Alpha7 Nicotinic Acetylcholine Receptor Regulation of Glucagon-Like Peptide- 1 Incretin Hormone Action.

Alpha7 烟碱乙酰胆碱受体对胰高血糖素样肽 - 1 肠促胰岛素激素作用的调节。

• 批准号: 10218302
• 负责人: GEORGE G HOLZ
• 金额: --
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-14 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218302
• 关键词: Alzheimer' s Disease; Amides; Anabolism; Attention; Autonomic nervous system; Beta Cell; Blood; Blood Circulation; Blood Glucose; Cell Nucleus; Cells; Communication; Deterioration; Diabetic mouse; Diagnosis; Eating; Endocrine system; Enteroendocrine Cell; Epidemic; Etiology; Fatty Acids; G-Protein-Coupled Receptors; GLP-I receptor; GPR119 receptor; GTS-21; Genetic Transcription; Glucagon; Goals; Health; Hormones; Human; In Vitro; Intestinal Absorption; Intestines; Investigation; Islets of Langerhans; Killer Cells; Knock-in; Knockout Mice; L Cells; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Mus; Nervous system structure; Neuraxis; Neurons; Nicotinic Receptors; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oral; Organ; Pancreas; Peptide YY; Phase II Clinical Trials; Phenotype; Physiology; Process; Prohormone Convertase; Reflex action; Regulation; Role; Structure of alpha Cell of islet; Structure of beta Cell of islet; System; Technology; Testing; Tissues; Validation; acetylcholine receptor agonist; afferent nerve; age group; alpha-bungarotoxin receptor; blood glucose regulation; cell type; gastric inhibitory polypeptide receptor; glucagon-like peptide 1; glucose tolerance; hindbrain; hormonal signals; improved; in vivo; incretin hormone; inhibitor/antagonist; insight; insulin secretion; islet; knockout gene; mortality; novel; paracrine; proglucagon; recombinase-mediated cassette exchange; relating to nervous system; response

The overall goal of this project is to establish the systems physiology of glucoregulation in which alpha 7 nicotinic acetylcholine receptors (α7nAChR) regulate the incretin hormone action of Glucagon-Like Peptide-1 (GLP-1). This project may reveal novel features of glucoregulation that are of relevance to our understanding of type 2 diabetes mellitus (T2DM) since we find that the α7nAChR agonist GTS-21 stimulates intestinal GLP-1 secretion, raises circulating levels of GLP-1, and improves glucose tolerance in mice. Thus, we propose a novel and important role for the α7nAChR in the control of glucose homeostasis by virtue of its ability to exert inter-organ control over GLP-1 secretion and GLP-1 action. To test this Hypothesis, our aims are as follows: Aim 1: We will use Cre/lox technology in combination with gene knockout or knock-in technology to determine how α7nAChR agonists lower levels of blood glucose in healthy mice or db/db and ob/ob mouse models of diabetes. A first goal is to evaluate baseline alterations of glucoregulation in tissue-specific α7nAChR knockout mice, while also assessing how α7nAChR agonist action is modified. A second goal is to identify which cell types express the GLP-1 receptor (GLP-1R) that mediates glucoregulatory actions of α7nAChR agonists. Four possibilities exist: 1) when mice are administered GTS-21 in combination with a DPP-4 inhibitor, the concentration of GLP-1 in the blood will reach high levels so that GLP-1 will act at the pancreatic β-cell GLP-1R to enhance insulin secretion, or 2) GLP-1 released from L-cells in response to GTS-21 might exert a local effect in the intestinal wall to initiate neural reflexes that stimulate insulin secretion, or 3) GTS-21 might act in the hindbrain nucleus tractus solitarius to stimulate GLP-1 release so that glucose homeostasis is improved, or 4) GTS-21 might stimulate GLP-1 release from pancreatic α-cells so that intra-islet GLP-1 will exert a paracrine hormone action at the β-cell GLP-1R. Aim 2: We will perform in vitro studies to test if GTS-21 acts exclusively at L-cells, or if it also acts at other types of enteroendocrine cells that may express the α7nAChR. For example, GTS-21 might lower levels of blood glucose by stimulating the release of GIP from K-cells so that GIP will then act at the β-cell GIP receptor to stimulate insulin secretion. Potentially, this action of GIP will be enhanced by a DPP-4 inhibitor. Since Peptide YY (PYY) is co-secreted with GLP-1 from L-cells, we may find that its release is also stimulated by GTS-21. This would be significant because PYY is important to the suppression of food intake in obesity-related T2DM. Finally, we will test for actions of GTS-21 to stimulate GLP-1 biosynthesis in L-cells and pancreatic α-cells. This possibility exists because we find that GTS-21 upregulates expression of a prohormone convertase (PC1/3) that liberates GLP-1 from proglucagon, while also upregulating expression of GPR119, a GPCR that stimulates glucagon gene transcription. It will be especially interesting to determine if the α7nAChR in pancreatic islets regulates coordinate expression of PC1/3 and GPR119 so that α-cells acquire the ability to secret GLP-1 under conditions of T2DM. Summary: Our long-term goal is to establish the systems physiology of glucoregulation under α7nAChR control.

