3-Month Post-Operative Increase in FGF21 is Predictive of One-Year Weight Loss After Bariatric Surgery.

PURPOSE: The association between bariatric surgery outcome and blood levels of fibroblast growth factor 21 (FGF21) remains controversial. Many patients displayed stable or decreased FGF21 one year after bariatric surgery. Nevertheless, there is often an early increase FGF21 concentration in the post-surgery period. The aim of this study was to investigate the relationship between 3-month FGF21 response and percentage total weight loss at one year after bariatric surgery. MATERIALS AND METHODS: In this prospective monocentric study, a total of 144 patients with obesity grade 2-3 were included; 61% of them underwent a sleeve gastrectomy and 39% a Roux-en-Y gastric bypass. Data analysis was carried out to determine the relation between 3-month plasma FGF21 response and weight loss one year after bariatric surgery. Multiple adjustments were done including degree of weight loss after 3 months. RESULTS: FGF21 significantly increased between baseline and Month 3 (n = 144, p < 10-3), then decreased between Month 3 and Month 6 (n = 142, p = 0.047) and was not different from baseline at Month 12 (n = 142, p = 0.86). The 3-month-FGF21 response adjusted to body weight loss was not different between types of bariatric surgery. The 3-month-FGF21 response was associated to body weight loss at Month 6 (r = -0.19, p = 0.02) and Month 12 (r = -0.34, p < 10-4). After multiple regression analysis, only Month 12 body weight loss remained associated to 3-month FGF21 response (r = -0.3, p = 0.02). CONCLUSION: This study showed that the magnitude of changes in FGF21 at 3 months after bariatric surgery emerged as an independent predictor of one-year body weight loss irrespective of the type of surgery.

A new 165-SNP low-density lipoprotein cholesterol polygenic risk score based on next generation sequencing outperforms previously published scores in routine diagnostics of familial hypercholesterolemia.

Genetic diagnosis of familial hypercholesterolemia (FH) remains unexplained in 30 to 70% of patients after exclusion of monogenic disease. There is now a growing evidence that a polygenic burden significantly modulates LDL-cholesterol (LDL-c) concentrations. Several LDL-c polygenic risk scores (PRS) have been set up. However, the balance between their diagnosis performance and their practical use in routine practice is not clearly established. Consequently, we set up new PRS based on our routine panel for sequencing and compared their diagnostic performance with previously-published PRS. After a meta-analysis, four new PRS including 165 to 1633 SNP were setup using different softwares. They were established using two French control cohorts (MONA LISA n=1082 and FranceGenRef n=856). Then the explained LDL-c variance and the ability of each PRS to discriminate monogenic negative FH patients (M-) versus healthy controls were compared with 4 previously-described PRS in 785 unrelated FH patients. Between all PRS, the 165-SNP PRS developed with PLINK showed the best LDL-c explained variance (adjusted R²=0.19) and the best diagnosis abilities (AUROC=0.77, 95%CI=0.74-0.79): it significantly outperformed all the previously-published PRS (p<1 × 10-4). By using a cut-off at the 75th percentile, 61% of M- patients exhibited a polygenic hypercholesterolemia with the 165-SNP PRS versus 48% with the previously published 12-SNP PRS (p =3.3 × 10-6). These results were replicated using the UK biobank. This new 165-SNP PRS, usable in routine diagnosis, exhibits better diagnosis abilities for a polygenic hypercholesterolemia diagnosis. It would be a valuable tool to optimize referral for whole genome sequencing.

Factors Predicting Statin Initiation During Childhood in Familial Hypercholesterolemia: Importance of Genetic Diagnosis.

