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Saint-Sauveur-en-Rue, France

Waget A.,French Institute of Health and Medical Research | Cabou C.,French Institute of Health and Medical Research | Masseboeuf M.,French Institute of Health and Medical Research | Cattan P.,University Paris Diderot | And 13 more authors.
Endocrinology | Year: 2011

Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4enzymeis highly expressedonthe surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r-/- and Gipr -/- mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an iv infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9 -39) and in Glp1r -/- and Gipr-/- mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis. Copyright © 2011 by The Endocrine Society. Source

Amar J.,Toulouse University Hospital Center | Amar J.,French Institute of Health and Medical Research | Chabo C.,French Institute of Health and Medical Research | Waget A.,French Institute of Health and Medical Research | And 13 more authors.
EMBO Molecular Medicine | Year: 2011

A fat-enriched diet modifies intestinal microbiota and initiates a low-grade inflammation, insulin resistance and type-2 diabetes. Here, we demonstrate that before the onset of diabetes, after only one week of a high-fat diet (HFD), live commensal intestinal bacteria are present in large numbers in the adipose tissue and the blood where they can induce inflammation. This translocation is prevented in mice lacking the microbial pattern recognition receptors Nod1 or CD14, but overtly increased in Myd88 knockout and ob/ob mouse. This 'metabolic bacteremia' is characterized by an increased co-localization with dendritic cells from the intestinal lamina propria and by an augmented intestinal mucosal adherence of non-pathogenic Escherichia coli. The bacterial translocation process from intestine towards tissue can be reversed by six weeks of treatment with the probiotic strain Bifidobacterium animalis subsp. lactis 420, which improves the animals' overall inflammatory and metabolic status. Altogether, these data demonstrate that the early onset of HFD-induced hyperglycemia is characterized by an increased bacterial translocation from intestine towards tissues, fuelling a continuous metabolic bacteremia, which could represent new therapeutic targets. © 2011 EMBO Molecular Medicine. Source

Briand F.,Physiogenex SAS | Thieblemont Q.,Physiogenex SAS | Burcelin R.,French Institute of Health and Medical Research | Sulpice T.,Physiogenex SAS
Diabetes, Obesity and Metabolism | Year: 2012

Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glycaemic control in type 2 diabetes, but their benefits on reverse cholesterol transport (RCT) remain unknown. We evaluated the effects of DPP-4i sitagliptin 500 mg/kg/day on RCT in obese insulin-resistant CETP-apoB100 transgenic mice. Metformin 300 mg/kg/day orally was used as a reference compound. Both metformin and sitagliptin showed the expected effects on glucose parameters. Although no significant effect was observed on total cholesterol and high-density lipoprotein (HDL) cholesterol levels, sitagliptin, but not metformin, increased faecal cholesterol mass excretion by 132% (p < 0.001 vs. vehicle), suggesting a potent effect on cholesterol metabolism. Mice were then injected i.p. with 3H-cholesterol labelled macrophages to measure RCT over 48 h. Compared with vehicle, sitagliptin significantly increased macrophage-derived 3H-cholesterol faecal excretion by 39%. Administration of 14C-cholesterol labelled olive oil orally showed a significant reduction of 14C-tracer plasma appearance over time with sitagliptin, indicating that this drug promotes RCT through reduced intestinal cholesterol absorption. © 2012 Blackwell Publishing Ltd. Source

Stenman L.K.,DuPont Company | Waget A.,Toulouse University Hospital Center | Garret C.,Toulouse University Hospital Center | Briand F.,Physiogenex SAS | And 3 more authors.
Diabetology and Metabolic Syndrome | Year: 2015

