Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer
Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer
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DOI：
10.1111/dom.13272
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发表时间：
2018-07-01
影响因子：
5.8
通讯作者：
Knop, Filip K.
中科院分区：
文献类型：
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作者：
Bronden, Andreas;Mikkelsen, Kristian;Knop, Filip K.
AIM Sevelamer是一种用于治疗高磷血症的不可吸收的胺基树脂，已被证明具有显著的胆汁酸结合潜力以及对脂肪和葡萄糖代谢的有益影响。本研究旨在探讨西维拉姆对2型糖尿病患者的降糖作用及其作用机制(S)。材料与方法采用双盲随机对照试验，将30例2型糖尿病患者随机分为西维拉姆组(n=20)和安慰剂组(n=10)。参与者在基线和治疗7天后接受标准化的4小时液体餐测试。主要观察指标为血浆胰高血糖素样肽-1的漂移，按曲线下面积测量。此外，采血测定血糖、血脂、葡萄糖依赖的促胰岛素多肽、C-肽、胰升糖素、成纤维细胞生长因子-19、胆囊素和胆汁酸。结果西维拉姆显著降低了安慰剂校正后的血糖，伴随成纤维细胞生长因子-19浓度降低，胆汁酸从头合成增加，向更亲水的胆酸池转变，并增加了脂肪生成。胰升糖素样肽-1对胰岛素、胰升糖素或胃排空的影响不明显，这表明这种胰岛素激素对西维拉姆的降糖作用贡献有限。此外，未观察到西维拉姆对肠道微生物区系组成或静息能量消耗的影响。结论西维拉姆降低2型糖尿病患者血糖浓度的机制似乎与降低肠道和肝脏胆汁酸介导的法尼西酮X受体激活有关。
Aims Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes.Materials and Methods In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and after 7 days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed.Results Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which points to a limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed.Conclusions Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.