OBJECTIVE: To identify childhood and parental factors associated with initiation of statin therapy in children with heterozygous familial hypercholesterolemia (HeFH), including underlying genetic diagnosis or parental premature atherosclerotic cardiovascular disease (ASCVD). STUDY DESIGN: This multicenter cohort study included 245 HeFH child-parent pairs from the REFERCHOL national register (2014-2020). Demographic and clinical characteristics at the last visit were collected. Vascular disease in parents was defined as a history of ASCVD, and/or a coronary artery calcium score >100, and/or stenosis of >50% in at least carotid artery. Statistical analyses included descriptive analysis, logistic regression for univariate and multivariate effects of statins, and a sensitivity analysis combining the characteristics of children and parents. RESULTS: Among the 245 children in the study cohort, 135 (58%), with a mean age of 14 ± 3 years, were treated with a statin. In multivariable analysis, the predictive childhood factors associated with statin treatment were genetic diagnosis (OR, 2.5; 95% CI, 1.3 to 4.9; P = .01), older age (OR, 4.4; 95% CI, 1.8-10.6; P = .01), more than 2 visits (OR, 2.36; 95% CI, 1.18-4.73; P = .015), and longer duration of follow-up (OR, 1.3; 95% CI, 1.1-1.6; P < .001). The predictive parental factor associated with childhood treatment was the presence of vascular disease (OR, 2.4; 95% CI, 1.0-5.7; P = .04). CONCLUSIONS: HeFH confirmed by DNA testing during childhood and a history of vascular disease in parents were independently associated with statin treatment in children with HeFH. Genetic diagnosis may be useful for cardiovascular prevention in children.

Metabolically healthy obesity and cardiovascular events: A nationwide cohort study.

AIM: To evaluate the associations between metabolically healthy obesity (MHO) and different types of incident cardiovascular events in a contemporary population. MATERIALS AND METHODS: All patients discharged from French hospitals in 2013 with at least 5 years of follow-up and without a history of major adverse cardiovascular event (MACE; myocardial infarction, heart failure [HF], ischaemic stroke or cardiovascular death [MACE-HF]) or underweight/malnutrition were identified. They were categorized by phenotypes defined by obesity and three metabolic abnormalities (diabetes, hypertension and hyperlipidaemia). Hazard ratios (HRs) for cardiovascular events during follow-up were adjusted on age, sex and smoking status at baseline. RESULTS: In total, 2 873 039 individuals were included in the analysis, among whom 272 838 (9.5%) had obesity. During a mean follow-up of 4.9 years, when pooling men and women, individuals with MHO had a higher risk of MACE-HF (multivariate-adjusted HR 1.22, 95% confidence interval [CI]: 1.19-1.24), new-onset HF (HR 1.34, 95% CI 1.31-1.37) and atrial fibrillation (AF; HR 1.33, 95% CI 1.30-1.37) compared with individuals with no obesity and zero metabolic abnormalities. By contrast, risks were not higher for myocardial infarction (HR 0.92, 95% CI 0.87-0.98), ischaemic stroke (HR 0.93, 95% CI 0.88-0.98) and cardiovascular death (HR 0.99, 95% CI 0.93-1.04). MHO in men was associated with a higher risk of clinical events compared with metabolically healthy men of normal weight (HR 1.12-1.80), while women with MHO had a lower risk for most events than metabolically healthy women of normal weight (HR 0.49-0.99). CONCLUSIONS: In a large and contemporary analysis of patients seen in French hospitals, individuals with MHO did not have a higher risk of myocardial infarction, ischaemic stroke or cardiovascular death than metabolically healthy individuals with no obesity. By contrast, they had a higher risk of new-onset HF and new-onset AF. However, notable differences were observed in men and women in the sex-stratified analysis.

Energy sensors and reproductive hypothalamo-pituitary ovarian axis (HPO) in female mammals: Role of mTOR (mammalian target of rapamycin), AMPK (AMP-activated protein kinase) and SIRT1 (Sirtuin 1).

In female, energy metabolism influences reproductive function by modulating the Hypothalamic Pituitary Ovarian axis including the hypothalamic GnRH neuronal network, the pituitary gonadotropin secretion and the ovarian follicle growth and steroidogenesis. Several hormones and neuropeptides or metabolites are important signals between energy balance and reproduction. These energy sensors mediate their action on reproductive cells through specific kinases or signaling pathways. This review focuses on the role of three main enzymes-specifically, mTOR, AMPK, and SIRT1 at the hypothalamic pituitary and ovarian axis in normal female fertility and then we discuss their possible involvement in some women reproductive disorders known to be associated with metabolic complications, such as polycystic ovary syndrome (PCOS) and premature ovarian failure (POF).

Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models.

