磺脲类药物可致高风险心脏病

最新研究显示，治疗老年人2型糖尿病的磺脲类药物在降低血糖水平的同时，可致比其他服用甲福明二甲双胍的糖尿病患者有较高的心脏病风险。研究人员在这项超过8，500名65岁或以上的2型糖尿病患者参加的研究中发现，服用磺脲类的患者出现心脏病发作以及心血管事件的风险是12．4％，然而服用甲福明二甲双胍的患者仅出现心脏及血管问题的风险是10．4％。除此之外。研究指出服用磺脲类的患者可能会更早出现心脏病。上述研究是在美国糖尿病协会的年度会议中报道。

Metformin induces apoptosis of pancreatic cancer cells

AIM:To assess the role and mechanism of metformin in inducing apoptosis of pancreatic cancer cells.METHODS:The human pancreatic cancer cell lines ASPC-1,BxPc-3,PANC-1 and SW1990 were exposed to metformin.The inhibition of cell proliferation and colony formation via apoptosis induction and S phase arrest in pancreatic cancer cell lines of metformin was tested.RESULTS:In each pancreatic cancer cell line tested,metformin inhibited cell proliferation in a dose dependent manner in MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays).Flow cytometric analysis showed that metformin reduced the number of cells in G1 and increased the percentage of cells in S phase as well as the apoptotic fraction.Enzymelinked immunosorbent assay(ELISA) showed that metformin induced apoptosis in all pancreatic cancer cell lines.In Western blot studies,metformin induced poly-ADP-ribose polymerase(PARP) cleavage(an indicator of caspase activation) in all pancreatic cancer cell lines.The general caspase inhibitor(VAD-fmk) completely abolished metformin-induced PARP cleavage and apoptosis in ASPC-1 BxPc-3 and PANC-1,the caspase-8 specific inhibitor(IETD-fmk) and the caspase-9 specific inhibitor(LEHD-fmk) only partially abrogated metformin-induced apoptosis and PARP cleavage in BxPc-3 and PANC-1 cells.We also observed that metformin treatment dramatically reduced epidermal growth factor receptor(EGFR) and phosphorylated mitogen activated protein kinase(P-MAPK) in both a time-and dose-dependent manner in all cell lines tested.CONCLUSION:Metformin significantly inhibits cell proliferation and apoptosis in all pancreatic cell lines.And the metformin-induced apoptosis is associated with PARP cleavage,activation of caspase-3,-8,and-9 in a time-and dose-dependent manner.Hence,both caspase-8 and-9-initiated apoptotic signaling pathways contribute to metformin-induced apoptosis in pancreatic cell lines.

Intestinal permeability of metformin using single-pass intestinal perfusion in rats

AIM： To characterize the intestinal transport and mechanism of metformin in rats and to investigate whether or not metformin is a substrate for P-glycoprotein （P-gp）. METHODS： The effective intestinal permeability of metformin was investigated using single-pass intestinal perfusion （SPIP） technique in male Waster rats. SPIP was performed in three isolated intestinal segments （duodenum, jejunum and ileum） at the same concentration of metformin （50 μg/mL） to test if the intestinal transport of metformin exhibited site- dependent changes, and in a same isolated intestinal segment （duodenal segment） at three different concentrations of metformin （10, 50, 200 μg/mL） to test if the intestinal transport of metformin exhibited concentration-dependent changes. Besides, P-gp inhibitor verapamil （400 μg/mL） was co-perfused with metformin （50 μg/mL） in the duodenum segment to find out if the intestinal absorption of metformin was affected by P-gp exiting along the gastrointestinal track. Stability studies were conducted to ensure that the loss of metformin could be attributed to intestinal absorption. RESULTS： The effective permeability values （Peff） of metformin in the jejunum and ileum at 50μg/mL were significantly lower than those in the duodenum at the same concentration. Besides, Peff values in the duodenum at high concentration （200 μg/mL） were found to be significantly lower than those at low and medium concentrations （10 and 50 μg/mL）. Moreover the coperfusion with verapamil did not increase the Peff value of metformin at 50 μg/mL in the duodenum.CONCLUSION： Metformin could be absorbed from the whole intestine, with the main absorption site at duodenum. This concentration-dependent permeability behavior in the duodenum indicates that metformin is transported by both passive and active carrier-mediated saturable mechanism. The Peff value can not be increased by co-perfusion with verapamil, indicating that absorption of metformin is not efficiently transported by P-gp in the gut wall. Furthermore metformin is neither a substrate nor an inducer of P-gp. Based on the Peff values obtained in the present study and using established relationships, the human fraction dose absorbed for metformin is estimated to be 74%-90% along human intestine.