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Accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) are implicated in the progression of pathologies associated with aging, chronic inflammation, diabetes, and cellular stress. RAGE activation is also implicated in cardiovascular complications of type 2 diabetes, such as nephropathy, retinopathy, accelerated vascular diseases, and cardiomyopathy. Studies investigating the effects of AGE/RAGE axis activation on skeletal muscle oxidative stress and metabolism are more limited. We tested whether a high-fat diet (HFD) would alter circulating AGE concentration, skeletal muscle AGE accumulation, and oxidative stress in wild-type and RAGE-deficient mice. The physiological significance of AGE/RAGE axis activation in HFD-fed mice was evaluated in terms of exercise tolerance and mitochondrial respiratory chain complex activity. HFD elicited adiposity, abnormal fat distribution, and oral glucose intolerance. HFD also induced accumulation of N ε -carboxymethyl-l-lysine, increased protein carbonyl levels, and impaired respiratory chain complex activity in soleus muscle. Ablation of RAGE had no effects on weight gain and oral glucose tolerance in HFD-fed mice. Peak aerobic capacity and mitochondrial cytochrome- c oxidase activity were restored in HFD-fed RAGE -/- mice. We concluded that RAGE signaling plays an important role in skeletal muscle homeostasis of mice under metabolic stress. Novelty HFD in mice induces accumulation of AGEs, oxidative stress, and mitochondrial dysfunction in the soleus muscle. RAGE, the multi-ligand receptor for AGEs, modulates oxidative stress and mitochondrial electron transport chain function in the soleus muscle of HFD-fed mice.

Background: Advanced glycation end-products play a role in diabetic vascular complications. Their optical properties allow to estimate their accumulation in tissues by measuring the skin autofluorescence (SAF). We searched for an association between SAF and major adverse cardiovascular events (MACE) incidence in subjects with Type 1 Diabetes (T1D) during a 7 year follow-up., Methods: During year 2009, 232 subjects with T1D were included. SAF measurement, clinical [age, sex, body mass index (BMI), comorbidities] and biological data (HbA1C, blood lipids, renal parameters) were recorded. MACE (myocardial infarction, stroke, lower extremity amputation or a revascularization procedure) were registered at visits in the center or by phone call to general practitioners until 2016., Results: The participants were mainly men (59.5%), 51.5 ± 16.7 years old, with BMI 25.0 ± 4.1 kg/m 2 , diabetes duration 21.5 ± 13.6 years, HbA1C 7.6 ± 1.1%. LDL cholesterol was 1.04 ± 0.29 g/L, estimated Glomerular Filtration Rates (CKD-EPI): 86.3 ± 26.6 ml/min/1.73 m 2 . Among these subjects, 25.1% were smokers, 45.3% had arterial hypertension, 15.9% had elevated AER (≥ 30 mg/24 h), and 9.9% subjects had a history of previous MACE. From 2009 to 2016, 22 patients had at least one new MACE: 6 myocardial infarctions, 1 lower limb amputation, 15 revascularization procedures. Their SAF was 2.63 ± 0.73 arbitrary units (AU) vs 2.08 ± 0.54 for other patients (p = 0.002). Using Cox-model, after adjustment for age (as the scale time), sex, diabetes duration, BMI, hypertension, smoking status, albumin excretion rates, statin treatment and a previous history of MACE, higher baseline levels of SAF were significantly associated with an increased risk of MACE during follow-up (HR = 4.13 [1.30-13.07]; p = 0.02 for 1 AU of SAF) and Kaplan-Meier curve follow-up showed significantly more frequent MACE in group with SAF upper the median (p = 0.001)., Conclusion: A high SAF predicts MACE in patients with T1D.

