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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK075617-02
Application #
7392327
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
May, Michael K
Project Start
2007-04-05
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$229,320
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Roche, Marjolaine; Neti, Prasad V S V; Kemp, Francis W et al. (2015) High Levels of Dietary Supplement Vitamins A, C and E are Absorbed in the Small Intestine and Protect Nutrient Transport Against Chronic Gamma Irradiation. Radiat Res 184:470-481
Douard, Veronique; Ferraris, Ronaldo P (2013) The role of fructose transporters in diseases linked to excessive fructose intake. J Physiol 591:401-14
Douard, Veronique; Suzuki, Takuji; Sabbagh, Yves et al. (2012) Dietary fructose inhibits lactation-induced adaptations in rat 1,25-(OH)?D? synthesis and calcium transport. FASEB J 26:707-21
Roche, Marjolaine; Kemp, Francis W; Agrawal, Amit et al. (2011) Marked changes in endogenous antioxidant expression precede vitamin A-, C-, and E-protectable, radiation-induced reductions in small intestinal nutrient transport. Free Radic Biol Med 50:55-65
Roche, Marjolaine; Neti, Prasad V S V; Kemp, Francis W et al. (2010) Radiation-induced reductions in transporter mRNA levels parallel reductions in intestinal sugar transport. Am J Physiol Regul Integr Comp Physiol 298:R173-82
Douard, Veronique; Asgerally, Abbas; Sabbagh, Yves et al. (2010) Dietary fructose inhibits intestinal calcium absorption and induces vitamin D insufficiency in CKD. J Am Soc Nephrol 21:261-71
Douard, Veronique; Choi, Hye-In; Elshenawy, Summer et al. (2008) Developmental reprogramming of rat GLUT5 requires glucocorticoid receptor translocation to the nucleus. J Physiol 586:3657-73
Kirchner, Severine; Muduli, Anjali; Casirola, Donatella et al. (2008) Luminal fructose inhibits rat intestinal sodium-phosphate cotransporter gene expression and phosphate uptake. Am J Clin Nutr 87:1028-38
Douard, Veronique; Ferraris, Ronaldo P (2008) Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocrinol Metab 295:E227-37