Pancreatic α- and ß-cellular clocks have distinct molecular properties and impact on islet hormone secretion and gene expression.

A critical role of circadian oscillators in orchestrating insulin secretion and islet gene transcription has been demonstrated recently. However, these studies focused on whole islets and did not explore the interplay between α-cell and ß-cell clocks. We performed a parallel analysis of the molecular properties of α-cell and ß-cell oscillators using a mouse model expressing three reporter genes: one labeling α cells, one specific for ß cells, and a third monitoring circadian gene expression. Thus, phase entrainment properties, gene expression, and functional outputs of the α-cell and ß-cell clockworks could be assessed in vivo and in vitro at the population and single-cell level. These experiments showed that α-cellular and ß-cellular clocks are oscillating with distinct phases in vivo and in vitro. Diurnal transcriptome analysis in separated α and ß cells revealed that a high number of genes with key roles in islet physiology, including regulators of glucose sensing and hormone secretion, are differentially expressed in these cell types. Moreover, temporal insulin and glucagon secretion exhibited distinct oscillatory profiles both in vivo and in vitro. Altogether, our data indicate that differential entrainment characteristics of circadian α-cell and ß-cell clocks are an important feature in the temporal coordination of endocrine function and gene expression.

Moderate to Severe Soft Tissue Diabetic Foot Infections: A Randomized, Controlled, Pilot Trial of Post-debridement Antibiotic Treatment for 10 versus 20 days.

BACKGROUND: The optimal duration of antibiotic therapy for soft-tissue infections of the diabetic foot remains unknown. OBJECTIVE: We determine if antibiotic therapy after debridement for a short (10 days), compared with a long (20 days), duration for soft-tissue infections of the diabetic foot results in similar rates of clinical remission and adverse events (AE). SUMMARY OF BACKGROUND DATA: The optimal duration of systemic antibiotic therapy, after successful debridement, for soft tissue infections of diabetic patients is unknown. Because of the high recurrence risk, overuse is commonplace. METHODS: This was a randomized, controlled, non-inferiority pilot trial of cases of diabetic foot infection (excluding osteomyelitis) with the primary outcome of "clinical remission at 2-months follow-up". RESULTS: Among 66 enrolled episodes (17% females; median age 71 years), we randomized 35 to the 10-day arm and 31 to the 20-day arm. The median duration of the parenteral antibiotic therapy was 1 day, with the remainder given orally. In the intention-to-treat population, we achieved clinical remission in 27 (77%) patients in the 10-day arm compared to 22 (71%) in the 20-days arm ( P = 0.57). There were a similar proportion in each arm of AE (14/35 versus 11/31; P = 0.71), and remission in the per-protocol population (25/32 vs 18/27; P = 0.32). Overall, 8 soft tissue DFIs in the 10-day arm and 5 cases in the 20-day arm recurred as a new osteomyelitis [8/35 (23%) versus 5/31 (16%); P = 0.53]. Overall, the number of recurrences limited to the soft tissues was 4 (6%). By multivariate analysis, rates of remission (intention-to-treat population, hazard ratio 0.6, 95%CI 0.3-1.1; per-protocol population 0.8, 95%CI 0.4-1.5) and AE were not significantly different with a 10-day compared to 20-day course. CONCLUSIONS: In this randomized, controlled pilot trial, post-debridement antibiotic therapy for soft tissue DFI for 10 days gave similar (and non-inferior) rates of remission and AEs to 20 days. A larger confirmatory trial is under way. TRIAL REGISTRATION: ClinicalTrials NCT03615807.

Three Weeks Versus Six Weeks of Antibiotic Therapy for Diabetic Foot Osteomyelitis: A Prospective, Randomized, Noninferiority Pilot Trial.

