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.

Integrins are transmembrane glycoproteins, composed of noncovalently associated ␣ and ␤ subunits, that are involved in cell-extracellular matrix (ECM) 1 and cell-cell interactions (1). Many integrin ␣ chains undergo a post-translational endoproteolytic cleavage. The ␣ 3 , ␣ 5 , ␣ 6 , ␣ 7 , ␣ 8 , ␣ 9 , ␣ v , and ␣ IIb subunits are cleaved in the membrane-proximal extracellular region, resulting in a heavy chain that is disulfide-linked to a membrane spanning light chain (2). The ␣ 4 and ␣ E subunits can also be cleaved, but at unusual positions, near the middle and in the N-terminal region of the molecule, respectively (3, 4). Endoproteolytic cleavage of integrin ␣ subunits occurs at specific sites comprising pairs of basic amino acids.Post-translational proteolysis is a common mechanism required for the synthesis of biologically active proteins in bacteria, fungi, yeast, invertebrates, and mammals (5). However, the role of endoproteolytic cleavage of integrin ␣ subunits is not clear. The cleavage is conserved, not only in different ␣ chains but also across species, suggesting that it might be of functional importance. It has been established, by site-directed mutagenesis of cleavage sites, that uncleaved ␣ IIb ␤ 3 and ␣ 4

We demonstrate that intestinal inflammation caused by high-fat diet is increased by the environmental contaminant benzo[a]pyrene. Our in vivo results indicate that a high-fat diet (HFD) induces a pre-diabetic state in mice compared with animals fed normal chow. HFD increased IL-1betamRNA concentration in the jejunum, colon, and liver, and TNFalpha was increased in the colon and strongly increased in the liver. HFD also increased the expression of other genes related to type 2 diabetes, such as the uncoupling protein UCP2, throughout the bowel and liver, but not in the colon. The treatment of HFD with BaP enhanced the expression of IL-1beta in the liver and TNFalpha throughout the bowel and in the liver. Adding BaP to the diet also caused a significant decrease in the expression of the incretin glucagon-like peptide 1, which plays an important role in insulin secretion. Our results suggest that intestinal inflammation may be involved in the onset of type 2 diabetes and that chronic exposure to environmental polycyclic aromatic hydrocarbons can increase the risk of type 2 diabetes by inducing pro-inflammatory cytokine production.

We showed previously that microtubule disassembly by vinblastine induces the proto-oncogene c-myc in epithelial mammary HBL100 cells. In this study, we demonstrate that vinblastine treatment in these cells, in contrast to what was observed with the colon adenocarcinoma cell line HT29-D4, activated the transcription factor NFkappaB, which has been involved in c-myc regulation. The microtubule disassembly also induced IkappaB degradation. Using transient transfection analysis, we show that the trans-activation of c-myc by vinblastine was decreased when NFkappaB binding sites on c-myc promoter were mutated. Additionally, we demonstrate that microtubule dissolution trans-activated a thymidine kinase-CAT construct containing an NFkappaB binding site at -1180 to -1080 bp relative to the P1 promoter. Thus, vinblastine up-regulates the enhancer activity of the NFkappaB binding site. These results suggest that microtubule disassembly induced by vinblastine can trans-activate the c-myc oncogene through NFkappaB. Taking into consideration the paradoxical roles of both c-myc and NFkappaB in proliferation or apoptosis, this data reveals the complex action mechanism of this microtubule interfering agent.