Regulation of intestinal phosphate uptake by dietary carbohydrate

膳食碳水化合物对肠道磷酸盐吸收的调节

• 批准号: 7255939
• 负责人: RONALDO PARAOAN FERRARIS
• 金额: $ 19.48万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-05 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7255939
• 关键词: Acute; Affect; Amino Acids; Apical; Applications Grants; Binding; Birds; Blood; Blood Glucose; Body Fluids; Budgets; Calcium; Carbohydrates; Cardiovascular system; Cells; Chronic; Chronic Kidney Failure; Complication; Condition; Consumption; Daily; Diagnosis; Dialysis procedure; Diet; Dietary Carbohydrates; Dietitian; Direct Costs; End stage renal failure; Endocrine; Epidemic; Equilibrium; Estrogens; Excretory function; Feces; Figs - dietary; Filtration; Food; Fructose; Future; GLUT2 gene; Genes; Genetic Transcription; Glomerular Filtration Rate; Glucose; Glucose Transporter; Glycolysis; Goals; Hemodialysis; Homeostasis; Hormones; Human; Hypertension; Incidence; Ingestion; Injection of therapeutic agent; Inorganic Phosphate Transporter; Insulin; Intake; Intestinal Absorption; Intestines; Kidney; Kidney Diseases; Literature; Maintenance; Mediating; Medicare; Messenger RNA; Metabolic; Metabolism; Methods; Minerals; Modeling; Molecular; NADH; National Institute of Diabetes and Digestive and Kidney Diseases; Niacinamide; Nicotinamide adenine dinucleotide; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Nutrient; Oxidative Phosphorylation; Pathway interactions; Patients; Phosphorus; Physical Dialysis; Pilot Projects; Plasma; Prevalence; Proteins; Publishing; Range; Rate; Rattus; Regulation; Reporting; Research; Respiration; Risk; Role; Serum; Signal Transduction; Small Intestines; Staging; Starch; Sugar Phosphates; System; Testing; Thinking; Transduction Gene; Vitamin D; Vitamins; absorption; analog; apical membrane; basolateral membrane; blood glucose regulation; brush border membrane; calcification; dietary restriction; experience; fibroblast growth factor 23; glucose analog; glucose transport; glucose uptake; in vivo; inorganic phosphate; mortality; novel; paracrine; programs; soft tissue; sugar; uptake

DESCRIPTION (provided by applicant): The rate of intestinal absorption of a nutrient is modulated by levels of that nutrient in the diet or in the body. No nutrient has been clearly demonstrated to regulate the absorption of other unrelated nutrients. While searching by microarray for genes regulating intestinal sugar transport, we inadvertently discovered that luminal glucose dramatically increases the expression and activity of the intestinal phosphate transporter NaPi2b thought to be regulated solely by its substrate and by phosphatemic hormones. No other intestinal Pi transporter was stimulated. Moreover, fructose, amino acids and nonmetabolizable glucose analogs did not stimulate NaPi2b expression and activity. This remarkable finding has dramatic implications for phosphorus (P) metabolism in 0.4 million patients diagnosed with end-stage renal disease (ESRD). Serum P concentration in normal humans is 0.81 - 1.45 mM, a range maintained by coordinated changes in rates of renal excretion and intestinal absorption of P. During ESRD, modest increases in serum P but not in calcium result in almost exponential increases in mortality risk. Unfortunately, dialysis removes only 70% of serum P, hence, the only method of minimizing hyperphosphatemia in ESRD is by reducing intestinal P absorption accomplished by restriction of dietary P and ingestion of P binding agents. Nutritionally essential foods contain P so complete dietary restriction is impossible. Unfortunately, most of the P binders have proven to be toxic, ineffective, expensive or unpalatable. Because modest reductions in serum P levels result in marked decreases in mortality risk of ESRD patients, novel methods that reduce intestinal P absorption must be discovered. This pilot study will test the general hypothesis that reductions in dietary glucose levels decrease rates of intestinal P absorption. Its long term goal is to establish that serum P concentrations in ESRD patients can be reduced by alterations in dietary carbohydrate composition. Its specific aims are (1) to determine whether acute and chronic reductions in dietary glucose or glucose-containing carbohydrates result in adaptive decreases in intestinal P absorption in normal rats and in rat models of ESRD; (2) to evaluate the role of glycolysis and oxidative phosphorylation in the glucose-mediated regulation of intestinal P transport; and (3) to distinguish whether the effect of dietary glucose on intestinal P absorption is direct or indirect, mediated by signals, specifically insulin, released during intestinal absorption of glucose. Two major themes of future studies are anticipated: one that would examine the molecular mechanisms underlying glucose control of NaPi2 in the intestine and kidney, and another that would evaluate the effect of alterations in dietary carbohydrate composition on serum Pi levels of patients undergoing dialysis. . Because of epidemic increases in the incidence of type II diabetes and hypertension, the two leading causes of chronic kidney disease, the prevalence of end stage renal disease (ESRD) has soared in the past 10 years while the direct costs for ESRD treatment has increased to $20 billion/year, consuming 6.4% of the Medicare budget. Modest increases in serum phosphate result in dramatic increases in mortality risk of ESRD patients, probably because hyperphosphatemia leads to cardiovalvular and cardiovascular calcification. Studies on regulation of intestinal P transport are therefore highly relevant to alleviating the complications of ESRD, because this intestinal pathway is so critical to alleviating hyperphosphatemia when the kidneys have failed.

