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

基本信息

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
项目类别：
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

项目摘要

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）：肠道吸收营养素的速率由饮食或体内该营养素的水平调节。没有任何营养素被明确证明可以调节其他不相关营养素的吸收。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，管腔葡萄糖显着增加了肠道磷酸盐转运蛋白 NaPi2b 的表达和活性，而该蛋白被认为仅受其底物和磷酸盐激素调节。没有其他肠道 Pi 转运蛋白受到刺激。此外，果糖、氨基酸和不可代谢的葡萄糖类似物不会刺激NaPi2b的表达和活性。这一非凡的发现对 40 万诊断为终末期肾病 (ESRD) 的患者的磷 (P) 代谢具有重大影响。正常人的血清 P 浓度为 0.81 - 1.45 mM，该范围是通过 P 的肾脏排泄率和肠道吸收率的协调变化来维持的。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级增加。不幸的是，透析只能去除 70% 的血清 P，因此，最大限度地减少 ESRD 中高磷血症的唯一方法是通过限制膳食 P 和摄入 P 结合剂来减少肠道 P 吸收。必需营养食品中含有磷，因此完全限制饮食是不可能的。不幸的是，大多数磷结合剂已被证明是有毒的、无效的、昂贵的或难吃的。由于血清 P 水平的适度降低会导致 ESRD 患者的死亡风险显着降低，因此必须发现减少肠道 P 吸收的新方法。这项初步研究将检验膳食葡萄糖水平降低会降低肠道磷吸收率的一般假设。其长期目标是确定 ESRD 患者的血清 P 浓度可以通过改变膳食碳水化合物成分来降低。其具体目标是（1）确定膳食葡萄糖或含葡萄糖碳水化合物的急性和慢性减少是否会导致正常大鼠和终末期肾病（ESRD）大鼠模型肠磷吸收的适应性下降； (2) 评估糖酵解和氧化磷酸化在葡萄糖介导的肠磷转运调节中的作用； (3) 区分膳食葡萄糖对肠道磷吸收的影响是直接的还是间接的，由信号介导，特别是肠道吸收葡萄糖期间释放的胰岛素。预计未来研究有两个主要主题：一个是检查肠道和肾脏中 NaPi2 葡萄糖控制的分子机制，另一个是评估饮食碳水化合物成分的改变对透析患者血清 Pi 水平的影响。。由于II型糖尿病和高血压这两个慢性肾脏病的主要原因发病率的流行增加，近10年来终末期肾病（ESRD）的患病率急剧上升，而ESRD治疗的直接费用已增加到每年 200 亿美元，消耗医疗保险预算的 6.4%。血清磷酸盐的适度增加会导致 ESRD 患者的死亡风险急剧增加，可能是因为高磷血症导致心脏瓣膜和心血管钙化。因此，肠道磷转运调节的研究与缓解 ESRD 并发症高度相关，因为当肾脏衰竭时，肠道途径对于缓解高磷血症至关重要。