BACKGROUND: In patients with diabetic foot osteomyelitis (DFO) who underwent surgical debridement, we investigated whether a short (3 weeks) duration compared with a long (6 weeks) duration of systemic antibiotic treatment is associated with noninferior results for clinical remission and adverse events (AEs). METHODS: In this prospective, randomized, noninferiority pilot trial, we randomized (allocation 1:1) patients with DFO after surgical debridement to either a 3-week or a 6-week course of antibiotic therapy. The minimal duration of follow-up after the end of therapy was 2 months. We compared outcomes using Cox regression and noninferiority analyses (25% margin, power 80%). RESULTS: Among 93 enrolled patients (18% females; median age 65 years), 44 were randomized to the 3-week arm and 49 to the 6-week arm. The median number of surgical debridements was 1 (range, 0-2 interventions). In the intention-to-treat (ITT) population, remission occurred in 37 (84%) of the patients in the 3-week arm compared with 36 (73%) in the 6-week arm (P = .21). The number of AEs was similar in the 2 study arms (17/44 vs 16/49; P = .51), as were the remission incidences in the per-protocol (PP) population (33/39 vs 32/43; P = .26). In multivariate analysis, treatment with the shorter antibiotic course was not significantly associated with remission (ITT population: hazard ratio [HR], 1.1 [95% confidence interval {CI}, .6-1.7]; PP population: HR, 0.8 [95% CI: .5-1.4]). CONCLUSIONS: In this randomized controlled pilot trial, a postdebridement systemic antibiotic therapy course for DFO of 3 weeks gave similar (and statistically noninferior) incidences of remission and AE to a course of 6 weeks. CLINICAL TRIALS REGISTRATION: NCT03615807; BASEC 2016-01008 (Switzerland).

Cellular circadian period length inversely correlates with HbA1c levels in individuals with type 2 diabetes.

AIMS/HYPOTHESIS: The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes. METHODS: We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters. RESULTS: We observed a significant inverse correlation (ρ = -0.592; p < 0.05) between HbA1c values and circadian period length within cells from the type 2 diabetes group. RNA sequencing analysis conducted on samples from this group revealed that ICAM1, encoding the endothelial adhesion protein, was differentially expressed in fibroblasts from individuals with poorly controlled vs well-controlled type 2 diabetes and its levels correlated with cellular period length. Consistent with this circadian link, the ICAM1 gene also displayed rhythmic binding of the circadian locomotor output cycles kaput (CLOCK) protein that correlated with gene expression. CONCLUSIONS/INTERPRETATION: We provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans. DATA AVAILABILITY: RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622.

[GLP-1 analogues in 2019†: for whom and how ?] / Analogues du GLP-1 en 2019†: pour qui et comment ?

GLP-1 analogues are a well-established treatment for type 2 diabetes. They act by improving glycemic control through several mechanisms. They also have the advantage of inducing weight loss without the risk of associated hypoglycemia. This class of molecules has also shown a benefit in cardiovascular events such as cardiovascular mortality, stroke and myocardial infarction, and albuminuria. These favorable effects place them, like SGLT-2 inhibitors, as a second option in the case of unsatisfactory glycemic control after metformin and dietary and lifestyle measures. This article provides an overview of the current knowledge of GLP-1 analogue therapy in patients with type 2 diabetes.

Les analogues du GLP-1 constituent un traitement bien établi du diabète de type 2 en permettant une amélioration du contrôle glycémique au travers de plusieurs mécanismes. Ils possèdent également comme avantage l'induction d'une perte de poids sans risque d'hypoglycémie associée. Cette classe de molécules a aussi montré un bénéfice sur les événements cardiovasculaires tels que la mortalité cardiovasculaire, la survenue d'AVC et d'infarctus du myocarde et l'albuminurie. Ces effets favorables les placent, comme les inhibiteurs du SGLT-2, en deuxième option en cas de contrôle glycémique non satisfaisant après la metformine et les mesures hygiéno-diététiques. Cet article fait un survol des connaissances actuelles du traitement par analogues du GLP-1 chez les patients avec un diabète de type 2.

Time zones of pancreatic islet metabolism.

Most living beings possess an intrinsic system of circadian oscillators, allowing anticipation of the Earth's rotation around its own axis. The mammalian circadian timing system orchestrates nearly all aspects of physiology and behaviour. Together with systemic signals originating from the central clock that resides in the hypothalamic suprachiasmatic nucleus, peripheral oscillators orchestrate tissue-specific fluctuations in gene transcription and translation, and posttranslational modifications, driving overt rhythms in physiology and behaviour. There is accumulating evidence of a reciprocal connection between the circadian oscillator and most aspects of physiology and metabolism, in particular as the circadian system plays a critical role in orchestrating body glucose homeostasis. Recent reports imply that circadian clocks operative in the endocrine pancreas regulate insulin secretion, and that islet clock perturbation in rodents leads to the development of overt type 2 diabetes. While whole islet clocks have been extensively studied during the last years, the heterogeneity of islet cell oscillators and the interplay between α- and ß-cellular clocks for orchestrating glucagon and insulin secretion have only recently gained attention. Here, we review recent findings on the molecular makeup of the circadian clocks operative in pancreatic islet cells in rodents and in humans, and focus on the physiologically relevant synchronizers that are resetting these time-keepers. Moreover, the implication of islet clock functional outputs in the temporal coordination of metabolism in health and disease will be highlighted.

Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway.

Insulin monotherapy can neither maintain normoglycemia in type 1 diabetes (T1D) nor prevent the long-term damage indicated by elevated glycation products in blood, such as glycated hemoglobin (HbA1c). Here we find that hyperglycemia, when unaccompanied by an acute increase in insulin, enhances itself by paradoxically stimulating hyperglucagonemia. Raising glucose from 5 to 25 mM without insulin enhanced glucagon secretion ∼two- to fivefold in InR1-G9 α cells and ∼18-fold in perfused pancreata from insulin-deficient rats with T1D. Mice with T1D receiving insulin treatment paradoxically exhibited threefold higher plasma glucagon during hyperglycemic surges than during normoglycemic intervals. Blockade of glucagon action with mAb Ac, a glucagon receptor (GCGR) antagonizing antibody, maintained glucose below 100 mg/dL and HbA1c levels below 4% in insulin-deficient mice with T1D. In rodents with T1D, hyperglycemia stimulates glucagon secretion, up-regulating phosphoenolpyruvate carboxykinase and enhancing hyperglycemia. GCGR antagonism in mice with T1D normalizes glucose and HbA1c, even without insulin.

[Endocrinopathies induced by immune checkpoint inhibitors]. / Endocrinopathies induites par les inhibiteurs de points de contrôle immunitaire.

Immune checkpoint Inhibitors are new immunomodulatory treatments that have proven their anti-tumor efficacy in several advanced cancers. Nevertheless, their use has paved the way for multiple immunological adverse effects that affect many systems and organs including endocrine glands such as the pituitary, thyroid, adrenal and pancreas. Hypophysitis is the most common complication of anti-CTLA-4 monoclonal antibodies, while anti-PD-1 and anti-PD-L1 antibodies cause more thyroid complications. Adrenal insufficiency and type 1 diabetes are relatively less common. Endocrinologists and primary care physicians as well as oncologists are likely to deal with these complications and as such, knowledge of these drugs and their side effects is essential for good practice.

Les inhibiteurs de points de contrôle immunitaire sont des nouveaux traitements immunomodulateurs qui ont prouvé leur efficacité antitumorale dans plusieurs cancers avancés. Néanmoins, leur utilisation a ouvert la voie à de multiples effets indésirables immunologiques touchant plusieurs systèmes et organes dont les glandes endocrines comme l'hypophyse, la thyroïde, les surrénales et le pancréas. L'hypophysite constitue la complication la plus fréquente des anticorps monoclonaux anti-CTLA-4, alors que ceux anti-PD-1 et anti-PD-L1 provoquent plus de complications thyroïdiennes. Les insuffisances surrénaliennes et le diabète de type 1 sont relativement moins fréquents. Les endocrinologues et les médecins de premier recours, tout comme les oncologues, sont susceptibles de prendre en charge ces complications et de ce fait, une connaissance spécifique de ces médicaments et de leurs effets indésirables est indispensable à la bonne pratique.

[Dyslipidemia management in patients with type 1 diabetes]. / Prise en charge de la dyslipidémie chez les patients avec un diabète de type 1.

Cardiovascular diseases are the main cause of mortality in patients with type 1 diabetes (T1DM) despite modern technology and careful metabolic control. The occurrence of dyslipidemia is frequent with T1DM and affects the risk for cardiovascular disease as occur with the occurrence of micro vascular complications. Lifestyle modifications and statin treatment should be regularly evaluated in patients with T1DM. There has been extensive discussion in the media about statin but facts are statins reduce the risk of cardiovascular disease in primary and secondary prevention. In individuals with T1DM, dyslipidemia remains underdiagnosed and insufficiently treated. This article provides a summary of the knowledge about dyslipidemia and T1DM and aims to better identify the patients that should be treated.

