Cyril Breuker

Skeletal Muscle Insulin Resistance and Absence of Inflammation Characterize Insulin-Resistant Grade I Obese Women

Context Obesity is associated with insulin-resistance (IR), the key feature of type 2 diabetes. Although chronic low-grade inflammation has been identified as a central effector of IR development, it has never been investigated simultaneously at systemic level and locally in skeletal muscle and adipose tissue in obese humans characterized for their insulin sensitivity. Objectives We compared metabolic parameters and inflammation at systemic and tissue levels in normal-weight and obese subjects with different insulin sensitivity to better understand the mechanisms involved in IR development. Methods 30 post-menopausal women were classified as normal-weight insulin-sensitive (controls, CT) and obese (grade I) insulin-sensitive (OIS) or insulin-resistant (OIR) according to their body mass index and homeostasis model assessment of IR index. They underwent a hyperinsulinemic-euglycemic clamp, blood sampling, skeletal muscle and subcutaneous adipose tissue biopsies, an activity questionnaire and a self-administrated dietary recall. We analyzed insulin sensitivity, inflammation and IR-related parameters at the systemic level. In tissues, insulin response was assessed by P-Akt/Akt expression and inflammation by macrophage infiltration as well as cytokines and IκBα expression. Results Systemic levels of lipids, adipokines, inflammatory cytokines, and lipopolysaccharides were equivalent between OIS and OIR subjects. In subcutaneous adipose tissue, the number of anti-inflammatory macrophages was higher in OIR than in CT and OIS and was associated with higher IL-6 level. Insulin induced Akt phosphorylation to the same extent in CT, OIS and OIR. In skeletal muscle, we could not detect any inflammation even though IκBα expression was lower in OIR compared to CT. However, while P-Akt/Akt level increased following insulin stimulation in CT and OIS, it remained unchanged in OIR. Conclusion Our results show that systemic IR occurs without any change in systemic and tissues inflammation. We identified a muscle defect in insulin response as an early mechanism of IR development in grade I obese post-menopausal women.

Medication errors at hospital admission and discharge in Type 1 and 2 diabetes

To assess the prevalence and characteristics of medication errors at hospital admission and discharge in people with Type 1 and Type 2 diabetes, and identify potential risk factors for these errors.

Non-achievement of LDL-cholesterol targets in patients with diabetes at very-high cardiovascular risk receiving statin treatment: Incidence and risk factors

BACKGROUND Cardiovascular diseases are the first cause of mortality in patients with diabetes, and LDL-cholesterol is a well-established cardiovascular risk factor. This study aimed to assess rate of LDL-cholesterol target attainment among patients with diabetes at very-high cardiovascular risk treated with statins, and to identify predictive factors of non-attainment of target in this population. METHODS Patients were recruited in the Nutrition-Diabetes unit of Montpellier University Hospital, France, from 2014 to 2017. We included all consecutive patients with type 1 or type 2 diabetes receiving statin treatment and at very-high cardiovascular risk according to 2016 ESC guidelines, therefore having a LDL-cholesterol target of <1.8 mmol/L. LDL-cholesterol levels were measured upon admission. Variables independently associated with non-attainment of LDL-Cholesterol target were assessed using multivariable logistic regression. RESULTS 654 patients were included. Mean age was 63.8 years (SD 11.0), 41.9% were women and 42.3% had a history of cardiovascular disease. 59% of patients did not achieve LDL-cholesterol target, with a median value (interquartile range) of 2.4 mmol/L (2.1-2.9) versus 1.4 mmol/L (1.1-1.6) in patients at target. Risk of non-attainment of LDL-cholesterol target value was increased in women (odds ratio [95% confidence interval]: 2.27 [1.62-3.17]) and decreased in patients with history of coronary artery disease (0.64 [0.45-0.89]) or history of stroke or transient ischemic attack (0.59 [0.33-1.07]). CONCLUSIONS Management of dyslipidemia is suboptimal, even in very-high risk patients with diabetes under statins. Lipid-lowering treatment should be intensified, in particular in very high risk patients with diabetes who are women or in primary cardiovascular prevention. Clinical Trial number: NCT03449784.

Evaluation of the sST2-guided optimization of medical treatments of patients admitted for heart failure, to prevent readmission: Study protocol for a randomized controlled trial

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Evaluation of the sST2-guided optimization of medical treatments of patients admitted for heart failure, to prevent readmission: Study protocol for a randomized controlled trial Corentin Curinier, Kamila Solecki, Anne Dupuy, Cyril Breuker, Manuela Lotierzo, Laetitia Zerkowski, Eran Kalmanovich, Mariama Akodad, Jérôme Adda, Pascal Battistella, et al.

Decreased RNF41 expression leads to insulin resistance in skeletal muscle of obese women

CONTEXT Toll-like receptor 4 (TLR4) activation contributes to obesity-associated insulin resistance in skeletal muscles (SM). TLR4 signaling involves two pathways: the myeloid differentiation primary response gene 88 (MyD88) leading to inflammatory cytokines production and the toll/interleukin-1 receptor domain-containing adapter-inducing interferon (IFN) I (TRIF)-dependent pathways leading to type 1 interferon (IFNI) and interferon stimulated genes (ISG) expression. The E3 ubiquitin ligase RNF41 allows the preferential activation of the TRIF-IFNI pathway; however, its role in insulin response has not been reported. METHODS We measured RNF41 level and IFNI pathway activation (ISG expression) in SM biopsies of obese insulin sensitive (OIS) and obese insulin resistant (OIR) women. Then we isolated and differentiated in myotubes, primary human SM cell progenitors from OIS and OIR SM biopsies. We modulated RNF41 and ISG expression in these myotubes and investigated their effects on insulin response. RESULTS RNF41 expression is down-regulated in vivo in OIR SM and myotubes compared to OIS SM and myotubes. TLR4 activation with palmitate induces TRIF-IFNI pathway and ISG in OIS myotubes but not in OIR myotubes. Inhibition of RNF41 expression with siRNF41 in OIS myotubes treated with palmitate attenuates insulin response, IFNI pathway activation and ISG induction, mimicking OIR phenotype. Further, overexpression of RNF41 in OIR myotubes increases insulin response and ISG expression. Exposure to IFNI or to its inducer polyinosinic-polycytidylic acid, restores ISG expression and insulin sensitivity in OIR myotubes and OIS myotubes transfected with siRNF41. CONCLUSION Our results identify RNF41 as essential to IFNI pathway activation in order to maintain muscle insulin sensitivity during human obesity.