Sweet taste receptors and glucose metabolism in healthy and T2DM humans

描述（由申请人提供）：最近在胃肠道中味觉受体信号元件的鉴定，对味觉系统在营养感知和营养代谢中的潜在作用产生了巨大的兴奋。构成甜味受体（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都在人类和其他动物的小肠中表达。虽然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。刺激STR可上调肠道钠-葡萄糖转运蛋白（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分泌胰高血糖素样肽（GLP）的肠l细胞中共同表达；在食物摄取过程中，刺激STR也会引起GLP的释放。用乳酸酯抑制剂或基因敲除gustducin或T1R3阻断STR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升高或降低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、延迟胃排空和抑制肝脏葡萄糖生成在葡萄糖稳态中起关键作用。2型糖尿病（T2DM）患者表现为GLP水平下降，提高GLP水平是新的糖尿病治疗方法的目标。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应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、内源性葡萄糖产生（EGP）、摄入葡萄糖的出现率和葡萄糖处理。迄今为止，STR对这些葡萄糖代谢指标的影响尚未在人类中进行过研究。我们拟研究刺激（Specific Aim 1）和抑制（Specific Aim 2）甜味受体对健康受试者和2型糖尿病（T2DM）患者GLP和餐后激素释放以及糖代谢指标的影响。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和2型糖尿病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

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