Background: Gut microbiota is now known to control glucose metabolism. Previous studies have shown that probiotics and prebiotics may improve glucose metabolism, but their effects have not been studied in combination with drug therapy. The aim of this study was to investigate whether probiotics and prebiotics combined with drug therapy affect diabetic outcomes. Methods: Two different study designs were used to test gut microbiota modulating treatments with metformin (MET) or sitagliptin (SITA) in male C57Bl/6J mice. In Design 1, diabetes was induced with four-week feeding with a ketogenic, 72 kcal% fat diet with virtually no carbohydrates. Mice were then randomly divided into four groups (n = 10 in each group): (1) vehicle, (2) Bifidobacterium animalis ssp. lactis 420 (B420) (109 CFU/day), (3) MET (2 mg/mL in drinking water), or (4) MET + B420 (same doses as in the MET and B420 groups). After another 4 weeks, glucose metabolism was assessed with a glucose tolerance test. Fasting glucose, fasting insulin and HOMA-IR were also assessed. In Design 2, mice were fed the same 72 kcal% fat diet to induce diabetes, but they were simultaneously treated within their respective groups (n = 8 in each group): (1) non-diabetic healthy control, (2) vehicle, (3) SITA [3 mg/(kg∗day)] (4) SITA with prebiotic polydextrose (PDX) (0.25 g/day), (5) SITA with B420 (109 CFU/day), and (6) SITA + PDX + B420. Glucose metabolism was assessed at 4 weeks, and weight development was monitored for 6 weeks. Results: In Design 1, with low-dose metformin, mice treated with B420 had a significantly lower glycemic response (area under the curve) (factorial experiment, P = 0.002) and plasma glucose concentration (P = 0.02) compared to mice not treated with B420. In Design 2, SITA + PDX reduced glycaemia in the oral glucose tolerance test significantly more than SITA only (area under the curve reduced 28 %, P < 0.0001). In addition, B420, PDX or B420+PDX, together with SITA, further decreased fasting glucose concentrations compared to SITA only (-19.5, -40 and -49 %, respectively, P < 0.01 for each comparison). The effect of PDX may be due to its ability to increase portal vein GLP-1 concentrations together with SITA (P = 0.0001 compared to vehicle) whereas SITA alone had no statistically significant effect compared to vehicle (P = 0.14). Conclusions: This study proposes that combining probiotics and/or prebiotics with antidiabetic drugs improves glycemic control and insulin sensitivity in mice. Mechanisms could be related to incretin secretion. © 2015 Stenman et al. Source

Briand F.,Physiogenex SAS | Thieblemont Q.,Physiogenex SAS | Muzotte E.,Physiogenex SAS | Burr N.,Physiogenex SAS | And 3 more authors.
European Journal of Pharmacology | Year: 2014

Cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib differentially alter LDL- and HDL-cholesterol levels, which might be related to the potency of each drug to inhibit CETP activity. We evaluated the effects of both drugs at similar levels of CETP inhibition on macrophage-to-feces reverse cholesterol transport (RCT) in hamsters. In normolipidemic hamsters, both anacetrapib 30 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~60%. After injection of 3H-cholesteryl oleate labeled HDL, anacetrapib and dalcetrapib reduced HDL-cholesteryl esters fractional catabolic rate (FCR) by 30% and 26% (both P<0.001 vs. vehicle) respectively, but only dalcetrapib increased HDL-derived 3H-tracer fecal excretion by 30% (P<0.05 vs. vehicle). After 3H-cholesterol labeled macrophage intraperitoneal injection, anacetrapib stimulated 3H-tracer appearance in HDL, but both drugs did not promote macrophage-derived 3H-tracer fecal excretion. In dyslipidemic hamsters, both anacetrapib 1 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~65% and reduced HDL-cholesteryl ester FCR by 36% (both P<0.001 vs. vehicle), but only anacetrapib increased HDL-derived 3H-tracer fecal excretion significantly by 39%. After 3H-cholesterol labeled macrophage injection, only anacetrapib 1 mg/kg QD stimulated macrophage-derived 3H-tracer appearance in HDL. These effects remained weaker than those observed with anacetrapib 60 mg/kg QD, which induced a maximal inhibition of CETP and stimulation of macrophage-derived 3H-tracer fecal excretion. In contrast, dalcetrapib 200 mg/kg BID reduced macrophage-derived 3H-tracer fecal excretion by 23% (P<0.05 vs. vehicle). In conclusion, anacetrapib and dalcetrapib differentially alter HDL metabolism and RCT in hamsters. A stronger inhibition of CETP may be required to promote macrophage-to-feces reverse cholesterol transport in dyslipidemic hamsters. © 2014 Elsevier B.V. Source

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