Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, T6G 2E1, AB, Canada.
Department of Pediatrics, University of Alberta, Edmonton, T6G 2E1, AB, Canada.
Trials. 2021 Feb 17;22(1):148. doi: 10.1186/s13063-021-05060-8.
Accumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Pre-clinical animal models have established that the addition of fiber to metformin monotherapy improves glucose tolerance. However, possible synergistic effects of combination therapy (metformin plus fiber) have not been investigated in humans. Moreover, the underlying mechanisms of synergy have yet to be elucidated. The aim of this study is to compare in adolescents with obesity the metabolic effects of metformin and fermentable fibers in combination with those of metformin or fiber alone. We will also determine if therapeutic responses correlate with compositional and functional features of the gut microbiome.
This is a parallel three-armed, double-blinded, randomized controlled trial. Adolescents (aged 12-18 years) with obesity, insulin resistance (IR), and a family history of type 2 diabetes mellitus (T2DM) will receive either metformin (850 mg p.o. twice/day), fermentable fibers (35 g/day), or a combination of metformin plus fiber for 12 months. Participants will be seen at baseline, 3, 6, and 12 months, with a phone follow-up at 1 and 9 months. Primary and secondary outcomes will be assessed at baseline, 6, and 12 months. The primary outcome is change in IR estimated by homeostatic model assessment of IR; key secondary outcomes include changes in the Matsuda index, oral disposition index, body mass index z-score, and fat mass to fat-free mass ratio. To gain mechanistic insight, endpoints that reflect host-microbiota interactions will also be assessed: obesity-related immune, metabolic, and satiety markers; humoral metabolites; and fecal microbiota composition, short-chain fatty acids, and bile acids.
This study will compare the potential metabolic benefits of fiber with those of metformin in adolescents with obesity, determine if metformin and fiber act synergistically to improve IR, and elucidate whether the metabolic benefits of metformin and fiber associate with changes in fecal microbiota composition and the output of health-related metabolites. This study will provide insight into the potential role of the gut microbiome as a target for enhancing the therapeutic efficacy of emerging treatments for T2DM prevention.
ClinicalTrials.gov NCT04578652 . Registered on 8 October 2020.
越来越多的证据表明，二甲双胍和可发酵纤维的代谢作用部分是通过对肠道微生物组的组成和代谢功能的不同或重叠影响来介导的。临床前动物模型已经证实，在二甲双胍单药治疗的基础上添加纤维可以改善葡萄糖耐量。然而，联合治疗（二甲双胍加纤维）的协同作用在人类中尚未得到研究。此外，协同作用的潜在机制尚未阐明。本研究旨在比较肥胖青少年中二甲双胍和可发酵纤维联合应用与单独应用二甲双胍或纤维的代谢效果。我们还将确定治疗反应是否与肠道微生物组的组成和功能特征相关。
这是一项平行的、三臂、双盲、随机对照试验。患有肥胖症、胰岛素抵抗（IR）和 2 型糖尿病（T2DM）家族史的青少年（12-18 岁）将接受二甲双胍（850mg 口服，每日 2 次）、可发酵纤维（35g/天）或二甲双胍加纤维联合治疗 12 个月。参与者将在基线、3、6 和 12 个月时接受检查，并在 1 和 9 个月时进行电话随访。主要和次要结局将在基线、6 和 12 个月时进行评估。主要结局是通过稳态模型评估的胰岛素抵抗变化；关键次要结局包括 Matsuda 指数、口服处置指数、体重指数 z 评分和脂肪质量与无脂肪质量比的变化。为了获得机制上的见解，还将评估反映宿主-微生物群相互作用的终点：肥胖相关免疫、代谢和饱腹感标志物；体液代谢物；粪便微生物群组成、短链脂肪酸和胆汁酸。
本研究将比较纤维与二甲双胍在肥胖青少年中的潜在代谢益处，确定二甲双胍和纤维是否协同作用以改善 IR，并阐明二甲双胍和纤维的代谢益处是否与粪便微生物群组成和健康相关代谢物的产生变化相关。本研究将为肠道微生物群作为增强新兴 2 型糖尿病预防治疗疗效的靶点提供见解。
ClinicalTrials.gov NCT04578652。于 2020 年 10 月 8 日注册。
