Sweet taste receptors and glucose metabolism in healthy and T2DM humans

描述(申请人提供)：最近在胃肠道中发现的味觉受体信号元件激起了人们对味觉系统在营养感知和营养新陈代谢中的潜在作用的极大兴奋。组成甜味受体(STR)的G蛋白偶联受体T1R2和T1R3以及参与味觉信号转导的G蛋白Gustducin在人类和其他动物的小肠中均有表达。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耐人寻味的迹象。刺激STR上调肠道钠-葡萄糖转运体(SGLT1)，从而促进肠道对葡萄糖的吸收。此外，由于味觉信号元件在肠道中的L细胞中共表达，这些细胞分泌激素-胰升糖素样肽(GLP)；在食物摄入过程中，刺激STR也会引起GLP的释放。用乳糖醇抑制剂阻断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可提高或降低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、延缓胃排空和抑制肝脏葡萄糖产生而在葡萄糖稳态中发挥关键作用。2型糖尿病(T2 DM)患者的GLP水平降低，提高GLP水平是新的糖尿病治疗方法的靶点。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应用于这一令人兴奋的新领域，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)、摄入葡萄糖的出现率和葡萄糖处置。到目前为止，STR对这些葡萄糖代谢指标的影响还没有在人类身上得到检验。我们建议研究刺激(特异性目标1)和抑制(特异性目标2)甜味感受器对健康受试者和2型糖尿病(T2 DM)患者的GLP和餐后激素释放以及糖代谢指标的影响。这项拟议研究的结果将对膳食糖和非营养性甜味剂对血糖稳态的影响和T2 DM的病因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受体参与餐后葡萄糖代谢和GLP水平的调节，但在T2 DM患者中，STR受体对激活或抑制没有反应 与公共健康相关：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感受器也存在于人类和其他动物的肠腔中。动物研究表明，这些肠道甜味受体可能在从肠道吸收葡萄糖和调节肠道激素分泌方面发挥作用。这些研究将探索这些肠道味觉细胞受体在健康对照组和2型糖尿病患者中的功能意义。

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.