Aim: We aimed to study the relationships between circulating 25-hydroxyvitamin D [25(OH)D], insulin resistance and leptin-to-adiponectin (L/A) ratio in Guadeloupean children and adolescents and to analyse the changes in 25(OH)D levels after a 1-year lifestyle intervention program., Methods: 25(OH)D concentrations were measured via a chemiluminescence assay. Cardiometabolic risk factors, homoeostasis model assessment of insulin resistance (HOMA-IR), and adipokines were measured. The lifestyle intervention included dietary counselling, regular physical activity., Results: Among 117 girls and boys (11-15 years old, 31.6% obese), 40% had vitamin D deficiency (25(OH)D levels < 20 ng/mL). With linear regression models where 25(OH)D and HOMA-IR acted as independent variables and age, sex, BMI, L/A ratio as covariates, 25(OH)D was significantly associated with HOMA-IR alone (P = 0.036). HOMA-IR was also associated with BMI z-score ≥ 2, L/A ratio and an interaction term BMI z-score ≥ 2*L/A ratio (P < 0.001 for all). After one year, in 78 children/adolescent, mean serum 25(OH)D increased significantly from 21.4 ± 4.9 ng/mL at baseline to 23.2 ± 6.0 after 1 year; P = 0.003 whereas BMI z-score, HOMA-IR and L/A ratio decreased significantly (P = 0.003, P < 0.001 and P = 0.012; respectively)., Conclusion: The association between 25(OH)D and HOMA-IR, independently of obesity and the high prevalence of vitamin D deficiency should be considered in order to prevent the later incidence of T2DM. A healthy lifestyle including non-sedentary and outdoor activities could be a way for improving vitamin D status.

Background: Despite excessive rates of cardiovascular risk factors such as hypertension, diabetes, and obesity, Afro-Caribbeans have lower mortality rates from coronary heart disease (CHD) than do whites. This study evaluated the association of genetic risk markers previously identified in whites and CHD in Afro-Caribbeans., Methods: We studied 537 Afro-Caribbean individuals (178 CHD cases and 359 controls) who were genotyped for 19 CHD-related single-nucleotide polymorphisms (SNPs). A genetic risk score (GRS) incorporating the 19 SNPs was calculated. These participants were compared with 1360 white individuals from the Second Northwick Park Heart Study., Results: In Afro-Caribbeans, patients with CHD had higher rates of hypertension (78.7% vs 30.1%), hypercholesterolemia (52.8% vs 15.0%), and diabetes (53.9% vs 14.8%) and were more often men (64.0% vs 43.7%) and smokers (27.5% vs 13.4%) compared with non-CHD controls (all P < 0.001). The GRS was higher in Afro-Caribbeans with CHD than in those without CHD (13.90 vs 13.17; P < 0.001) and was significantly associated with CHD after adjustment for cardiovascular risk factors, with an odds ratio of 1.40 (95% confidence interval, 1.09-1.80) per standard deviation change. There were significant differences in allelic distributions between the 2 ethnic groups for 14 of the 19 SNPs. The GRS was substantially lower in Afro-Caribbean controls compared with white controls (13.17 vs 16.59; P < 0.001)., Conclusions: This study demonstrates that a multilocus GRS composed of 19 SNPs associated with CHD in whites is a strong predictor of the disease in Afro-Caribbeans. The differences in CHD occurrence between Afro-Caribbeans and whites might be a result of significant discrepancies in common gene variant distribution., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Bilateral adrenalectomy is the reference treatment for Cushing's syndrome (CS) related to primary bilateral macronodular adrenal hyperplasia (PBMAH). It is, however, responsible for definitive adrenal insufficiency., Objective: The objective of the study was to evaluate the clinical interest of unilateral adrenalectomy (UA) of the larger gland for the treatment of CS related to PBMAH., Design, Setting, Patients, and Intervention: This was a retrospective study in four tertiary French centers including all 15 patients with PBMAH and CS who underwent UA of the larger gland between 2001 and 2015., Main Outcome Measures: Urinary free cortisol, plasma cortisol, ACTH, body mass index, blood pressure, plasma glucose, and lipids were registered pre- and postoperatively and on follow-up. Median follow-up was 60 months (interquartile range 39-105), including 8 of 15 patients followed up for at least 5 years., Results: A normal or low urinary free cortisol was obtained in 15 of 15 patients (100%) postoperatively. Six patients (40%) became adrenal insufficient, of whom three of six recovered a quantitatively normal cortisol secretion on follow-up. Decrease of both body mass index and blood pressure were observed at 1 year, and decrease of blood pressure was persistent 5 years postoperatively. Diabetes was cured in four of six patients. Two patients experienced a recurrence of hypercortisolism, and one was treated with mitotane, whereas the other underwent a second adrenal surgery 9 years after initial UA., Conclusion: UA induced remission of hypercortisolism in all patients, with sustained significant clinical improvement. The rates of both definitive adrenal insufficiency and 5-year recurrence were low. UA appears an interesting alternative to bilateral adrenalectomy as a first-line treatment in PBMAH responsible for overt CS.

