Resveratrol Increases Glucose Induced GLP-1 Secretion in Mice: A Mechanism which Contributes to the Glycemic Control

Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo

Gut microbiota and diabetes: from pathogenesis to therapeutic perspective

More than several hundreds of millions of people will be diabetic and obese over the next decades in front of which the actual therapeutic approaches aim at treating the consequences rather than causes of the impaired metabolism. This strategy is not efficient and new paradigms should be found. The wide analysis of the genome cannot predict or explain more than 10–20% of the disease, whereas changes in feeding and social behavior have certainly a major impact. However, the molecular mechanisms linking environmental factors and genetic susceptibility were so far not envisioned until the recent discovery of a hidden source of genomic diversity, i.e., the metagenome. More than 3 million genes from several hundreds of species constitute our intestinal microbiome. First key experiments have demonstrated that this biome can by itself transfer metabolic disease. The mechanisms are unknown but could be involved in the modulation of energy harvesting capacity by the host as well as the low-grade inflammation and the corresponding immune response on adipose tissue plasticity, hepatic steatosis, insulin resistance and even the secondary cardiovascular events. Secreted bacterial factors reach the circulating blood, and even full bacteria from intestinal microbiota can reach tissues where inflammation is triggered. The last 5 years have demonstrated that intestinal microbiota, at its molecular level, is a causal factor early in the development of the diseases. Nonetheless, much more need to be uncovered in order to identify first, new predictive biomarkers so that preventive strategies based on pre- and probiotics, and second, new therapeutic strategies against the cause rather than the consequence of hyperglycemia and body weight gain

Molecular characterization of apoptosis induced by CARF silencing in human cancer cells

Collaborator of ARF (CARF) was cloned as an ARF-interacting protein and shown to regulate the p53–p21WAF1–HDM2 pathway, which is central to tumor suppression via senescence and apoptosis. We had previously reported that CARF inhibition in cancer cells led to polyploidy and caspase-dependent apoptosis, however, the mechanisms governing this phenomenon remained unknown. Thus, we examined various cell death and survival pathways including the mitochondrial stress, ataxia telangiectasia mutated (ATM)–ATR, Ras–MAP kinase and retinoblastoma cascades. We found that CARF is a pleiotropic regulator with widespread effects; its suppression affected all investigated pathways. Most remarkably, it protected the cells against genotoxicity; CARF knockdown elicited DNA damage response as evidenced by increased levels of phosphorylated ATM and γH2AX, leading to induction of mitotic arrest and eventual apoptosis. We also show that the CARF-silencing-induced apoptosis in vitro translates to in vivo. In a human tumor xenograft mouse model, treatment of developing tumors with short hairpin RNA (shRNA) against CARF via an adenovirus carrier induced complete suppression of tumor growth, suggesting that CARF shRNA is a strong candidate for an anticancer reagent. We demonstrate that CARF has a vital role in genome preservation and tumor suppression and CARF siRNA is an effective novel cancer therapeutic agent