Role of Na+/H+ exchanger in diabetic diarrhea

Na /H 交换剂在糖尿病腹泻中的作用

• 批准号: 10044405
• 负责人: Changhyon Chris Yun
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044405
• 关键词: Adenosine Monophosphate; Adverse effects; Affect; Antidiabetic Drugs; Bicarbonates; Bifidobacterium; Bile Acids; Biological; Biological Products; Butyrates; Caring; Cell model; Complications of Diabetes Mellitus; Coupled; Data; Diabetes Mellitus; Diarrhea; Drug Prescriptions; Electrolytes; Epithelial Cells; Exocytosis; Experimental Models; FRAP1 gene; Freedom; Functional disorder; Gastrointestinal Motility; Gastrointestinal Transit; Genomics; Goals; Health; Health Services; Human; Hydrogen; In Vitro; Incidence; Inflammatory; Intestines; Ions; Link; Liquid substance; Malabsorption Syndromes; Mediating; Mediator of activation protein; Messenger RNA; Metformin; Military Personnel; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; PRKCA gene; Patients; Pharmaceutical Preparations; Pharmacology; Phospholipids; Phosphotransferases; Preclinical Testing; Probiotics; Refractory; Regulation; Reporting; Research Design; Role; Scheme; Severities; Signal Pathway; Sodium; Soldier; Testing; Time; Tissues; Type 2 diabetic; Ubiquitination; United States; United States Department of Veterans Affairs; Veterans; Volatile Fatty Acids; absorption; clinically relevant; clinically significant; db/db mouse; diabetic; diabetic patient; efficacy testing; experience; gastrointestinal; glycemic control; humanized mouse; improved; in vivo; intestinal epithelium; lysophosphatidic acid; mouse model; new therapeutic target; non-genomic; operation; preclinical study; prevent; protein protein interaction; service member; targeted treatment; type I diabetic; ubiquitin-protein ligase

Diarrhea is one of the most frequent complaints in deployed military personnel from the United States and has significant adverse effects on the health of service members. It was reported that 76.8 % of soldiers in Operation Iraqi Freedom and Operation Enduring Freedom experienced diarrhea. Diabetes is becoming an increasing health concern for veterans, with one in four veterans receiving care from the Department of Veterans Affairs has diabetes. A common troublesome gastrointestinal complication of diabetes is diarrhea. Diabetic diarrhea attains clinical significance because of its severity and refractory nature. The overall incidence of diabetic diarrhea can reach as high as 22%. Although diarrhea is less frequent in type 2 diabetic mellitus (T2DM), the frequent cause of diarrhea in T2DM is associated with drugs, including metformin, which is commonly used for glycemic control in T2DM. Clinical Relevance to the Department of Veterans Affair is that with more than 70% of patients in VA facilities being overweight or obese, T2DM is a major health concern. Yet the underlying cause of diarrhea in T2DM has not been studied and there is a need to improve treatment for diabetic diarrhea. Diarrhea is caused by altered intestinal transport of electrolytes and fluid, but the link between the aberrant electrolyte transport and diabetic diarrhea is not established. The major Na+ absorptive mechanism in the intestine is electroneutral NaCl absorption mediated by the Na+/H+ exchanger 3 (NHE3). Inhibition of NHE3 is associated with both enterotoxigenic and inflammatory diarrhea. Our recent study of type 1 diabetic mellitus (T1DM) showed that NHE3 expression is downregulated in T1DM humans and mice, which helped to identify a specific ion transporter as a cause of diabetic diarrhea for the first time. Preliminary studies have demonstrated that NHE3 expression is decreased in human diabetic tissues and db/db mice, a mouse model for T2DM. Additionally, we have compelling evidence that metformin, a widely prescribed drug to treat T2DM, inhibits NHE3, suggesting NHE3 dysfunction is associated with frequent diarrhea caused by metformin. Adenosine monophosphate kinase (AMPK) is a major effector of anti-diabetic metformin, and activation of AMPK causes NHE3 inhibition, suggesting the critical role of AMPK in NHE3 regulation by metformin. The objective of the proposed study is determine the impact of decreased NHE3 expression and activity in diabetic diarrhea, in particular T2DM. The central hypothesis of this proposed study is that inhibition of NHE3 by elevated PKCα is a major cause of NHE3 inhibition in T2DM, and activation of AMPK by anti-diabetic drugs such as metformin further inhibits NHE3, contributing to diarrhea in some patients. The proposed studies designed to test this hypothesis will establish a new paradigm that diabetic diarrhea is caused by aberrant regulation of sodium and fluid transport by NHE3. We propose to test the hypothesis that PKCα is a major cause of reduced NHE3 activity and fluid absorption in T2DM mice using intestinal epithelial cells and experimental models of T2DM (Aim 1). We propose to determine that AMPK inhibits NHE3 in vitro and in vivo. We will determine the underlying mechanism of NHE3 inhibition by AMPK by investigating signal pathways responsible NHE3 inhibition. We also plan to determine whether AMPK activation by metformin mediates NHE3 inhibition via ubiquitination of NHE3 by using humanized mice (Aim 2). As a pre-clinical test to improve the treatment for diabetic diarrhea, we will test the efficacy of a biologically occurring phospholipid, lysophosphatidic acid, and probiotics in mitigating the inhibition of NHE3 (Aim 3).

