This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Uric acid plays a role not only in the pathogenesis of gout but is also a predictor of cardiovascular disease, hypertension and renal disease in man. We have identified the human urate ion channel transporter (hUAT), located in the proximal convoluted tubule of the kidney that is involved in both the secretion and reabsorption of urate across the tubule. This channel has a unique lectin binding site that in in-vitro studies, has been found to be modulated by glucose, galactose and lactose. We have also identified a mutation (G/A polymorphism) in our laboratory, that, in in-vitro studies has demonstrated diminished hUAT channel activity. Cross-sectional studies have earlier shown that uric acid levels vary with serum glucose levels (decreased excretion of uric acid with hyperglycemia, but increased excretion with overt diabetes mellitus). Studies have also reported that a low-fat dairy diet reduces the incidence of gout, while others have shown that this diet reduces blood pressure significantly when compared with a non-dairy diet. We hypothesize that the varying effects of blood glucose levels on uric acid excretion is through the regulation of hUAT channel activity (with hyperglycemia only, the hUAT channel on the basolateral side of the renal tubule is activated and there is increased reabsorption of uric acid, with overt diabetes glucose is spilled in the urine and hUAT channel on the luminal side are activated leading to increased excretion of urate). We also hypothesize that a low-fat dairy diet reduces serum uric acid levels through hUAT regulation leading to a decrease in the incidence of gout and a reduction in blood pressure levels. In our proposed randomized, controlled, cross-over trial in healthy adult volunteers, we aim to study the effect of a low-fat dairy diet and a non-dairy diet on serum uric acid levels, the renal fractional excretion of uric acid and blood pressure. We will also study the effect of an acute intravenous infusion of glucose on these parameters. DNA analysis for hUAT mutations of study subjects will be done to assess if there is a blunted response of hUAT activity in subjects with the polymorphism as compared to normal subjects. Hypothesis:We hypothesize that the varying effects of blood glucose levels in lowering uric acid levels is through the regulation of hUAT channel activity (with hyperglycemia the hUAT channel on the basolateral (blood) side is activated and there is increased reabsorption of uric acid and with overt diabetes the hUAT channel on the luminal (urine) side are activated leading to increased excretion of urate) .We also hypothesize that a low-fat dairy diet reduces serum uric acid levels through hUAT regulation by absorbed galactose leads to a decrease in the incidence of gout and a reduction in blood pressure levels. We also hypothesize that there will be a blunted response to low fat dairy diet and acute infusion of glucose in subjects with the polymorphism of hUAT as compared to normal subjects.
Showing the most recent 10 out of 869 publications