It is well known that adipokines are endocrine factors that are mainly secreted by white adipose tissue. Their central role in energy metabolism is currently accepted. More recently, their involvement in fertility regulation and the development of some reproductive disorders has been suggested. Data concerning the role of leptin and adiponectin, the two most studied adipokines, in the control of the reproductive axis are consistent. In recent years, interest has grown about some novel adipokines, chemerin, visfatin, resistin and apelin, which have been found to be strongly associated with obesity and insulin-resistance. Here, we will review their expression and role in male and female reproduction in humans and animal models. According to accumulating evidence, they could regulate the secretion of GnRH (Gonadotropin-Releasing Hormone), gonadotropins and steroids. Furthermore, their expression and that of their receptors (if known), has been demonstrated in the human and animal hypothalamo-pituitary-gonadal axis. Like leptin and adiponectin, these novel adipokines could thus represent metabolic sensors that are able to regulate reproductive functions according to energy balance changes. Therefore, after investigating their role in normal fertility, we will also discuss their possible involvement in some reproductive troubles known to be associated with features of metabolic syndrome, such as polycystic ovary syndrome, gestational diabetes mellitus, preeclampsia and intra-uterine growth retardation in women, and sperm abnormalities and testicular pathologies in men.

Circulating PCSK9 levels are not associated with the severity of hepatic steatosis and NASH in a high-risk population.

BACKGROUND AND AIMS: Some studies suggested that proprotein convertase subtilisin kexin type 9 (PCSK9) is linked to liver steatosis severity and non-alcoholic steatohepatitis (NASH). We aimed to assess whether circulating PCSK9 levels are associated with either liver fat content (LFC) or histological markers of NASH in high-risk patients. METHODS: We present results from three cross-sectional studies from two French Hospitals: Dijon and Numevox (departments of Endocrinology) and Angers (department of Hepatology). Only patients without lipid-lowering therapy were included. All 132 patients had type 2 diabetes in Dijon, compared to 55/224 in Numevox (25%) and 39/122 in Angers (32%). LFC was assessed on MRI (Dijon and Numevox), and NASH lesion on liver biopsy (Angers). Additionally, we included mRNA results from 138 overweight patients of a Belgian Hospital (Antwerp). RESULTS: While circulating levels of PCSK9 were positively correlated with total cholesterol, LDL-C, triglycerides and non-HDL-C in all 3 cohorts, no significant association was found between PCSK9 and transaminases. Furthermore, no association was found between plasma PCSK9 levels and LFC in both Numevox (ßadjusted = 0.71 ±â€¯1.33, p = 0.60) and Dijon (ßadjusted = -1.03 ±â€¯0.90, p = 0.25). There was no correlation between circulating PCSK9 and histological liver lesions: steatosis severity (ßadjusted = -3.95 ±â€¯2.75, p = 0.15), NASH activity score (ßadjusted = -0.31 ±â€¯0.17, p = 0.082), lobular (ß = -0.067 ±â€¯0.055, p = 0.22) or portal inflammation (ß = -0.088 ±â€¯0.079, p = 0.27), ballooning (ß = -0.025 ±â€¯0.065, p = 0.70) and fibrosis (ß = -0.17 ±â€¯0.11, p = 0.12). Finally, hepatic PCSK9 mRNA levels were not correlated with NASH histological severity. CONCLUSIONS: Circulating PCSK9 concentrations are not associated with the severity of liver steatosis or histological markers of NASH. These data are reassuring regarding the clinical use of PCSK9 inhibitors in cardiovascular diseases.

Food addiction, in obese patients seeking bariatric surgery, is associated with higher prevalence of current mood and anxiety disorders and past mood disorders.

The current cross-sectional study investigates the prevalence of the food addiction (FA) phenotype and its association with psychiatric disorders in bariatric surgery candidates. It also investigates the eating behavior characteristics associated with FA and the association between FA and loss of control over specific foods high in sugar, salt and/or fat. We included 128 bariatric surgery candidates and we assessed FA (YFAS 2.0), mood and anxiety disorders, suicidality, eating disorders (current bulimia nervosa and current anorexia nervosa), alcohol and tobacco use disorders (MINI 5.0.0, beck depression inventory, AUDIT, Fagerström Test for Nicotine Dependence) and eating behavior (DEBQ). Prevalence of FA in our sample was 25%. FA was significantly associated with higher prevalence of current mood and anxiety disorders and past mood disorders, higher current suicidality but not with eating disorders and alcohol use disorder. FA was significantly associated with higher emotional eating, and with loss of control over consumption of foods high in fat, sugar and/or salt, but not of fruits, vegetables or grain products. Our results provide arguments for considering psychiatric disorders and suicidality in FA and for considering FA as an addictive disorder in obese patients, with many risk factors in common with other addictions.