Les maladies cardiovasculaires restent la première cause de mortalité chez les patients avec diabète de type 1 (DT1) malgré les progrès technologiques et l'attention portée au contrôle métabolique. L'occurrence d'une dyslipidémie est fréquente en cas de DT1 et constitue un facteur de risque cardiovasculaire bien identifié au même titre que l'existence de complications microvasculaires. Le renforcement des mesures hygiéno-diététiques et la prescription de statine sont à évaluer régulièrement. Les controverses médiatiques sur les statines ne devraient pas occulter leur efficacité tant en prévention secondaire que primaire, car la dyslipidémie reste sous-diagnostiquée et insuffisamment traitée dans le DT1. Cet article résume les données de la littérature et vise à mieux identifier les patients à traiter.

[Endocrinology, what's new in 2016]. / Endocrinologie.

The European Society of Endocrinology has published this year a series of guidelines for hypoparathyroidism, the management of adrenal incidentalomas as well as for the long-term follow-up of patients operated on for a phaeochromocytoma/paraganglioma (PPGL). For hypoparathyroidism, guidelines insist on screening for chronic complications and monitoring treatment with calcium and vitamin D; the use of recombinant PTH may provide new opportunities for the future. Concerning adrenal incidentalomas, the panel of the guidelines primarily recommends non contrast CT for the evaluation of the risk of malignancy. Patients operated on for a PPGL, should be offered an individualized follow-up plan based on assessment of their risk of tumor recurrence.

Des nouvelles recommandations concernant l'hypoparathyroïdie, l'évaluation des incidentalomes surrénaliens ainsi que le suivi à long terme des patients opérés d'un phéochromocytome/paragangliome (PPGL), ont été publiées en 2016 par la Société européenne d'endocrinologie. Pour l'hypoparathyroïdie, l'accent est mis sur l'évaluation des complications chroniques et la titration du traitement par calcium et vitamine D; la supplémentation par PTH-recombinante (rhPTH) est un traitement prometteur. Concernant l'évaluation du risque de malignité des incidentalomes surrénaliens, les études montrent une supériorité de la densité spontanée (DS) de ces tumeurs au CT-scan non injecté, en tant que critère diagnostique. Enfin, un suivi personnalisé est indiqué pour les patients opérés d'un PPGL, après évaluation du risque de récidive à long terme.

[Musculoskeletal complications in diabetes mellitus]. / Manifestations musculosquelettiques du diabète sucré : une complication fréquente.

Musculoskeletal abnormalities are common and multiple in diabetic patients. They often result from pathologic changes in the microvasculature (microangiopathy), connective tissue, and peripheral nerves related to chronic hyperglycaemia. Their prevalence in patients with diabetes vary depending upon the diagnostic criteria, the study population and is generally correlated with poor glycaemic control and the occurrence of other complications of diabetes. These entities are important to recognize because they often respond to treatment, preventing pain and disability and improving quality of life.

Les complications rhumatologiques du diabète sont fréquentes et multiples. Elles sont souvent la conséquence de modifications pathologiques de la microcirculation (microangiopathies), du tissu conjonctif et des nerfs périphériques en lien avec l'hyperglycémie chronique. Leur prévalence chez les patients diabétiques varie en fonction des critères diagnostiques employés, de la population étudiée et est généralement corrélée au mauvais équilibre glycémique et à la survenue d'autres complications du diabète. Ces entités sont importantes à reconnaître afin d'instaurer un traitement ciblé, prévenir la douleur et le handicap et améliorer la qualité de vie.

[The combination of GLP-1 analogs and SGLT2 inhibitors : new perspectives ?] / Association des analogues du GLP-1 et des inhibiteurs du SGLT2 : de nouvelles perspectives ?

Type 2 diabetes therapy has expanded considerably over the last decade. Two anti-diabetic therapeutic groups, which are GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 inhibitors (sodium-glucose co-transporter-2), have shown efficacy not only on glycemic control but also on weight and other parameters that will be detailed in this article. Cardiovascular safety studies for two of these molecules were shown for the first time to decrease overall and cardiovascular mortality. The combination of these two therapeutic classes provides a logical solution due to their different mechanisms of action. The DURATION-8 study designed to demonstrate the benefits of this combination will also be discussed in this article.

