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).

腹泻是美国部署军事人员中最常投诉的人之一， 对服务成员健康的重大不利影响。据报道，有76.8％的士兵正在运营 伊拉克自由和运作持久自由经历了腹泻。糖尿病正在增加 退伍军人的健康关注，四分之一的退伍军人从退伍军人事务部接受护理 糖尿病的常见麻烦胃肠道并发症是腹泻。 由于其严重性和难治性，具有临床意义。糖尿病的总体发生率 腹泻可以达到高达22％。尽管腹泻在2型糖尿病性麦芽胶（T2DM）中的频率较低，但 T2DM中腹泻的原因经常与包括二甲双胍在内的药物有关，二甲双胍通常用于 T2DM中的血糖控制。与退伍军人事务部的临床相关性是超过70％ VA设施中的患者超重或肥胖，T2DM是一个主要的健康问题。然而，根本原因是 T2DM中的腹泻尚未研究，需要改善糖尿病性腹泻的治疗方法。 是由电解质和流体的肠道转运改变引起的，但是异常电解质之间的联系 未建立运输和糖尿病性腹泻。肠中的主要Na+吸收机制是 由Na+/H+交换器3（NHE3）介导的电负立NaCl抽象。抑制NHE3是相关的 肠毒素和炎症性腹泻。我们最近对1型糖尿病性梅利氏菌（T1DM）的研究 在T1DM人类和小鼠中，NHE3表达被下调，这有助于识别特定的离子 转运蛋白首次作为糖尿病性腹泻的原因。初步研究表明NHE3 人类糖尿病组织和DB/DB小鼠的表达降低，DB/DB小鼠是T2DM的小鼠模型。另外，我们 有令人信服的证据表明，二甲双胍是一种被广泛处方的药物治疗T2DM，抑制NHE3，表明 NHE3功能障碍与二甲双胍引起的频繁腹泻有关。腺苷一磷酸激酶 （AMPK）是抗糖尿病二甲双胍的主要效应因子，AMPK的激活会引起NHE3抑制作用， 表明AMPK在二甲双胍调节NHE3调节中的关键作用。拟议的研究的目的是 确定NHE3表达降低和活性在糖尿病性腹泻的影响，特别是T2DM。 这项拟议的研究的中心假设是，升高PKCα对NHE3的抑制是NHE3的主要原因 抑制T2DM，并通过抗糖尿病药物（例如二甲双胍）激活AMPK，进一步抑制了NHE3， 在某些患者中导致腹泻。旨在检验该假设的拟议研究将建立 糖尿病性腹泻是由NHE3对钠和液体转运的异常调节引起的新范式。我们 提议测试PKCα是T2DM中NHE3活性和流体吸收的主要原因的假设 使用肠上皮细胞和T2DM的实验模型的小鼠（AIM 1）。我们建议确定 AMPK在体外和体内抑制NHE3。我们将确定NHE3抑制的潜在机制 通过研究负责NHE3抑制的信号途径的AMPK。我们还计划确定是否AMPK 二甲双胍激活通过使用人源化小鼠的NHE3泛素化介导NHE3抑制（AIM 2）。 作为改善糖尿病性腹泻治疗的临床前测试，我们将测试生物学上的有效性 发生磷脂，溶物磷脂酸和益生菌在减轻NHE3的抑制时（AIM 3）。