Food Addiction is Associated with Higher Neuroticism, Lower Conscientiousness, Higher Impulsivity, but Lower Extraversion in Obese Patient Candidates for Bariatric Surgery.

BACKGROUND: The "food addiction" phenotype identifies a subpopulation of individuals experiencing substance-dependence symptoms toward specific foods. In the current debate on whether the "food addiction" phenotype should be considered as an addictive disorder, assessment of the personality traits associated with this phenotype would provide arguments for or against the "food addiction" phenotype and its inclusion in the "substance-related and addictive disorder" category. OBJECTIVES: To assess the personality characteristics associated with the "food addiction" phenotype in obesity surgery candidates (i.e., big five personality dimensions, alexithymia and impulsivity). METHODS: We assessed food addiction (Yale Food Addiction Scale), personality dimensions (Big Fig Inventory), impulsivity (Barratt Impulsiveness Scale-11th version) and alexithymia (Toronto Alexithymia Scale-20 items) in 188 bariatric surgery candidates recruited between July 2013 and November 2015 in the Nutrition Department of the University Hospital of Tours. We used chi-squared tests and Student's tests or Mann-Whitney-U-tests to determine the factors associated with food addiction. RESULTS: Prevalence of current food addiction was 16.5%. Patients with (vs. without) food addiction had lower conscientiousness (p = .047), higher neuroticism and lower extraversion (ps < 0.001), but there was no difference in terms of agreeableness (p = 0.42) or openness (p = 0.16). They were more frequently single (p = .021) and reported higher alexithymia (ps < .001) and higher impulsivity sub-scores (ps<.05). Conclusions/Importance: Food addiction shares personality traits with substance-related disorders (regarding neuroticism, conscientiousness, impulsivity, alexithymia), and one distinctive trait (low extraversion). This study provides additional data that enrich the discussion on whether the "food addiction" phenotype should be included or not in the "substance-related and addictive disorder" category.

Food Addiction in Bariatric Surgery Candidates: Prevalence and Risk Factors.

BACKGROUND: This study assessed the prevalence and risk factors for food addiction (FA) in bariatric surgery candidates. METHODS: We assessed BMI, FA (Yale Food Addiction Scale), quality of life (Quality Of Life, Obesity and Dietetics), depression (Beck Depression Inventory), and binge eating (Binge Eating Scale) in 188 obese patients. RESULTS: The most prevalent addiction criteria were persistent desire to control food consumption (93.1 %), continuing to eat certain foods despite problems (40.4 %), and tolerance (38.8 %); current prevalence of FA was 16.5 %. Patients with (vs. without) FA were more often single and had lower physical, psycho-social, and sexual quality of life and higher depression and binge eating. CONCLUSIONS: Systematic screening for and treatment of FA symptoms before obesity surgery is critical because FA symptoms are prevalent and associated with poorer psychosocial outcome.

[The psychiatric, psychological and addiction evaluation in bariatric surgery candidates: What should we assess, why and how?]. / L'évaluation psychiatrique, psychologique et addictologique avant chirurgie bariatrique : que faut-il évaluer en pratique, pourquoi et comment ?

