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: 9780816
• 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/9780816
• 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; 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抱怨的问题之一， 对服役人员的健康产生重大不利影响。据报道，76.8%的士兵参加了行动 伊拉克自由和持久自由行动经历了腹泻。糖尿病正在成为日益严重的 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护理 患有糖尿病。糖尿病常见的令人烦恼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具有临床意义。糖尿病总体发病率 腹泻率高达22%。尽管 2 型糖尿病 (T2DM) 中腹泻的发生率较低，但 T2DM 腹泻的常见原因与药物有关，包括二甲双胍，其常用于治疗 T2DM 的血糖控制。与退伍军人事务部的临床相关性是，超过 70% 退伍军人管理局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 尚未对 T2DM 腹泻进行研究，因此需要改进糖尿病腹泻的治疗。腹泻 是由电解质和液体的肠道运输改变引起的，但异常电解质之间的联系 运输和糖尿病腹泻的关系尚未确定。肠道吸收Na+的主要机制是 由 Na+/H+ 交换器 3 (NHE3) 介导的电中性 NaCl 吸收。 NHE3 的抑制相关 伴有肠毒素性腹泻和炎性腹泻。我们最近对 1 型糖尿病 (T1DM) 的研究表明 NHE3 表达在 T1DM 人类和小鼠中下调，这有助于识别特定离子 转运蛋白首次成为糖尿病腹泻的原因。初步研究表明 NHE3 在人类糖尿病组织和 db/db 小鼠（T2DM 小鼠模型）中表达降低。此外，我们 有令人信服的证据表明二甲双胍（一种广泛用于治疗 T2DM 的药物）可以抑制 NHE3，这表明 NHE3 功能障碍与二甲双胍引起的频繁腹泻有关。单磷酸腺苷激酶 (AMPK) 是抗糖尿病二甲双胍的主要效应物，AMPK 的激活会导致 NHE3 抑制， 表明 AMPK 在二甲双胍 NHE3 调节中发挥关键作用。拟议研究的目标是 确定 NHE3 表达和活性降低对糖尿病腹泻（特别是 T2DM）的影响。这 这项研究的中心假设是 PKCα 升高对 NHE3 的抑制是 NHE3 的主要原因 T2DM 的抑制作用以及二甲双胍等抗糖尿病药物激活 AMPK 进一步抑制 NHE3， 导致某些患者出现腹泻。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 NHE3 对钠和液体运输的异常调节引起的新范例。我们 提议检验以下假设：PKCα 是 T2DM 中 NHE3 活性和液体吸收降低的主要原因 使用肠上皮细胞和 T2DM 实验模型的小鼠（目标 1）。我们建议确定 AMPK 在体外和体内抑制 NHE3。我们将通过以下方式确定 NHE3 抑制的潜在机制： AMPK 通过研究负责 NHE3 抑制的信号通路。我们还计划确定 AMPK 是否 使用人源化小鼠，二甲双胍激活通过泛素化 NHE3 介导 NHE3 抑制（目标 2）。 作为改善糖尿病腹泻治疗的临床前测试，我们将测试生物制剂的功效 磷脂、溶血磷脂酸和益生菌可减轻 NHE3 的抑制（目标 3）。