Sweet taste receptors and glucose metabolism in healthy and T2DM humans

健康人和 T2DM 人类的甜味受体和葡萄糖代谢

• 批准号: 8189922
• 负责人: KAREN L TEFF
• 金额: $ 20.75万
• 依托单位: MONELL CHEMICAL SENSES CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189922
• 关键词: Animal Model; Animals; Appearance; Area; Beryllium; Clinical; Cobalt; Data; Diabetes Mellitus; Dietary Sugars; Etiology; Exhibits; Experimental Designs; Food; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gastrointestinal tract structure; Gastroparesis; Genetic; Glucagon; Glucose; Glucose Transporter; Hepatic; Hormonal; Hormones; Human; Indium; Individual; Ingestion; Insulin; Intestinal Absorption; Intestinal Hormones; Intestines; Knock-out; L Cells; Measures; Methodology; Monitor; Non-Insulin-Dependent Diabetes Mellitus; Patients; Plasma; Play; Receptor Cell; Receptor Inhibition; Receptor Signaling; Regulation; Reporting; Role; Signal Transduction; Small Intestines; Sodium; Solutions; Sweetening Agents; System; Taste Perception; Therapeutic; Tongue; Up-Regulation; absorption; blood glucose regulation; detection of nutrient; diabetic; fasting glucose; gastric inhibitory polypeptide receptor; glucagon-like peptide; glucose disposal; glucose metabolism; glucose production; hormone metabolism; indexing; inhibitor/antagonist; interest; nutrient metabolism; prevent; rat Gnat3 protein; receptor; response; stable isotope; sugar; sweet taste perception; trichlorosucrose

DESCRIPTION (provided by applicant): The recent identification of taste-receptor signaling elements in the gastrointestinal tract has fueled tremendous excitement with regards to the potential role of the taste system in nutrient sensing and nutrient metabolism. The G-protein coupled receptors, T1R2 and T1R3 which form the sweet taste receptor (STR) and gustducin, the G protein involved in taste signal transduction are all expressed in the small intestine of humans and other animals. Although the functional significance of these receptors in humans has yet to be demonstrated, recent animal model studies provide intriguing indications. Stimulation of the STR upregulates the intestinal sodium-glucose transporter (SGLT1), thereby, promoting glucose absorption from the intestinal lumen. In addition, because the taste signaling elements are co-expressed in the intestinal L-cells which secrete the hormone, glucagon-like peptide (GLP); during food ingestion, stimulation of the STR also elicits the release of GLP. Blockade of the STR with the inhibitor lactisole or genetic knock out of gustducin or T1R3 inhibits upregulation of SGLT1 and the GLP response to glucose. These data provide evidence for a role of the STR in regulating glucose absorption and intestinal hormone release. The possibility that the STR could increase or decrease GLP levels is of significant clinical interest as GLP plays a critical role in glucose homeostasis by stimulating insulin release, delaying gastric emptying and inhibiting hepatic glucose production. Patients with type 2 diabetes mellitus (T2DM) exhibit blunted GLP levels and enhancing GLP is the target of new diabetes therapeutics. In the proposed studies, we will bring our expertise in glucose metabolism and apply it to this exciting new area by using stable isotope methodologies to monitor post-prandial hormonal release as well as endogenous glucose production (EGP),the rate of appearance of ingested glucose and glucose disposal. To date, the effect of the STR on these indices of glucose metabolism have not been examined in humans. We are proposing to investigate the effects of stimulating (Specific Aim 1) and inhibiting (Specific Aim 2) the sweet taste receptor on GLP and post-prandial hormone release as well as indices of glucose metabolism in healthy subjects and patients with Type 2 diabetes mellitus (T2DM). Findings from the proposed studies will have important clinical implications with respect to the impact of dietary sugars and non- nutritive sweeteners on glucose homeostasis and the etiology of T2DM. Our overall hypothesis is that in healthy subjects, the STR receptor is involved in the regulation of post-prandial glucose metabolism and GLP levels but in T2DM, the STR receptor is unresponsive to activation or inhibition PUBLIC HEALTH RELEVANCE: Exciting new findings demonstrate that sweet taste receptors, originally thought to be located specifically on the tongue, are also present in the lumen of the small intestine of humans and other animals. Animal's studies suggest that these intestinal sweet taste receptors may play a role in glucose absorption from the intestine and regulation of intestinal hormone secretion. The proposed studies will explore the functional significance of these intestinal taste cell receptors in healthy control subjects and type 2 diabetes mellitus patients.

描述（由申请人提供）：最近对胃肠道中味觉受体信号元件的鉴定激起了人们对味觉系统在营养感知和营养代谢中的潜在作用的巨大兴奋。形成甜味受体 (STR) 的 G 蛋白偶联受体 T1R2 和 T1R3 以及味觉素（参与味觉信号转导的 G 蛋白）均在人类和其他动物的小肠中表达。尽管这些受体在人类中的功能意义尚未得到证实，但最近的动物模型研究提供了有趣的迹象。 STR 的刺激会上调肠道钠葡萄糖转运蛋白 (SGLT1)，从而促进肠腔中的葡萄糖吸收。此外，由于味觉信号元件在分泌激素胰高血糖素样肽（GLP）的肠道L细胞中共表达；在食物摄入过程中，刺激 STR 也会引起 GLP 的释放。用抑制剂lactisole 阻断STR 或基因敲除gustducin 或T1R3 可抑制SGLT1 的上调和GLP 对葡萄糖的反应。这些数据为 STR 在调节葡萄糖吸收和肠道激素释放中的作用提供了证据。 STR 可能增加或降低 GLP 水平的可能性具有重要的临床意义，因为 GLP 通过刺激胰岛素释放、延迟胃排空和抑制肝葡萄糖产生，在葡萄糖稳态中发挥关键作用。 2 型糖尿病 (T2DM) 患者的 GLP 水平较低，而增强 GLP 是新糖尿病治疗的目标。在拟议的研究中，我们将把我们在葡萄糖代谢方面的专业知识运用到这个令人兴奋的新领域，通过使用稳定同位素方法来监测餐后激素释放以及内源性葡萄糖产生（EGP）、摄入葡萄糖和葡萄糖处理的出现率。迄今为止，STR 对这些葡萄糖代谢指标的影响尚未在人体中得到检验。我们拟研究刺激（具体目标 1）和抑制（具体目标 2）甜味受体对健康受试者和 2 型糖尿病 (T2DM) 患者的 GLP 和餐后激素释放以及葡萄糖代谢指标的影响。拟议研究的结果将对膳食糖和非营养性甜味剂对葡萄糖稳态的影响以及 T2DM 的病因学产生重要的临床意义。我们的总体假设是，在健康受试者中，STR 受体参与餐后葡萄糖代谢和 GLP 水平的调节，但在 T2DM 中，STR 受体对激活或抑制没有反应 公共卫生相关性：令人兴奋的新发现表明，最初被认为专门位于舌头上的甜味受体也存在于人类和其他动物的小肠腔中。动物研究表明，这些肠道甜味受体可能在肠道吸收葡萄糖和调节肠道激素分泌中发挥作用。拟议的研究将探讨这些肠道味觉细胞受体在健康对照受试者和 2 型糖尿病患者中的功能意义。