该项目的总体目标是建立葡萄糖调节的系统生理学，其中α7烟碱乙酰胆碱受体（α7NACHR）调节了胰糖明样肽-1（GLP-1）的肠立型素激素作用的增加。该项目可能揭示了葡萄糖调节的新特征，这与我们对2型糖尿病（T2DM）的理解相关，因为我们发现α7NACHR激动剂GTS-21刺激了肠道GLP-1分泌，从而提高了GLP-1的循环水平，并提高了小鼠GLCOSE耐受性。因此，我们提出了α7NACHR在葡萄糖稳态控制中的一种新颖而重要的作用，因为它能够对GLP-1分泌和GLP-1的作用施加器官间控制和GLP-1作用。为了检验这一假设，我们的目标如下：目标1：我们将使用CRE/LOX技术与基因敲除或敲门技术结合使用CRE/LOX技术来确定健康小鼠或糖尿病模型的α7NACHR激动剂如何降低血糖水平。第一个目标是评估组织特异性α7NACHR敲除小鼠中葡萄糖调节的基线改变，同时还评估了如何修改α7NACHR激动剂作用。第二个目标是确定哪种细胞类型表达GLP-1受体（GLP-1R），介导α7NACHR激动剂的葡萄糖调节作用。存在四种可能性：1）当将小鼠与DPP-4抑制剂结合使用小鼠时，血液中的GLP-1浓度将达到高水平，以便GLP-1在胰腺β-Cell GLP-1R上起作用，以增强胰岛素分泌的胰岛素分泌，或者对GLP-1释放的GLP-1的启动，可能会在GTS上释放glps-2）可能会在GTS中释放出来。 that stimulate insulin secretion, or 3) GTS-21 might act in the hindbrain nucleus tractus Solitarius to stimulate GLP-1 release so that glucose homeostasis is improved, or 4) GTS-21 might stimulate GLP-1 release from pancreatic α-cells so that intra-islet GLP-1 will exert a paracrine homone action at the β-cell GLP-1R. AIM 2：我们将进行体外研究，以测试GTS-21是否仅在L细胞上起作用，或者它也对可能表达α7NACHR的其他类型的肠内分泌细胞作用。例如，GTS-21可能通过刺激从K细胞释放GIP来降低血糖水平，从而使GIP在β-细胞GIP受体上作用以刺激胰岛素的分泌。可能，DPP-4抑制剂将增强GIP的这种作用。由于肽YY（PYY）与L细胞的GLP-1共归化，因此我们可能会发现它的释放也受到GTS-21的刺激。这将是重要的，因为PYY对于与肥胖相关的T2DM中的抑制食物摄入很重要。最后，我们将测试GTS-21在L细胞和胰腺α细胞中刺激GLP-1生物合成的作用。这种可能性之所以存在，是因为我们发现GTS-21上调了激素转化酶（PC1/3）的表达，该转化酶（PC1/3）从proglucagon中释放了GLP-1，同时也上调GPR119的表达，GPR119是一种刺激胰甘蓝基因转录的GPCR。确定胰岛中的α7NACHR是否调节PC1/3和GPR119的坐标表达是否会使α7NACHR在T2DM条件下获得秘密GLP-1的能力。摘要：我们的长期目标是在α7NACHR控制下建立葡萄糖调节的系统生理。