Bariatric surgery is indicated in obese patients with a BMI ≥ 40 kg/m(2) or ≥ 35 kg/m(2) with serious comorbidities, in second intention in patients who failed to achieve significant weight loss after a well-managed medical, nutritional and psychotherapeutic treatment for 6 to 12 months, and in patients who are aware of the consequences of bariatric surgery and who agree with a long term medical and surgical follow-up. Such a treatment requires a preoperative multidisciplinary assessment and management, which includes a mandatory consultation with a psychiatrist or a psychologist that should be member of the multidisciplinary staff and participate in these staffs. Although one of this consultation's aim is to screen for the few patients who for which surgery is contra-indicated, in most cases, the main aim of this assessment is to screen for and manage psychiatric and psychopathologic disorders that could be temporary contra-indication, because these disorders could lead to poorer postoperative outcome when untreated. By explaining to the patient how these disorders could affect postoperative outcome and which benefits he could retrieve from their management, the patient will increase his motivation for change and he will be more likely to seek professional help for these disorders. In all cases, a systematic examination of the patient's personality and his/her ability to understand the postoperative instructions is essential before surgery because clinicians should check that the patient is able to be adherent to postoperative instructions. In addition to clinical interview, use of self-administered questionnaires before the consultation might help to determine which psychiatric or psychopathologic factors should be more closely screened during the consultation. Psychiatric disorders and addictions are highly prevalent in this population (e.g., mood and anxiety disorders, binge eating disorder, attention deficit hyperactivity disorder, addictions, personality disorders, pathological personality traits and dimensions), and when untreated, they can lead to poorer postoperative outcome (postoperative occurrence of psychiatric disorders, poorer quality of life, and sometimes to poorer weight loss or excessive weight rebound when the disorder is present during the postoperative period). A complementary training in addiction medicine is helpful given the higher risk for addictions in this population. Given that this evaluation is often the first meeting with a psychiatrist, an empathic and motivational approach is helpful to improve the patient's ability to request for a future psychiatric consultation during the follow-up. Some conditions are required for a high quality assessment: the objectives and expectations of the consultation should be systematically explained to the patient prior to the consultation by the physician who enquires for the assessment; it needs time; the psychiatrist should systematically be member of the multidisciplinary staff and should take part in regular multisciplinary staff meetings; patients should be seen alone to assess his/her readiness to change. After the consultation, a contact with the physician who enquires for the assessment should be systematic (e.g., use of a medical letter that sum up the main conclusions of the consultation; participation in regular multisciplinary staff meetings).

Associations between visceral adipose tissue, inflammation and sex steroid concentrations in men.

CONTEXT: In men, obesity and the metabolic syndrome are accompanied by decreased testosterone levels, but little is known about the associations between visceral adipose tissue (VAT), VAT-related inflammation and sex steroids. OBJECTIVE: To examine the relative impact of VAT, abdominal subcutaneous adipose tissue (SAT) and interleukin 6 (IL-6), a marker of VAT-induced inflammation, on testosterone (T) and 17ß-oestradiol (E2) levels in dysmetabolic men. METHODS: We study the NUMEVOX cohort of 229 men, aged 27-77 years, who all had at least one metabolic syndrome criterion (on average three). IL-6, C-reactive protein, Homeostasis Model Assessment of (HOMA) insulin resistance index (HOMA-IR), liver enzymes, E2, LH, sex hormone-binding globulin (SHBG), T, waist circumference and body mass index (BMI) were measured; bioavailable testosterone (BT) was calculated from T and SHBG; MRI-assessed VAT and SAT were analysed in 109 of these men. RESULTS: Visceral adipose tissue was strongly correlated with E2 (Spearman r = 0.38, P < 0.001) and with BT/E2 ratio (r = -0.42, P < 0.001), while SAT was not correlated with either. IL-6 was correlated with E2 (r = 0.19, P = 0.007), BT (r = -0.19, P = 0.006) and BT/E2 ratio (r = -0.30 P < 0.001). In multivariate linear analysis, the relation between VAT and E2 was independent of age, BMI (P = 0.008), leptin (P < 0.001), T and SHBG. Log(IL-6) was significantly inversely related with log(BT) (P = 0.032) independently of age, VAT, leptin and HOMA-IR. CONCLUSIONS: 17ß-oestradiol levels were positively associated with VAT, but not with SAT, while T and BT were negatively and independently associated with IL-6. The significant inverse association between IL-6 and T suggests an important role of low-grade visceral fat inflammation in the central hypogonadism associated with the metabolic syndrome.

Regulation of hepatic mitochondrial metabolism in response to a high fat diet: a longitudinal study in rats.

