. T1 was 1.29 (1.04-1.59), p = 0.02 (DIABHYCAR), and 1.58 (1.23-2.04), p = 0.0004 (SURDIAGENE), adjusted for sex, age, BMI, duration of diabetes, systolic blood pressure, arterial hypertension, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, estimated glomerular filtration rate (eGFR), urinary albumin concentration (UAC), active tobacco smoking, and previous history of myocardial infarction at baseline. No interaction was observed between plasma copeptin and eGFR (p = 0.40) or UAC (p = 0.61) categories on the risk of cardiovascular events in analyses of pooled cohorts. CONCLUSIONS: Plasma copeptin was positively associated with major cardiovascular events in people with type 2 diabetes. This association cannot be solely accounted for by the association of copeptin with kidney-related traits.

Dairy products and the metabolic syndrome in a prospective study, DESIR.

OBJECTIVE: In previous cross-sectional analyses of the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, we have found inverse associations between dairy product consumption and metabolic syndrome (MetS) traits. We have now analyzed in a prospective way the influence of dairy product and calcium consumption at inclusion on the 9-year cumulative incidence of the MetS and associated traits in the French prospective study with a 9-year follow-up, DESIR. METHODS: After exclusion of diabetic subjects and those being on a diet at inclusion, 3417 men and women who completed a food frequency at baseline could be studied. Logistic regression models were used to study associations between dairy products and dietary calcium density at baseline and incident MetS and impaired fasting glycemia/type 2 diabetes (IFG/T2D) after adjusting for gender, age, and lifestyle parameters (alcohol, smoking, physical activity, fat intake). An additional model adjusting for the same covariates and for body mass index (BMI) was also used. Associations between dairy products and continuous variables were studied by repeated measures analysis of covariance, using the same covariates. RESULTS: Total dairy product consumption, dairy (except cheese) consumption, and dietary calcium density were inversely associated with incident MetS and IFG/T2D. Cheese consumption was negatively associated with incident MetS but not with glycemic disorders. All parameters were associated with lower diastolic blood pressure and triglycerides (average over the 9-year period) and with a lower BMI gain in the same period. Higher total dairy and cheese intake and calcium density were associated with a lower increase in waist circumference and triglycerides during the 9-year follow-up. CONCLUSION: In the French general population, these results show beneficial effects of dairy product consumption on the metabolic syndrome and glycemic disorders. Therefore, dairy product consumption could be protective against cardiovascular risk.

Dairy consumption and the incidence of hyperglycemia and the metabolic syndrome: results from a french prospective study, Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR).

OBJECTIVE: In the French Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, cross-sectional analyses have shown that a higher consumption of dairy products and calcium are associated with a lower prevalence of the metabolic syndrome (MetS). We assess the influence of dairy products on 9-year incident MetS and on impaired fasting glycemia and/or type 2 diabetes (IFG/T2D). RESEARCH DESIGN AND METHODS: Men and women who completed a food frequency questionnaire at baseline and after 3 years were studied (n = 3,435). Logistic regression models were used to study associations between the average year 0 and year 3 consumption of milk and dairy products, cheese, dietary calcium density, and incident MetS and IFG/T2D after adjusting for 1) sex, age, alcohol, smoking, physical activity, fat intake and 2) additionally for BMI. Associations between dairy products and continuous variables were studied by repeated-measures ANCOVA, using the same covariates. RESULTS: Dairy products other than cheese, and dietary calcium density, were inversely associated with incident MetS and IFG/T2D; cheese was negatively associated with incident MetS. All three parameters were associated with lower diastolic blood pressure, and with a lower BMI gain. Higher cheese intake and calcium density were associated with a lower increase in waist circumference and lower triglyceride levels. Calcium density was also associated with a lower systolic blood pressure and a lower 9-year increase in plasma triglyceride levels. CONCLUSIONS: A higher consumption of dairy products and calcium was associated with a lower 9-year incidence of MetS and IFG/T2D in a large cohort drawn from the general population.

Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study.

BACKGROUND: Fatty liver is known to be linked with insulin resistance, alcohol intake, diabetes and obesity. Biopsy and even scan-assessed fatty liver are not always feasible in clinical practice. This report evaluates the predictive ability of two recently published markers of fatty liver: the Fatty Liver Index (FLI) and the NAFLD fatty liver score (NAFLD-FLS), for 9-year incident diabetes, in the French general-population cohort: Data from an Epidemiological Study on the Insulin Resistance syndrome (D.E.S.I.R). METHODS: At baseline, there were 1861 men and 1950 women, non-diabetic, aged 30 to 65 years. Over the follow-up, 203 incident diabetes cases (140 men, 63 women) were identified by diabetes-treatment or fasting plasma glucose > or = 7.0 mmol/l. The FLI includes: BMI, waist circumference, triglycerides and gamma glutamyl transferase, and the NAFLD-FLS: the metabolic syndrome, diabetes, insulin, alanine aminotransferase, and asparate aminotransferase. Logistic regression was used to determine the odds ratios for incident diabetes associated with categories of the fatty liver indices. RESULTS: In comparison to those with a FLI < 20, the age-adjusted odds ratio (95% confidence interval) for diabetes for a FLI > or = 70 was 9.33 (5.05-17.25) for men and 36.72 (17.12-78.76) for women; these were attenuated to 3.43 (1.61-7.28) and 11.05 (4.09 29.81), after adjusting on baseline glucose, insulin, hypertension, alcohol intake, physical activity, smoking and family antecedents of diabetes; odds ratios increased to 4.71 (1.68-13.16) and 22.77 (6.78-76.44) in those without an excessive alcohol intake. The NAFLD-FLS also predicted incident diabetes, but with odds ratios much lower in women, similar in men. CONCLUSIONS: These fatty liver indexes are simple clinical tools for evaluating the extent of liver fat and they are predictive of incident diabetes. Physicians should screen for diabetes in patients with fatty liver.

