La recherche clinique au service de nouvelles thérapeutiques dans le traitement du diabète de type 2 (cas des inhibiteurs des co-transporteurs sodium-glucose de type 2)

Le diabète représente une véritable "pandémie" puisqu'il touche environ 220 millions de personnes dans le monde et cette incidence devrait doubler dans les 20 prochaines années. Traiter cette pathologie est donc un enjeu de santé publique. Un important arsenal thérapeutique existe mais les classes médicamenteuses mises à disposition des patients présentent de nombreux effets indésirables et les patients gardent un mauvais contrôle de leur glycémie à long terme. Afin d'améliorer cette prise en charge, les chercheurs se sont interessés à une nouvelle cible thérapeutique: les co-transporteurs sodium-glucose de type 2 (SGLT2 ). Ils ont démontré lors d'essais cliniques, qu'en inhibant les SGLT2, les patients présentaient une amélioration de leur glycémie et une diminution de leur masse corporelle. Les molécules inhibitrices des SGLT2 les plus prometteuses (la dapagliflozine, le BI 10773 et la canagliflozine) sont actuellement en phase 3 de leur développement pharmaceutique.With 220 million people affected worldwide and an occurrence that should double within the next 20 years, diabetes represents a true pandemic disease. Treating this pathology is a public health challenge. A large number of therapeutic means exist but the medicinal classes that are made available to the patients present negative side effects and the patients can hardly control their glycemia on the long term. In order to improve the patient condition, researchers have investigated a novel therapeutic target: type 2 sodium-glucose co-transporters (SGLT2 ). They have shown through clinical trials that, by inhibiting SGLT2, patients could improve their glycemia and loose weight. The most promising molecules inhibiting SGLT2 (dapagliflozine, BI 10773 and canagliflozine) are currently in phase 3 of pharmaceutical development.LYON1-BU Santé (693882101) / SudocRENNES1-BU Santé (352382103) / SudocSudocFranceF

Fasting plasma chenodeoxycholic acid and cholic acid concentrations are inversely correlated with insulin sensitivity in adults

<p>Abstract</p> <p>Background</p> <p>Accumulating data suggest a novel role for bile acids (BAs) in modulating metabolic homeostasis. BA treatment has been shown to improve glucose tolerance and to increase energy expenditure in mice. Here, we investigated the relationship between fasting plasma BAs concentrations and metabolic parameters in humans.</p> <p>Findings</p> <p>Fasting plasma glucose, insulin and lipid profile were measured in 14 healthy volunteers, 20 patients with type 2 diabetes (T2D), and 22 non-diabetic abdominally obese subjects. Insulin sensitivity was also assessed by the determination of the glucose infusion rate (GIR) during a hyperinsulinemic-euglycemic clamp in a subgroup of patients (9 healthy and 16 T2D subjects). Energy expenditure was measured by indirect calorimetry. Plasma cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) concentrations were analyzed by gas chromatograph-mass spectrometry. In univariable analysis, a positive association was found between HOMA-IR and plasma CDCA (β = 0.09, p = 0.001), CA (β = 0.03, p = 0.09) and DCA concentrations (β = 0.07, p < 0.0001). Spearman analysis retrieved an inverse relationship between plasma CDCA (r = -0.44, p = 0.03), CA (r = -0.65, p = 0.001) and the GIR. HOMA-IR remained positively associated with CDCA (β = 0.11, p = 0.01), CA (β = 0.04, p = 0.01) and DCA (β = 0.06, p = 0.007) in multivariable analysis, after adjustment for age, gender, BMI, HbA1C and plasma lipid parameters. In contrast, HbA1c, energy expenditure and plasma lipid concentrations were not correlated with plasma BAs levels in multivariable analysis.</p> <p>Conclusions</p> <p>Both plasma CDCA, CA and DCA concentrations were negatively associated with insulin sensitivity in a wide range of subjects.</p

A combined natural supplement lowers LDL cholesterol in subjects with moderate untreated hypercholesterolemia: A randomized placebo-controlled trial

Objective: To investigate the effect of a natural cholesterol-lowering supplement (NCLS) containing red yeast rice, policosanols and artichoke leaf extracts on blood lipid concentrations as well as on safety parameters when given over 16 weeks in 100 volunteers with untreated moderate hypercholesterolemia, in a randomized, double-blind, placebo-controlled trial. Results: Reduction of primary outcome low-density lipoprotein cholesterol [-0.22 g/L (95% confidence interval, CI:-0.31 to-0.12) corresponding to-14.3% from baseline (95% CI:-21.5 to-7.2) compared to placebo], as well as total cholesterol, apolipoprotein B100 and apolipoprotein B100/apolipoprotein A-I ratio, were observed after 16 weeks of supplementation with NCLS. These effects were already observed at Week 4 and 10 of supplementation. No significant changes were observed in high-density lipoprotein, triacylglycerol, creatine kinase, lactate dehydrogenase and coenzyme Q10 levels, as well as in markers of liver and renal function. Conclusions: The NCLS was effective in reducing low-density lipoprotein cholesterol and apolipoprotein B100 in subjects with moderate hypercholesterolemia, without modifying safety parameters. © 2013 Informa UK Ltd. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Fatty liver index is a strong predictor of changes in glycemic status in people with prediabetes: The IT-DIAB study

International audienceBACKGROUND & AIMS:In patients at metabolic risk, nonalcoholic fatty liver disease is a strong and highly prevalent predictor for type 2 diabetes. Its assessment in clinical practice is not easy but the fatty liver index (FLI) could be used as a surrogate. Here, we studied the association between the FLI and the conversion to new-onset diabetes (NOD) or prediabetes reversion in patients with prediabetes.METHODS:The IT-DIAB observational study included 389 individuals with prediabetes, defined as fasting plasma glucose (FPG) between 110 and 125 mg/dL. NOD conversion was defined as a first FPG value ≥ 126 mg/dL and prediabetes reversion as a first FPG value < 110 mg/dL. The associations of both events with baseline FLI were studied separately using multivariate Cox models.RESULTS:After a median follow-up of 3.9 years (range 0.1-6.1), 138 individuals (35.5%) converted to NOD. FLI was associated with a higher risk of NOD conversion (unadjusted HR per SD = 1.54, 95%CI 1.27-1.86, p<0.0001), even after multiple adjustment on FPG, HbA1c and diabetes risk score (adjusted HR per SD 1.31, 95%CI 1.07-1.61, p = 0.008). FLI was also associated with prediabetes reversion: adjusted HR per SD = 0.85, 95%CI 0.75-0.96, p = 0.0077. Changes in FLI were significantly associated with changes in FPG during follow-up (p<0.0001). When compared to a full model including the diabetes risk score, FPG, HbA1C and FLI, only HbA1C added a significant prediction information (AUROC: 72.8% for full model vs 69.4% for the model without HbA1C; p = 0.028), while the removal of FLI to the full model did not alter its predictive value (AUROC 72.2%). The predictive value for NOD conversion was not significantly better for HOMA-IR compared to FLI (AUROC: 69.3 vs 63.7%, p = 0.067).CONCLUSIONS:FLI is a simple, practical score to further stratify the risk of conversion to NOD or the possibility of prediabetes reversion in clinical practice, independently of classical glucose parameters.TRIAL REGISTRATION:ClincialTrials.gov number NCT01218061 and NCT01432509