Mechanistic and Metabolic Impacts of Non-Nutritive Sweeteners

非营养性甜味剂的机制和代谢影响

• 批准号: RGPIN-2018-04238
• 负责人: Shearer, Jane
• 金额: $ 3.42万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=712784
• 关键词: Mechanistic; Metabolic; Impacts; Non; Nutritive

OVERVIEW. Novel work from my laboratory shows that the regular use of low-dose, non-caloric artificial sweeteners compounds ubiquitous in the Canadian marketplace and widely believed to reduce daily caloric intake, promote satiety, encourage weight loss and facilitate glucoregulation, unintentionally disrupt the balance of the gut microbiota resulting in distorted glucose metabolism. OBJECTIVES. This grant tests the central hypothesis that aspartame consumption either directly or indirectly (via changes in the gut microbiome and its metabolite production) alters glucose management thus contributing to insulin resistance. It will determine the sites of glucose regulation affected and probe the mechanism(s) or metabolites that are communicating this response. Primary aims are as follows: 1. Determine the impact of chronic aspartame consumption on the gut microbiota and the means by which aspartame heightens the response to a glucose challenge by examining the intrinsic ability of the liver to both consume and produce glucose. 2. Examine the effects of aspartame-induced glucose-intolerance on whole body and tissue specific glucose disposal and insulin action. 3. Establish the contribution of the gut microbiota to aspartame induced alterations in glucose metabolism and its specific impacts on circulating factors. METHODOLOGY. As aspartame is one of the most commonly consumed artificial sweeteners in Canada, predominantly in the form of diet soda, it will be the primary focus. Fundamental studies will elucidate the mechanistic basis of how a commonly consumed sweetener alters host metabolism. The experimental model that will be used is the well-characterized, chronically catheterized, conscious rat. Rats will be fed a chow or high fat diet in combination with either water or low-dose aspartame. Glucose fluxes will be carefully monitored in vivo employing sophisticated isotopic tracers and euglycemic-hyperinsulinemic clamps. These techniques will provide an indication of whether aspartame either directly or indirectly (via alterations in the gut microbiota, altered production of metabolites) contributes to aberrant hepatic glucose production (gluconeogenesis) or declines in peripheral insulin sensitivity. Sequencing will assess the microbiome at both functional and taxonomical levels while extensive serum and fecal metabolomic profiling will uncover gut-host mediators influencing glucose metabolism. IMPACT. This grant will explore the mechanistic basis of artificial sweetener induced metabolic disturbances. Results have the potential to alter current perceptions that aspartame is a harmless food additive and may have far reaching implications for food industry, agriculture (artificial sweeteners are commonly added to animal starter feeds to encourage food consumption and weight gain), medical professionals and legislators alike.

概述。我的实验室的新工作表明，经常使用低剂量、无热量的人工甜味剂化合物在加拿大市场上普遍存在，人们普遍认为它可以减少每日卡路里摄入量，促进饱腹感，鼓励减肥和促进血糖调节，无意中破坏肠道微生物区系的平衡，导致葡萄糖代谢扭曲。 目标。这笔赠款检验了一个中心假设，即阿斯巴甜的摄入直接或间接(通过肠道微生物组及其代谢物产生的变化)改变了血糖管理，从而导致胰岛素抵抗。它将确定受影响的葡萄糖调节位置，并探索传递这种反应的机制(S)或代谢物。主要目标如下： 1.通过检查肝脏消耗和产生葡萄糖的内在能力，确定长期摄入阿斯巴甜对肠道微生物区系的影响，以及阿斯巴甜提高对葡萄糖挑战的反应的方法。 2.检测阿斯巴甜诱导的糖耐量异常对机体和组织特异性糖代谢及胰岛素作用的影响。 3.确定肠道微生物区系在阿斯巴甜引起的糖代谢改变中的作用及其对循环因子的具体影响。 方法论。由于阿斯巴甜是加拿大最常用的人工甜味剂之一，主要以无糖苏打水的形式存在，因此它将是主要的关注点。基础研究将阐明一种常用甜味剂如何改变宿主新陈代谢的机制基础。将使用的实验模型是具有良好特征的、长期导尿的清醒大鼠。大鼠将被喂以食物或高脂肪饮食，并配以水或低剂量的阿斯巴甜。将使用复杂的同位素示踪剂和正常血糖-高胰岛素钳夹在体内仔细监测葡萄糖的流动。这些技术将提供阿斯巴甜是否直接或间接(通过肠道微生物区系的改变，代谢物产生的改变)导致肝脏葡萄糖产生异常(糖异生)或外周胰岛素敏感性下降的指示。测序将在功能和分类水平上评估微生物组，而广泛的血清和粪便代谢组谱将揭示影响葡萄糖代谢的肠道宿主介体。 冲击力。这笔赠款将探索人工甜味剂引起代谢紊乱的机制基础。研究结果有可能改变目前人们的看法，即阿斯巴甜是一种无害的食品添加剂，并可能对食品工业、农业(人工甜味剂通常添加到动物起始饲料中，以鼓励食物消费和体重增加)、医疗专业人员和立法者等产生深远影响。