An Intimate Relationship between ROS and Insulin Signalling: Implications for Antioxidant Treatment of Fatty Liver Disease

Oxidative stress damages multiple cellular components including DNA, lipids, and proteins and has been linked to pathological alterations in nonalcoholic fatty liver disease (NAFLD). Reactive oxygen species (ROS) emission, resulting from nutrient overload and mitochondrial dysfunction, is thought to be a principal mediator in NAFLD progression, particularly toward the development of hepatic insulin resistance. In the context of insulin signalling, ROS has a dual role, as both a facilitator and inhibitor of the insulin signalling cascade. ROS mediate these effects through redox modifications of cysteine residues affecting phosphatase enzyme activity, stress-sensitive kinases, and metabolic sensors. This review highlights the intricate relationship between redox-sensitive proteins and insulin signalling in the context of fatty liver disease, and to a larger extent, the importance of reactive oxygen species as primary signalling molecules in metabolically active cells

Implications juridiques et éthiques des algorithmes d'intelligence artificielle dans le domaine de la santé

International audienceArtificial Intelligence (AI) is invading our daily lives and the health field, notably to help with diagnosis, makes therapeutic choices or even to aim for precise predictive medicine. Absent from the French bioethics law of July 7, 2011, AI was very present during the "États Généraux" accompanying the revision of the law in 2018. The profusion of ethical guides or recommendations on AI (soft law), motivated by the need to win the trust of users, encourages us to be concerned about their normative force, in connection with the legal texts promulgated since the entry into action on 25 May 2018 of the GDPR (regulation 2016/679/EU general regulation on the protection of personal data). A joint analysis of these texts, of the AI algorithms deployed and of concrete applications in health, enables us to consider the main ethical and legal questions raised in this field: the principle of free and informed consent of the patient faced to the opacity of algorithms, potential risks of discrimination in access to care, public interest or common good expected from research in comparison with risks incurred by opening access to personal data. The responses lead to ethical or regulatory recommendations that are essential for the transparency of these tools: drastic protection of health data, particularly genetic data, and their uses, rigorous research practices to produce reproducible and therefore scientific results, detection of biases before certification of health devices and clarification of the patient information protocol.L'Intelligence Artificielle (IA) envahit nos quotidiens et le domaine de la santé notamment pour aider au diagnostic, faire des choix thérapeutiques ou encore viser une médecine prédictive de précision. Absente de la loi française de bioéthique du 7 juillet 2011, l'IA fut très présente lors des États Généraux accompagnant la révision de la loi en 2018. La profusion de guides ou recommandations éthiques sur l'IA (soft law), motivées par la nécessité de conquérir la confiance des usagers, incite préalablement à se préoccuper de leur vigueur normative, en lien avec les textes juridiques promulgués depuis l'entrée en vigueur le 25 mai 2018 du RGPD (règlement 2016/679/UE règlement général de protection des données personnelles). Une analyse conjointe de ces textes, des algorithmes d'IA déployés et d'applications concrètes en santé permet de poser les principales questions éthiques et légales soulevées dans ce domaine : principe du consentement libre et éclairé du patient face à l'opacité des algorithmes, risques potentiels de discrimination dans l'accès au soin, intérêt public ou bien commun attendu de la recherche en comparaison des risques encourus par l'ouverture de l'accès aux données personnelles. Les réponses conduisent à des recommandations déontologiques ou règlementaires indispensables à la transparence des ces outils : protection drastique des données de santé, notamment génétiques, et de leurs utilisations, rigueur des pratiques de recherche pour produire des résultats reproductibles donc scientifiques, détection des biais avant certification des dispositifs de santé et explicitation du protocole d'information des patients

Renal tubular fluid shear stress promotes endothelial cell activation.

International audienceModified urinary fluid shear stress (FSS) induced by variations of urinary fluid flow and composition is observed in early phases of most kidney diseases. In this study, we hypothesized that changes in urinary FSS represent a tubular aggression that contributes to the development of inflammation, a key event in progression of nephropathies. Human renal tubular cells (HK-2) were exposed to FSS for 30 min at 0.01 Pa. Treatment of human endothelial cells (HMEC-1) with the resulting conditioned medium (FSS-CM) increased C-C chemokine ligand 2 (CCL2) and tumor necrosis factor (TNF)-α protein secretion, increased endothelial vascular adhesion molecule-1 (VCAM-1) mRNA expression and stimulated adhesion of human (THP-1) monocytes to the endothelial monolayer. These effects were TNF-α dependent as they were abolished by neutralization of TNF-α. Interestingly, the origin of TNF-α was not epithelial, but resulted from autocrine endothelial production. However, in contrast to short term FSS, long term FSS (5h) induced the release of the key inflammatory proteins CCL2 and TNF-α directly from tubular cells. In conclusion, these results suggest for the first time that urinary FSS can contribute to the inflammatory state involved in initiation/perpetuation of renal diseases

Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.

When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity

In vivo fatty acid fluxes in HFD-fed HSL^+/− and WT mice.

<p>(A) Plasma parameters of fatty acid fluxes. (B) Rate of radiolabelled fatty acid incorporation in the TG pool of tissues. (C) Total TG content in tissues. Values are means ± SEM. WT mice (▪) (<i>n</i> = 5) and HSL^+/<b>−</b> mice (□) (<i>n</i> = 6). * <i>p</i><0.05, *** <i>p</i><0.001 versus WT mice.</p

Glucose metabolism and insulin sensitivity in mice with reduced HSL activity.

<p>(A) In vivo 2-deoxy-D-[³H] glucose uptake under stimulation by insulin in skeletal muscle (<i>biceps femoris</i>—BF—and <i>soleus</i>) and WAT. (B) Ex vivo glucose oxidation in <i>soleus</i> muscle. (C) Respiratory quotient assessed by indirect calorimetry and expressed as percentage of cumulative relative frequencies (PCRF). EC₅₀ are represented by arrows. (D) In vivo insulin bolus. Variation in plasma glucose 15 min after injection of saline or insulin (a.u., arbitrary unit). (E) Effect of insulin bolus in vivo on hepatic insulin signalling. IRS1, insulin receptor substrate 1; Akt, protein kinase B. (F) Hepatic de novo lipogenesis. Measurement of radiolabelled glucose incorporation in lipid fraction of liver after insulin stimulation. (G) Pyruvate tolerance test. (H) Liver glycogen content assessed in mice starved for 24 h and then refed for 18 h. Values are means ± SEM. WT mice (▪ or ▴) and HSL^+/− mice (□) mice (<i>n</i> = 4–10 in each group). * <i>p</i><0.05, ** <i>p</i><0.01 versus WT mice.</p

Fasting plasma parameters in 12-wk wild type (WT) and HSL^+/− HFD-fed mice and in 12-wk wild type HFD-fed mice treated with vehicle or HSL specific inhibitor (HSLi) for 7 consecutive days.

<p>Values (<i>n</i> = 6–17) are means ± SEM. NEFA, nonesterified fatty acid; QUICKI, quantitative insulin sensitivity check index; RBP4, retinol binding protein 4.</p