Regulation of intestinal phosphate uptake by dietary carbohydrate

描述(申请人提供)：肠道对营养物质的吸收速度受饮食或身体中该营养物质水平的调节。目前还没有明确的证据表明营养素可以调节其他无关营养素的吸收。在利用基因芯片寻找调节肠道糖转运的基因时，我们无意中发现，腔内葡萄糖显著增加了肠道磷酸盐转运蛋白NaPi2b的表达和活性，该转运蛋白被认为仅受其底物和促磷激素的调节。其他肠道PI转运体均未被刺激。此外，果糖、氨基酸和非代谢葡萄糖类似物不能刺激NaPi2b的表达和活性。这一显着的发现对40万被诊断为终末期肾病(ESRD)的患者的磷(P)代谢具有重大意义。正常人的血清磷浓度为0.81-1.45 mM，这一范围由肾脏排泄率和肠道磷吸收速率的协调变化所维持。在终末期肾病期间，血清磷的轻微增加而不是钙的增加会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%的血清磷，因此，减少终末期肾病患者高磷血症的唯一方法是通过限制饮食磷和摄入磷结合剂来减少肠道磷吸收。营养必需的食物含有磷，所以完全限制饮食是不可能的。不幸的是，大多数P粘合剂已被证明是有毒的、无效的、昂贵的或令人不快的。由于血清磷水平的适度降低会显著降低终末期肾病患者的死亡风险，因此必须找到减少肠道磷吸收的新方法。这项初步研究将检验一个普遍的假设，即饮食中葡萄糖水平的降低会降低肠道磷的吸收率。它的长期目标是确定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中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终末期肾病模型大鼠肠道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道磷运输调节中的作用；以及(3)区分饮食中葡萄糖对肠道磷吸收的影响是直接的还是间接的，是由葡萄糖在肠道吸收过程中释放的信号，特别是胰岛素介导的。预计未来研究的两个主要主题：一个是研究NaPi2在肠道和肾脏控制血糖的分子机制，另一个是评估饮食碳水化合物组成变化对透析患者血清PI水平的影响。。由于慢性肾脏疾病的两大主要原因--II型糖尿病和高血压的发病率普遍上升，终末期肾病(ESRD)的患病率在过去10年里飙升，而ESRD治疗的直接成本已增加到200亿美元/年，消耗了医疗保险预算的6.4%。血清磷的适度增加导致终末期肾病患者死亡风险的显著增加，可能是因为高磷血症导致心脏瓣膜和心血管钙化。因此，对肠道P转运调节的研究对于减轻ESRD的并发症具有重要意义，因为这一肠道途径对于缓解肾脏衰竭时的高磷血症至关重要。

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.