La thérapie du diabète de type 2 s'est considérablement élargie les dix dernières années. Deux groupes thérapeutiques antidiabétiques, qui sont les analogues du GLP-1 et les inhibiteurs du SGLT2 ont montré une efficacité non seulement sur le contrôle glycémique mais aussi sur le poids et sur d'autres paramètres cliniques et biologiques qui seront détaillés dans cet article. Les études de sécurité cardiovasculaire pour deux de ces molécules ont montré pour la première fois une baisse de la mortalité globale et cardiovasculaire. La combinaison de ces deux classes thérapeutiques offre une solution logique de par leurs différents mécanismes d'action. L'étude DURATION-8 conçue pour démontrer le bienfait de cette combinaison sera aussi discutée dans cet article.

[Treatment of type 2 diabetes : risk and benefits of metabolic surgery]. / Traitement du diabète de type 2 : risques et bénéfices de la chirurgie métabolique.

Metabolic surgery is a serious option to treat type 2 diabetes. The latest guidelines consider surgery as one of the first option, especially in patients suffering from severe obesity or those who have uncontrolled diabetes. However, the radicality of metabolic surgery limits its prescription and is difficult to handle. Indeed, criteria of success remain insufficently understood in order to help caregivers to rigorously select the right candidates. This article proposes a review of the literature on the risks and benefits of metabolic surgery for the diabetic obese patient.

La chirurgie métabolique constitue une réelle alternative thérapeutique chez le patient avec un diabète de type 2. Les dernières recommandations prônent d'ailleurs de l'intégrer précocement parmi les options thérapeutiques à considérer, en particulier chez les patients souffrant d'une obésité sévère ou avec un diabète insuffisamment contrôlé. Dans les faits, la radicalité de la chirurgie limite sa prescription et place les soignants face à un dilemme lors de la sélection des patients candidats, les critères prédictifs de succès restant insuffisamment compris. Cet article propose une revue de la littérature relative aux risques et bénéfices de la chirurgie métabolique chez le patient obèse diabétique.

Effects of liver transplantation on endocrine function: a systematic review.

Patients with chronic liver disease (CLD) often experience secondary endocrine dysfunction. Therefore, because the liver plays a major role in endocrine function, liver transplantation (LT) may also be beneficial for the restoration of hormonal regulation. This systematic review collects and interprets the available literature on the effect of LT on endocrine and sexual function in adult patients. A systematic review was conducted by searching Pubmed (including Medline) and EMBASE for studies published from database inception until November 2015. We collected all relevant studies that discussed changes in hormonal and sexual function after LT. Studies were included if they assessed the effect of LT on sexual function or one of the following components of the hormone/endocrine axis: the hypothalamus-pituitary-gonadal axis, growth hormone (GH), insulin-like growth factor-1 (IGF-1) or thyroid function. The results are reported according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Twenty-one studies with a total of 1274 patients were included. The results collected from the included studies suggested that LT improves the hormonal perturbation associated with CLD by restoring physiological levels of circulating GH, IGF-1, testosterone, estradiol, prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Thyroid function was not affected by LT, and sexual function was partially improved after LT. This systematic review suggests that LT is associated with an improvement in endocrine and sexual function in patients with CLD. This information should encourage clinicians who treat CLD patients to identify endocrine disturbances in this population, inform their patients of the effects of LT and assess post-transplantation improvements.

[Iodine excess induced thyroid dysfunction]. / Dysthyroïdies liées à une surcharge iodée.

The principle sources of iodine overload, amiodarone and radiologic contrast media, are frequently used in modern medicine. The thyroid gland exerts a protective effect against iodine excess by suppressing iodine internalization into the thyrocyte and iodine organification, the Wolff-Chaikoff effect. Insufficiency of this effect or lack of escape from it leads to hypo- or hyperthyroidism respectively. Amiodarone induced thyrotoxicosis is a complex condition marked by two different pathophysiological mechanisms with different treatments. Thyroid metabolism changes after exposure to radiologic contrast media are frequent, but they rarely need to be treated. High risk individuals need to be identifed in order to delay the exam or to monitor thyroid function or apply prophylactic measures in selected cases.

[Prevention and remission of diabetes: is it feasible?]. / Prévention et guérison du diabète: est-ce possible?