描述（由申请人提供）：营养素的肠道吸收速率受饮食或体内营养素水平的调节。没有营养素被明确证明可以调节其他无关营养素的吸收。在通过微阵列寻找调节肠道糖转运的基因时，我们无意中发现，鲁米那葡萄糖显著增加了肠道磷酸盐转运蛋白NaPi 2b的表达和活性，该转运蛋白被认为仅受其底物和磷酸盐血症激素的调节。没有其他肠道Pi转运蛋白被刺激。此外，果糖，氨基酸和不可代谢的葡萄糖类似物没有刺激NaPi 2b的表达和活性。这一显著的发现对40万诊断为终末期肾病（ESRD）的患者的磷（P）代谢具有重大意义。正常人的血清P浓度为0.81 - 1.45 mM，这一范围由肾脏排泄率和肠道吸收率的协调变化维持。在ESRD期间，血清P的适度增加而不是钙的增加导致死亡风险几乎呈指数增加。不幸的是，透析仅去除70%的血清P，因此，最大限度地减少ESRD高磷血症的唯一方法是通过限制饮食P和摄入P结合剂来减少肠道P吸收。营养必需的食物含有磷，所以完全的饮食限制是不可能的。不幸的是，大多数磷结合剂已被证明是有毒的，无效的，昂贵的或不好吃的。由于血清P水平的适度降低导致ESRD患者死亡风险的显著降低，因此必须发现减少肠道P吸收的新方法。这项初步研究将测试的一般假设，即降低饮食中的葡萄糖水平降低肠道磷的吸收率。其长期目标是确定ESRD患者的血清P浓度可以通过改变饮食碳水化合物组成来降低。其具体目的是：（1）确定急性和慢性饮食葡萄糖或含葡萄糖碳水化合物的减少是否导致正常大鼠和ESRD大鼠模型肠道P吸收的适应性减少;（2）评价糖酵解和氧化磷酸化在葡萄糖介导的肠道P转运调节中的作用;以及（3）区分膳食葡萄糖对肠道P吸收的影响是直接的还是间接的，由肠道吸收葡萄糖期间释放的信号，特别是胰岛素介导。预计未来研究的两个主要主题：一个是研究肠道和肾脏中NaPi 2葡萄糖控制的分子机制，另一个是评估饮食碳水化合物组成改变对透析患者血清Pi水平的影响。.由于II型糖尿病和高血压（慢性肾脏疾病的两个主要原因）发病率的流行性增加，终末期肾脏疾病（ESRD）的患病率在过去10年中飙升，而ESRD治疗的直接费用已增加至200亿美元/年，占医疗保险预算的6.4%。血清磷的适度增加导致ESRD患者死亡风险的急剧增加，可能是因为高磷血症导致心瓣膜和心血管钙化。因此，对肠道磷转运调节的研究与缓解ESRD的并发症高度相关，因为当肾脏衰竭时，肠道途径对缓解高磷血症至关重要。