Sex-dependent associations of leptin with metabolic syndrome-related variables: the Stanislas study.

Serum leptin has been reported to be associated in a sex-dependent manner with C-reactive protein (CRP), independently of adiposity. We tested the hypothesis that leptin is associated, independently of anthropometry indexes and in a sex-dependent way, with other inflammatory markers and variables related to metabolic syndrome (MS). In 384 healthy middle-aged adults (192 men and 192 women) total fat mass (FM), waist circumference (WC), serum leptin and 15 MS-related parameters (systolic and diastolic blood pressure, triglycerides, cholesterol, high density lipoprotein (HDL)-cholesterol, apo AI and B, fasting glucose, uric acid, CRP, orosomucoid and haptoglobin levels and aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities) were measured. After adjustment for age, alcohol and cigarette consumption, WC, and total FM, leptin concentration was significantly associated with serum triglycerides, total cholesterol, apo B, uric acid and haptoglobin concentrations and liver enzyme activity only in men, and with apo AI, HDL-cholesterol (only borderline) and CRP only in women. Sex interaction terms were significant for total cholesterol, apo B, HDL cholesterol, uric acid, ALAT and GGT, and borderline significant for triglycerides, apo AI and ASAT. In this healthy population, leptin is significantly associated with various MS factors, independently of WC and total FM, depending on gender. Our study provides further evidence of sex-related differences mediated by leptin in inflammatory mechanisms and other MS-related metabolic pathways.

Relationships between common polymorphisms of adenosine triphosphate-binding cassette transporter A1 and high-density lipoprotein cholesterol and coronary heart disease in a population with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (T2D) have a high coronary risk partly because of low levels of high-density lipoprotein-cholesterol (HDL-C). The adenosine triphosphate-binding cassette transporter A1 (ABCA1) plays a key role in HDL metabolism. We studied the association of common single nucleotide polymorphisms (SNPs) in the ABCA1 gene with HDL-C levels and coronary risk in a cohort of subjects with T2D. We studied 5 SNPs: +69C>T, +378G>C, R219K, I883M, and R1587K. The C allele of +378G>C was significantly associated with lower HDL-C concentrations (P = .04); and the M allele of I883M, with higher HDL-C concentrations (P = .03). No significant association was found between these SNPs and the incidence of new coronary events. Nevertheless, cross-sectional data on entry showed that the frequency of K219 was lower in patients with previous coronary heart disease (angina pectoris and/or myocardial infarction) (odds ratio, OR [95% confidence interval, CI] = 0.80 [0.65-0.98], P = .03, after adjustment for multiple risk factors other than HDL-C). The frequency of K1587 was higher in patients with angina pectoris (OR [95% CI] = 1.27 [1.01-1.58], P = .04, after multiple adjustment). The TT genotype of the C69T SNP was less frequent in subjects with prior myocardial infarction (OR [95% CI] = 0.28 [0.13-0.61], P = .001, after multiple adjustment). These associations persisted after further adjustment for HDL-C levels. In conclusion, common genetic variations of ABCA1 had a moderate influence on HDL-C levels and/or coronary heart disease in patients with T2D. These 2 effects were independent.

Predicting diabetes: clinical, biological, and genetic approaches: data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR).

OBJECTIVE: To provide a simple clinical diabetes risk score and to identify characteristics that predict later diabetes using variables available in the clinic setting as well as biological variables and polymorphisms. RESEARCH DESIGN AND METHODS: Incident diabetes was studied in 1,863 men and 1,954 women, 30-65 years of age at baseline, with diabetes defined by treatment or by fasting plasma glucose >or=7.0 mmol/l at 3-yearly examinations over 9 years. Sex-specific logistic regression equations were used to select variables for prediction. RESULTS: A total of 140 men and 63 women developed diabetes. The predictive clinical variables were waist circumference and hypertension in both sexes, smoking in men, and diabetes in the family in women. Discrimination, as measured by the area under the receiver operating curves (AROCs), were 0.713 for men and 0.827 for women, a little higher than for the Finish Diabetes Risk (FINDRISC) score, with fewer variables in the score. Combining clinical and biological variables, the predictive equation included fasting glucose, waist circumference, smoking, and gamma-glutamyltransferase for men and fasting glucose, BMI, triglycerides, and diabetes in family for women. The number of TCF7L2 and IL6 deleterious alleles was predictive in both sexes, but after including the above clinical and biological variables, this variable was only predictive in women (P < 0.03) and the AROC statistics increased only marginally. CONCLUSIONS: The best clinical predictor of diabetes is adiposity, and baseline glucose is the best biological predictor. Clinical and biological predictors differed marginally between men and women. The genetic polymorphisms added little to the prediction of diabetes.