Prevention of type 2 diabetes is a major public health objective in view of the increasing prevalence of obesity in the population, the medical community and politicians to develop preventive strategies as well as effective interventions to induce remission of diabetes. Clinical studies indicate that intensive medical treatment through lifestyle adaptations and even more bariatric surgery can prevent or rather delay type 2 diabetes onset and factor remission but with a positive effect which progressively decreases with time. Duration of diabetes and weight loss are major prognostic factors. New strategies are necessary to improve both short- and long-term efficacy of diabetes prevention and remission.

[Insulin and oral antidiabetes drugs: how associate these treatments in ambulatory care?]. / Insuline et antidiabétiques oraux: comment les associer dans la pratique ambulatoire?

Type 2 diabetes mellitus is a complex and progressive metabolic disease involving more than 400 millions of people worldwide. The treatments need to be constantly managed to maintain appropriate glycemic control and avoiding complications. There is a wide variety of therapeutic option including oral antidiabetes drugs or new insulin on the market. The initiation of insulin treatment seems a mandatory step for a large panel of patients. Therefore, it is important to know the indications to initiate insulin treatment and the best way to associate it with antidiabetes drugs.

A truncated hnRNP A1 isoform, lacking the RGG-box RNA binding domain, can efficiently regulate HIV-1 splicing and replication.

Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is one of the most abundant RNA binding proteins. hnRNP A1 is localized prevalently in the nucleus but it can relocate to the cytoplasm in response to specific stimuli shuttling between nuclear and cytoplasmic compartments. The cellular localization of this protein is regulated by a short C-terminus motif (M9) and other less defined sequences. The RNA binding specificity of this protein is dependent on multiple RNA binding domains (RBDs), which regulate its role in RNA processing and expression. hnRNP A1 plays multiple roles in gene expression by regulating the biogenesis and translation of messengers RNAs, the processing of miRNAs, affecting transcription and controlling telomere maintenance. The multiple functions of this protein correlate with diverse roles in genetic disease, cancer and the replication of viral pathogens. Utilizing a tagged hnRNP A1 deletion library we have shown that the three hnRNP A1 RBDs contribute to the prevalent nuclear distribution of the protein. Our data also indicate that a truncated form of the protein, lacking one of the RBDs, the RGG-box, can regulate splicing of a splicing reporter minigene and down-regulate replication of the HIV-1 virus with efficiency comparable to the wild-type protein. This functional hnRNP A1 deletion mutant is similar to a predicted hnRNP A1 isoform, which had not been previously experimentally characterized.

Free Fatty Acids Impair FGF21 Action in HepG2 Cells.

BACKGROUND/AIMS: Fibroblast growth factor 21 (FGF21) is a key mediator of glucose and lipid metabolism. However, the beneficial effects of exogenous FGF21 administration are attenuated in obese animals and humans with elevated levels of circulating free fatty acids (FFA). METHODS: We investigated in vitro how FFA impact FGF21 effects on hepatic lipid metabolism. RESULTS: In the absence of FFA, FGF21 reduced lipogenesis and increased lipid oxidation in HepG2 cells. Inhibition of lipogenesis was associated with a down regulation of SREBP-1c, FAS and SCD1. The lipid-lowering effect was associated with AMPK and ACC phosphorylation, and up regulation of CPT-1α expression. Further, FGF21 treatment reduced TNFα gene expression, suggesting a beneficial action of FGF21 on inflammation. In contrast, the addition of FFA abolished the positive effects of FGF21 on lipid metabolism. CONCLUSION: In the absence of FFA, FGF21 improves lipid metabolism in HepG2 cells and reduces the inflammatory cytokine TNFα. However, under high levels of FFA, FGF21 action on lipid metabolism and TNFα gene expression is impaired. Therefore, FFA impair FGF21 action in HepG2 cells potentially through TNFα.

[Polycystic ovaries: what's news in 2015?]. / Syndrome des ovaires polykystiques: quoi de neuf?

Polycystic ovary syndrome is a very common endocrine disorder in women of reproductive age, with important clinical implications (fertility issues, hirsutism, metabolic abnormalities). The Endocrine society has published in 2013 a series of diagnostic and treatment recommendations, followed by the European society of endocrinology in 2014. Recently, advances have been made in the measure of androgen biomarker and the evaluation of ovarian morphology with 3D ultrasound techniques. New treatments have emerged for fertility problems associated with the syndrome (ex. letrozole).