腹泻是美国部署的军事人员最常见的主诉之一， 对服务人员的健康产生重大不利影响。据报道，76.8%的士兵在行动中 伊拉克自由和持久自由行动经历了腹泻。糖尿病正在成为一种日益严重的 退伍军人的健康问题，四分之一的退伍军人接受退伍军人事务部的照顾 患有糖尿病糖尿病常见的胃肠道并发症是腹泻。糖尿病腹泻 由于其严重性和难治性而达到临床意义。糖尿病的总体发病率 腹泻可高达22%。虽然腹泻在2型糖尿病（T2 DM）中不太常见， 2型糖尿病腹泻的常见原因与药物有关，包括二甲双胍，二甲双胍通常用于 2型糖尿病的血糖控制。与退伍军人事务部的临床相关性是，超过70%的 VA机构中的患者超重或肥胖，T2 DM是主要的健康问题。然而， 尚未研究T2 DM中的腹泻，需要改善糖尿病腹泻的治疗。腹泻 是由电解质和液体的肠道转运改变引起的，但异常电解质之间的联系 运输和糖尿病性腹泻没有建立。肠内Na+吸收的主要机制是 由Na+/H+交换器3（NHE 3）介导的电中性NaCl吸收。NHE 3的抑制与 同时伴有肠源性腹泻和炎症性腹泻我们最近对1型糖尿病（T1 DM）的研究表明 在T1 DM人类和小鼠中，NHE 3表达下调，这有助于确定一种特定的离子， 这是第一次发现这种转运蛋白是糖尿病腹泻的原因。初步研究表明，NHE 3 在人糖尿病组织和db/db小鼠（T2 DM的小鼠模型）中表达降低。另外我们 有令人信服的证据表明，二甲双胍，一种广泛用于治疗T2 DM的处方药，抑制NHE 3，这表明 NHE 3功能障碍与二甲双胍引起的频繁腹泻相关。腺苷一磷酸激酶 （AMPK）是抗糖尿病二甲双胍的主要效应物，并且AMPK的活化导致NHE 3抑制， 提示AMPK在二甲双胍调节NHE 3中的关键作用。拟议研究的目的是 确定NHE 3表达和活性降低在糖尿病性腹泻，特别是T2 DM中的影响。的 这项研究的中心假设是，升高的PKCα对NHE 3的抑制是NHE 3的主要原因， 在T2 DM中的抑制和抗糖尿病药物如二甲双胍对AMPK的激活进一步抑制NHE 3， 导致某些病人腹泻旨在检验这一假设的拟议研究将建立一个 糖尿病腹泻是由NHE 3对钠和液体转运的异常调节引起的新范式。我们 我建议检验PKCα是T2 DM患者NHE 3活性降低和液体吸收减少的主要原因这一假设 小鼠使用肠上皮细胞和实验模型的T2 DM（目的1）。我们建议确定， AMPK在体外和体内抑制NHE 3。我们将通过以下方式确定NHE 3抑制的潜在机制： AMPK通过研究负责NHE 3抑制的信号通路。我们还计划确定AMPK是否 通过使用人源化小鼠，二甲双胍的活化通过NHE 3的泛素化介导NHE 3抑制（Aim 2）。 作为改善糖尿病腹泻治疗的临床前试验，我们将测试一种生物学上的 磷脂、溶血磷脂酸和益生菌减轻NHE 3的抑制作用（目的3）。