Adiponectin gene and cardiovascular risk in type 2 diabetic patients: a review of evidences

Diabetic patients have a 3-fold higher risk of developing atherosclerosis and its clinical complications as compared to non-diabetic individuals. Part of the cardiovascular risk associated with diabetes is probably due to genetic determinants influencing both glucose homeostasis and the development of atherosclerosis. However, type 2 diabetes frequently coexists with other cardiovascular risk factors like arterial hypertension, central obesity and dyslipidemia. Genetic variability affecting many areas such as lipid and energy metabolisms, hypertension and haemodynamic mechanisms, blood clotting homeostasis, inflammation, and matrix turnover in the vascular wall will have an impact on the development of macrovascular complications in diabetic patients. Adiponectin is abundantly secreted by adipocytes. It plays important roles in lipid and glucose metabolisms and has direct anti-inflammatory and anti-atherogenic effects. In this review, we summarize recent data from the literature suggesting an implication of allelic variations of the adiponectin gene (ADIPOQ) in the genetic determinants of cardiovascular disease in diabetic subjects.

Os pacientes com diabetes apresentam risco três vezes maior de desenvolverem aterosclerose e suas complicações quando comparados a indivíduos sem hiperglicemia. Parte desse risco associado ao diabetes é provavelmente relacionado a determinantes genéticos que influenciam tanto a homeostase glicídica quanto o desenvolvimento da aterosclerose. Entretanto, o diabetes tipo 2 freqüentemente coexiste com outros fatores de risco cardiovascular, tais como hipertensão arterial, obesidade central e dislipidemia. A variabilidade genética interfere em várias áreas tais como o metabolismo lipídico, o metabolismo energético, hipertensão, mecanismos hemodinâmicos, mecanismos de coagulação, inflamação e na formação da matriz na parede vascular, que podem estar envolvidos nas complicações macrovasculares dos pacientes com diabetes. A adiponectina é secretada com abundância pelos adipócitos. Apresenta importante papel no metabolismo lipídico e glicídico, tendo ação direta tanto antiinflamatória quanto anti-aterogênica. Na atual revisão, nós resumimos os dados recentes da literatura que sugerem uma implicação de variantes alélicas do gene da adiponectina (ADIPOQ) que podem estar envolvidos na determinação genética da doença cardiovascular em indivíduos com diabetes.

ABCA1 single nucleotide polymorphisms on high-density lipoprotein-cholesterol and overweight: the D.E.S.I.R. study.

The adenosine triphosphate-binding cassette A1 (ABCA1) gene plays a key role in reverse cholesterol transport. Some ABCA1 gene polymorphisms have been associated with high-density lipoprotein-cholesterol (HDL-C) concentrations. The aim of this study was to assess the effect of three polymorphisms, C69T, G378C, and G1051A (R219K), on HDL-C levels and their interaction with BMI in more than 5000 French whites from the D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance syndrome) cohort study. The T allele of the C69T single nucleotide polymorphism (SNP) was associated with higher HDL-C levels in normal-weight men (BMI <25 kg/m(2)). The C allele of the G378C SNP was associated with lower HDL-C in overweight subjects (BMI > or =25 kg/m(2)). For the G1051A SNP, in the normal-weight group, the minor A allele was significantly associated with higher HDL-C levels. In contrast, in overweight people, the minor allele was associated with lower HDL-C levels. After accounting for multiple testing, empiric p values remained significant for the associations between G378C SNP and HDL-C in the overweight group and between G1051A SNP and HDL-C in the normal-weight group. This study suggests that ABCA1 gene polymorphisms modulate HDL-C concentrations, in interaction with BMI, and, thus, they might influence cardiovascular risk in the general population.

Association between endothelin receptor B nonsynonymous variants and melanoma risk.

The endothelin signaling pathway plays a crucial role in melanocyte differentiation and migration. In this study, we investigated whether germline mutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung disease (HSCR), could also predispose for malignant melanoma (MM). The coding region of EDNRB was sequenced in 137 MM patients and in 130 ethnically matched Caucasian control subjects. Six nonsynonymous EDNRB variants were found in 15 patients (11%), but only two were found in four control subjects (3%, odds ratio [OR] = 3.87, 95% confidence interval [CI] = 1.25 to 12; P = .012). Overall, 14 out of 15 MM patients carried EDNRB mutations reported in HSCR, some of which had previously been shown to lead to loss of function. In multivariable logistic regression analysis including skin type, eye and hair color, number of nevi, and dorsal lentigines (freckles), the association between EDNRB mutations and MM risk remained statistically significant (OR = 19.9, 95% CI = 1.34 to 296.2; P = .03). Our data strongly suggest that EDNRB is involved in predisposition for two different multigenic disorders, HSCR and melanoma.