Background: We assessed the prognostic value of protein-energy wasting (PEW) on mortality in Afro-Caribbean MHD patients and analysed how diabetes, cardiovascular disease (CVD) and inflammation modified the predictive power of a severe wasting state., Method: A 3-year prospective study was conducted in 216 patients from December 2011. We used four criteria from the nomenclature for PEW proposed by the International Society of Renal Nutrition and Metabolism in 2008: serum albumin 38 g/L, body mass index (BMI) ≤23 kg/m(2), serum creatinine ≤818 µmol/L and protein intake assessed by nPCR ≤0.8 g/kg/day. PEW status was categorized according the number of criteria. Cox regression analyses were used., Results: Forty deaths (18.5 %) occurred, 97.5 % with a CV cause. Deaths were distributed as follows: 7.4 % in normal nutritional status, 13.2 % in slight wasting (1 PEW criterion), 28 % in moderate wasting (2 criteria) and 50 % in severe wasting (3-4 criteria). Among the PEW markers, low serum albumin (HR 3.18; P = 0.001) and low BMI (HR 1.97; P = 0.034) were the most significant predictors of death. Among the PEW status categories, moderate wasting (HR 3.43; P = 0.021) and severe wasting (HR 6.59; P = 0.001) were significant predictors of death. Diabetes, CVD, and inflammation were all additives in predicting death in association with severe wasting with a strongest HR (7.76; P < 0.001) for diabetic patients., Conclusions: The nomenclature for PEW predicts mortality in our Afro-Caribbean MHD patients and help to identify patients at risk of severe wasting to provide adequate nutritional support.

Background: Traditional risk factors are strong predictors of the incidence of coronary artery disease (CAD), but their association with disease severity remains controversial and could differ across ethnic groups., Aims: In this study, we assessed the prevalence of cardiovascular risk factors (CRFs) in Afro-Caribbean patients with documented CAD, and sought to identify which of these factors are related to disease severity., Methods: We retrospectively studied 420 consecutive patients with CAD. Disease severity was determined from the results of invasive coronary angiography, based on the presence or absence of multiple (two or three) diseased vessels and the myocardial jeopardy (MJ) score., Results: In the studied population (mean age 64.7 ± 12.4 years), hypertension, diabetes and dyslipidaemia were the most frequent modifiable CRFs, present in 75.9, 47.8 and 37.8% of patients, respectively. Multiple logistic regression analysis showed that diabetes, male sex and personal cardiovascular history significantly increased the risk of multivessel CAD: odds ratios (ORs) of 1.53 (1.01-2.33; P=0.048), 1.61 (1.02-2.55; P=0.043) and 1.68 (1.11-2.56; P=0.015), respectively. Obesity was an independent negative predictor, with an OR of 0.48 (0.29-0.79; P=0.004). Other traditional CRFs (hypertension, dyslipidaemia, smoking, age and family history of vascular disease) were not associated with CAD severity. For high-risk lesions (MJ score ≥8), both diabetes and hypertension were independent predictors of disease severity, whereas obesity was no longer a protective factor., Conclusion: Diabetes emerged as the strongest modifiable risk factor predictor of multivessel disease in Afro-Caribbean patients, whereas obesity was an independent protective factor. The underlying mechanisms of these associations should be relevant to disease prevention., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: SHBG and liver enzymes levels are both associated with the risk of type 2 diabetes. However, the relationship between SHBG with liver enzymes and intrahepatic fat content remain poorly understood., Objective: To investigate whether SHBG is correlated with glucose and lipids levels and whether this association depends on fatty liver content, liver enzymes or sex hormone concentrations., Design and Patients: We studied 233 dysmetabolic men with measures of plasma SHBG, total testosterone, 17β-oestradiol, glucose, adiponectin, liver enzymes and hepatokines. Intrahepatic liver fat and visceral fat contents were measured by magnetic resonance imaging in 108 of these individuals., Results: After adjustment for age, SHBG concentration was inversely correlated with fasting glucose (βstandardized  = -0·21, P = 0·0007), HbA1c (βstandardized  = -0·27, P < 0·0001), triglycerides (βstandardized  = -0·19, P = 0·003) and positively correlated with HDL-Cholesterol (βstandardized  = 0·14, P = 0·03). These correlations persisted after adjustment for either total testosterone or 17β-oestradiol levels. SHBG was not related to either fetuin A or FGF 21 concentrations. The inverse association of SHBG with HbA1c and glycaemia was not altered after adjusting for liver markers but was no longer significant after adjustment for hepatic fat content., Conclusion: The significant association between SHBG and fasting glycaemia, HbA1c and lipid levels in dysmetabolic men was not related to either sex hormones or markers of liver function, but was dependent on intrahepatic fat. This suggests that intrahepatic fat, but not alterations in liver function markers, may be involved in the association between SHBG and glucose and lipid metabolism., (© 2012 John Wiley & Sons Ltd.)

