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: 8313879
• 负责人: KAREN L TEFF
• 金额: $ 18.42万
• 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/8313879
• 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

描述（由申请人提供）：胃肠道中最近鉴定的味觉受体信号传导元素，就味觉系统在营养感应和营养代谢中的潜在作用方面引起了极大的兴奋。 G蛋白偶联受体T1R2和T1R3形成了甜味受体（STR）和Gustducin，涉及味觉信号转导的G蛋白都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明，但最近的动物模型研究提供了有趣的指示。 Str的刺激上调肠道钠 - 葡萄糖转运蛋白（SGLT1），从而促进肠腔中的葡萄糖吸收。另外，由于味觉信号传导元件在分泌激素的肠L细胞中共表达，因此胰高血糖素样肽（GLP）；在食物摄入期间，刺激STR还会引起GLP的释放。用抑制剂乳酸或遗传敲除古斯杜丁蛋白或T1R3的遗传抑制作用会抑制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激素释放中的作用提供了证据。 STR可能会增加或降低GLP水平的可能性具有显着的临床兴趣，因为GLP通过刺激胰岛素释放，延迟胃排空并抑制肝葡萄糖的产生，在葡萄糖稳态中起关键作用。 2型糖尿病（T2DM）的患者表现出钝性的GLP水平，而GLP的增强是新型糖尿病疗法的靶标。在拟议的研究中，我们将通过使用稳定的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），摄入的葡萄糖和葡萄糖分配的外观速度，将其应用于葡萄糖代谢方面的专业知识，并将其应用于这一令人兴奋的新领域。迄今为止，尚未在人类中检查STR对这些葡萄糖代谢指数的影响。我们提议研究刺激的影响（特定目标1）并抑制（特定目标2）在健康受试者和2型糖尿病类型患者中，GLP和丙糖代谢释放的甜味受体以及葡萄糖代谢的指标（T2DM）。拟议研究的结果将对饮食糖和非营养甜味剂对葡萄糖稳态的影响以及T2DM病因的影响具有重要的临床意义。我们的总体假设是，在健康受试者中，STR受体参与了餐后葡萄糖代谢和GLP水平的调节，但是在T2DM中，STR受体对激活或抑制无反应。