Mitochondrial dysfunctions have been detected in non-alcoholic steatohepatitis, but less information exists regarding adaptation of mitochondrial function during the initiation of hepatic steatosis. This study aimed to determine in rat liver the sequence of mitochondrial and metabolic adaptations occurring during the first 8 weeks of a moderate high fat diet (HFD). Sprague-Dawley rats were fed a HFD during 2, 4, and 8 weeks. Mitochondrial oxygen consumption, respiratory chain complexes activity, and oxidative phosphorylation efficiency were assessed in isolated liver mitochondria. Gene expression related to fat metabolism and mitochondrial biogenesis were determined. Results were compared to data collected in a group of rats sacrificed before starting the HFD feeding. After 2 and 4 weeks of HFD, there was a development of fatty liver and a concomitant increase the expression of mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT) and peroxisome proliferator-activated receptor γ. Higher serum ß-hydroxybutyrate levels and enhanced hepatic pyruvate dehydrogenase kinase 4 expression suggested increased fatty acid oxidation. However, mitochondrial respiration and respiratory chain activity were normal. After 8 weeks of HFD, lower accumulation of liver triglycerides was associated with reduced expression of mtGPAT. At this time, oxygen consumption with palmitoyl-L: -carnitine was decreased whereas oxidative phosphorylation efficiency (ATP/O) with succinate was enhanced. Hepatic levels of mtDNA were unchanged whatever the time points. This longitudinal study in rats fed a HFD showed that hepatic lipid homeostasis and mitochondrial function can adapt to face the increase in fatty acid availability.

Microparticles from patients with metabolic syndrome induce vascular hypo-reactivity via Fas/Fas-ligand pathway in mice.

Microparticles are membrane vesicles with pro-inflammatory properties. Circulating levels of microparticles have previously been found to be elevated in patients with metabolic syndrome (MetS). The present study aimed to evaluate the effects of in vivo treatment with microparticles, from patients with MetS and from healthy subjects (HS), on ex vivo vascular function in mice. Microparticles isolated from MetS patients or HS, or a vehicle were intravenously injected into mice, following which vascular reactivity in response to vasoconstrictor agonists was assessed by myography with respect to cyclo-oxygenase pathway, oxidative and nitrosative stress. Injection of microparticles from MetS patients into mice induced vascular hypo-reactivity in response to serotonin. Hypo-reactivity was associated with up-regulation of inducible NO-synthase and increased production of NO, and was reversed by the NO-synthase inhibitor (N(G)-nitro-L-arginine). The selective COX-2 inhibitor (NS398) reduced the contractile effect of serotonin in aortas from mice treated with vehicle or HS microparticles; however, this was not observed within mice treated with MetS microparticles, probably due to the ability of MetS microparticles to enhance prostacyclin. MetS microparticle-mediated vascular dysfunction was associated with increased reactive oxygen species (ROS) and enhanced expression of the NADPH oxidase subunits. Neutralization of the pro-inflammatory pathway Fas/FasL completely prevented vascular hypo-reactivity and the ability of MetS microparticles to enhance both inducible NO-synthase and monocyte chemoattractant protein-1 (MCP-1). Our data provide evidence that microparticles from MetS patients induce ex vivo vascular dysfunction by increasing both ROS and NO release and by altering cyclo-oxygenase metabolites and MCP-1 through the Fas/FasL pathway.

Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum.

OBJECTIVES: Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and calcification in the cutaneous, ophthalmologic, and vascular tissues. Cardiovascular manifestations such as peripheral arterial disease (PAD) are frequent in PXE. Because of the changes in the elastic properties and medial calcification of the arterial wall in PXE, the impact of the arterial remodeling on the ankle brachial index (ABI), a well-established diagnostic method for the detection and follow-up of PAD, remains to be determined in this disease. METHODS: This was a cross-sectional, comparative, open study, which took place at the PXE Consultation Center, University Hospital of Angers. The subjects were 53 patients (mean age, 49 ± 14 years; 35 females) with PXE clinically proven on the basis of established criteria (skin changes, angioid streaks, and skin biopsy). The ABI at rest, symptoms of intermittent claudication (IC), carotid intima-media thickness (IMT), carotid-femoral pulse wave velocity (c-f PWV), compliance (CC), and ß stiffness index were measured in a single-center cohort. RESULTS: Forty-five percent of the PXE patients had an ABI ≤0.90, but only one patient had an ABI >1.40. IC was found in 23% of the patients with an ABI ≤0.90. There were no significant differences between the patients with a low and normal ABI in terms of IMT (P = .566) or ß stiffness index (P = .194), but differences were significant for c-f PWV (P = .010) and CC (P = .011). Adjusted multivariate linear regression for the Framingham-Laurier score showed that patients with a low ABI had less compliant carotid arteries (B = 0.318, P = .039). CONCLUSIONS: PAD detected by a low ABI is very frequent in PXE, although with limited prevalence of symptomatic claudication. Unexpectedly, ABI was low in such calcifying PAD and associated with lower CC, independently of atherosclerosis risk factors. These findings demonstrate that PXE represents a unique monogenic model of PAD in which the specific arterial wall remodeling could change the diagnostic value of the ABI to detect PAD.

Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3ß signaling.

Recent studies reported cardioprotective effects of erythropoietin (EPO) against ischemia-reperfusion (I/R) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been reported to be impaired in diabetes and insulin resistance syndrome, we examined whether EPO-induced cardioprotection was maintained in rat models of type 1 diabetes and insulin resistance syndrome. Isolated hearts were obtained from three rat cohorts: healthy controls, streptozotocin (STZ)-induced diabetes, and high-fat diet (HFD)-induced insulin resistance syndrome. All hearts underwent 25 min ischemia and 30 min or 120 min reperfusion. They were assigned to receive either no intervention or a single dose of EPO at the onset of reperfusion. In hearts from healthy controls, EPO decreased infarct size (14.36 ± 0.60 and 36.22 ± 4.20% of left ventricle in EPO-treated and untreated hearts, respectively, p < 0.05) and increased phosphorylated forms of Akt, ERK1/2, and their downstream target GSK-3ß. In hearts from STZ-induced diabetic rats, EPO did not decrease infarct size (32.05 ± 2.38 and 31.88 ± 1.87% in EPO-treated and untreated diabetic rat hearts, respectively, NS) nor did it increase phosphorylation of Akt, ERK1/2, and GSK-3ß. In contrast, in hearts from HFD-induced insulin resistance rats, EPO decreased infarct size (18.66 ± 1.99 and 34.62 ± 3.41% in EPO-treated and untreated HFD rat hearts, respectively, p < 0.05) and increased phosphorylation of Akt, ERK1/2, and GSK-3ß. Administration of GSK-3ß inhibitor SB216763 was cardioprotective in healthy and diabetic hearts. STZ-induced diabetes abolished EPO-induced cardioprotection against I/R injury through a disruption of upstream signaling of GSK-3ß. In conclusion, direct inhibition of GSK-3ß may provide an alternative strategy to protect diabetic hearts against I/R injury.

Fatty liver and insulin resistance in obese Zucker rats: no role for mitochondrial dysfunction.

The relationship between insulin resistance and mitochondrial function is of increasing interest. Studies looking for such interactions are usually made in muscle and only a few studies have been done in liver, which is known to be a crucial partner in whole body insulin action. Recent studies have revealed a similar mechanism to that of muscle for fat-induced insulin resistance in liver. However, the exact mechanism of lipid metabolites accumulation in liver leading to insulin resistance is far from being elucidated. One of the hypothetical mechanisms for liver steatosis development is an impairment of mitochondrial function. We examined mitochondrial function in fatty liver and insulin resistance state using isolated mitochondria from obese Zucker rats. We determined the relationship between ATP synthesis and oxygen consumption as well as the relationship between mitochondrial membrane potential and oxygen consumption. In order to evaluate the quantity of mitochondria and the oxidative capacity we measured citrate synthase and cytochrome c oxidase activities. Results showed that despite significant fatty liver and hyperinsulinemia, isolated liver mitochondria from obese Zucker rats display no difference in oxygen consumption, ATP synthesis, and membrane potential compared with lean Zucker rats. There was no difference in citrate synthase and cytochrome c oxidase activities between obese and lean Zucker rats in isolated mitochondria as well as in liver homogenate, indicating a similar relative amount of hepatic mitochondria and a similar oxidative capacity. Adiponectin, which is involved in bioenergetic homeostasis, was increased two-fold in obese Zucker rats despite insulin resistance. In conclusion, isolated liver mitochondria from lean and obese insulin-resistant Zucker rats showed strictly the same mitochondrial function. It remains to be elucidated whether adiponectin increase is involved in these results.

Hormonal regulation of mitochondrial energy production.