Background: The atrial natriuretic peptide (ANP) is known mainly for its effects on kidney function and blood pressure homeostasis. We investigated the association between two ANP polymorphisms and pre-existing coronary artery disease (CAD) in patients of African descent with type 2 diabetes (T2D)., Methods: We conducted a cross-sectional and retrospective study of 218 volunteer Afro-Caribbean patients with T2D. Two polymorphisms (rs5064, 708C>T; and rs5065, 2238T>C) of ANP were genotyped using PCR-restriction fragment length polymorphism analysis. ANCOVA, χ2-test, and logistic regression were used for statistical analysis., Results: Among these patients (92 men; 128 women), 67 (30.7%) had CAD, of whom 75% had had myocardial infarction. The frequency of rs5065-C carriers (TC/CC) was significantly lower in patients with CAD than in those without CAD (24 vs. 41%, P = 0.01). The frequency of hypertension did not differ significantly according to genotype. Univariate logistic regression revealed that male sex, age, dyslipidemia, hypertension, and rs5065-C carrier status were associated significantly with CAD. After adjustment for the variables of interest, the odds ratio (ORs) of CAD for rs5065-C carriers (TC/CC) was 0.50 (0.26-0.96; P = 0.038). No association was found between the rs5064 (708C>T) single-nucleotide polymorphisms (SNPs) and pre-existing CAD or cardiovascular risk factors., Conclusions: The ANP rs5065 (2238T>C) C allele seems to exert a protective effect against CAD in T2D patients of African descent. The relevance of ANP polymorphisms for CAD should be determined in different populations.

Background: Primary hyperparathyroidism (PHPT) associates hypocalcemia and hypophosphatemia secondary to parathyroid hormone (PTH) excess. PHPT is asymptomatic for 80% of patients and responsible for a decrease in bone mineral density particularly in women. Vitamin D deficiency increases the risk of bone fractures., Methods: We performed a prospective analysis of patients with PHPT in order to evaluate the prevalence of vitamin D deficiency. We determined the effects of vitamin D deficiency on bone metabolism: calcium, phosphate and PTH levels. We also analyzed biochemical markers of bone remodeling and bone mineral density (BMD) before and 6 months after vitamin D replacement., Results: 75 patients with PHPT were identified: 38 patients with vitamin D deficiency but only 22 patients could be followed (G1). 14 patients with a normal level of vitamin D were followed (G2). Prevalence of vitamin D deficiency was 51%. Calcium and phosphate levels were similar into both groups. PTH levels were higher in the G1 group. Calciuria was significantly lower in the G1. For markers of bone formation (fragments of collagen CTX and alkaline phosphatase): osteocalcine levels were higher in G1 group. For bone resorption: télopeptides levels were significantly higher in the G1 group. T score was significantly lower in this group, favoring a significant osseous attack. After 6 months of substitution with vitamin D, calcium decreased and hypophosphatemia normalized. PTH levels decreased (-50.7%). Calciuria increased without risks of urinary lithiasis. Bone mineral density loss decreased while markers of bone turn over increased., Discussion: Vitamin D deficiency increases the risk of bone fragility in PHPT. Few data are available in France concerning the prevalence of vitamin D deficiency in PHPT. Our results were similar to data in other countries. Vitamin D replacement with regular monitoring of calcium and calciuria levels is beneficial for metabolic and hormonal status, improves bone density, without systematic opposing effects. The follow-up of effectiveness by BMD could be associated with measurement of markers of bone remodeling., Conclusion: In asymptomatic PHPT, particularly those for which surgery is not indicated, measurement of 25 OH Vitamin D should be systematic. It is recommended before surgery., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)