PURPOSE OF REVIEW: It had been thought for a long time that thyroid hormones were the only ones to regulate energy production within mitochondria. Recent findings show that other hormones (steroids, leptin, insulin) regulate the efficiency of mitochondrial adenosine triphosphate production. Furthermore, a mismatch between oxygen consumption and energy intake may not be sufficient to understand body weight regulation. It appears that the efficiency of adenosine triphosphate production may play a role. RECENT FINDINGS: Over the past 2 years a series of results argued that glucocorticoids influence energy balance, the efficiency of adenosine triphosphate production, and are thermogenic. The sites for this effect are discussed, probably both the liver and muscle. Evidence of the genes involved in this regulation is substantial for muscle but remains to be studied in the liver. On the other hand, leptin could be a thermogenic hormone, especially in situations of calorie restriction. Finally, recent data and opinions suggest that mitochondria and adenosine triphosphate production could be central in the pathogenesis of both insulin resistance and beta cell deficiency. SUMMARY: The adaptation of mitochondrial adenosine triphosphate production appears to play a role in both diabetes and weight loss (voluntary and involuntary). Hormonal and nutritional manipulation could be a therapeutic possibility for weight management.

Glucose-to-insulin ratio rather than sex hormone-binding globulin and adiponectin levels is the best predictor of insulin resistance in nonobese women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), the main androgen disorder in women, has been suggested to be associated with a high risk of developing cardiovascular disease and type 2 diabetes. In many PCOS patients, overweight or central obesity is generally associated with increases in fasting insulin levels, insulin resistance, and glucose intolerance, and has been identified as a target for new therapeutic strategy, including early change in lifestyle. Early biochemical marker(s) for identifying at-risk patients will be useful for prevention studies. The main goal of the present study was to search for such tool(s). We investigated 16 nonobese PCOS women by performing euglycemic hyperinsulinemic clamp and measuring insulin levels during fasting and oral glucose tolerance test, as well as the serum concentrations of SHBG, leptin, and adiponectin, the newly identified adipose factors. Eight of the 16 patients had a steady-state glucose disposal rate less than 8.5 mg/kg.min, the lowest normal value for nonobese control women. These insulin-resistant patients had significant higher body mass index (BMI) and waist-to-hip ratio (WHR), and lower high-density lipoprotein cholesterol and SHBG levels. As expected, glucose disposal correlated negatively with BMI (P = 0.01), WHR (P = 0.01), and fasting insulin level (P = 0.003). On stepwise regression analysis, however, the glucose-to-insulin ratio (GIR) emerged as the strongest independent parameter to appraise insulin resistance (R(2) = 0.61). SHBG level correlated positively with GIR (P < 0.001) and negatively with BMI (P = 0.003) but did not correlate with either insulin response during the glucose tolerance test or plasma leptin and/or adiponectin levels. In contrast, BMI was the only independent predictive parameter of SHBG (P = 0.003, R(2) = 0.73). Interestingly, plasma adiponectin levels were positively associated with glucose disposal rate (P = 0.043) and negatively with WHR (P = 0.024), waist circumference being the best predictor of adiponectin level (P < 0.01). Leptin level correlated only with BMI (r = 0.62, P = 0.01). This study confirmed that insulin resistance, despite the lack of obesity as such, is clearly present in many PCOS women, and demonstrated that GIR is the best predictor for insulin resistance. It was also shown that adiponectin level is a good indicator of abdominal fat mass and is associated to insulin resistance. Finally, low SHBG levels in PCOS are intimately associated with BMI, suggesting that some signal(s) from the adipose tissue, independent of adiponectin and leptin, may regulate liver production of SHBG.

Functional consequence of targeting protein kinase B/Akt to GLUT4 vesicles.

We have investigated the role of protein kinase B (Akt) in the insulin-stimulated translocation of vesicles containing the insulin-responsive isoform of glucose transporter (GLUT4) to the plasma membrane of adipocytes. Previous reports have suggested that protein kinase B can bind to intracellular GLUT4 vesicles in an insulin-dependent manner, but the functional consequence of this translocation is not known. In this study we have artificially targeted constitutively active and kinase-inactive mutants of protein kinase B to intracellular GLUT4 vesicles by fusing them with the N-terminus of GLUT4 itself. We examined the effect of these mutants on the insulin-dependent translocation of the insulin-responsive amino peptidase IRAP (a bona fide GLUT4-vesicle-resident protein). A kinase-inactive protein kinase B targeted to GLUT4 vesicles was an extremely effective dominant-negative inhibitor of insulin-stimulated IRAP translocation to the plasma membrane. By contrast, a kinase-inactive protein kinase B expressed in the cytoplasm did not have an effect. The results suggest that protein kinase B has an important functional role at, or in the vicinity of, GLUT4 vesicles in the insulin-dependent translocation of those vesicles to the plasma membrane of adipocytes.