Sodium-glucose cotransporter 2 inhibition does not improve the acute pressure natriuresis response in rats with type 1 diabetes.

NEW FINDINGS: What is the central question of this study? Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk in patients with both diabetic and non-diabetic kidney disease: can SGLT2 inhibition improve renal pressure natriuresis (PN), an important mechanism for long-term blood pressure control, which is impaired in type 1 diabetes mellitus (T1DM)? What is the main finding and its importance? The SGLT2 inhibitor dapagliflozin did not enhance the acute in vivo PN response in either healthy or T1DM Sprague-Dawley rats. The data suggest that the mechanism underpinning the clinical benefits of SGLT2 inhibitors on health is unlikely to be due to an enhanced natriuretic response to increased blood pressure. ABSTRACT: Type 1 diabetes mellitus (T1DM) leads to serious complications including premature cardiovascular and kidney disease. Hypertension contributes importantly to these adverse outcomes. The renal pressure natriuresis (PN) response, a key regulator of blood pressure (BP), is impaired in rats with T1DM as tubular sodium reabsorption fails to down-regulate with increasing BP. We hypothesised that sodium-glucose cotransporter 2 (SGLT2) inhibitors, which reduce cardiovascular risk in kidney disease, would augment the PN response in T1DM rats. Non-diabetic or T1DM (35-50 mg/kg streptozotocin i.p.) adult male Sprague-Dawley rats were anaesthetised (thiopental 50 mg/kg i.p.) and randomised to receive either dapagliflozin (1 mg/kg i.v.) or vehicle. Baseline sodium excretion was measured and then BP was increased by sequential arterial ligations to induce the PN response. In non-diabetic animals, the natriuretic and diuretic responses to increasing BP were not augmented by dapagliflozin. Dapagliflozin induced glycosuria, but this was not influenced by BP. In T1DM rats the PN response was impaired. Dapagliflozin again increased urinary glucose excretion but did not enhance PN. Inhibition of SGLT2 does not enhance the PN response in rats, either with or without T1DM. SGLT2 makes only a minor contribution to tubular sodium reabsorption and does not contribute to the impaired PN response in T1DM.

Physiological regulation of phosphate homeostasis.

Phosphate homeostasis is dependent on the interaction and coordination of four main organ systems: thyroid/parathyroids, gastrointestinal tract, bone and kidneys, and three key hormonal regulators, 1,25-hydroxyvitamin D3, parathyroid hormone and FGF23 with its co- factor klotho. Phosphorus is a critical nutritional element for normal cellular function, but in excess can be toxic to tissues, particularly the vasculature. As phosphate, it also has an important interaction and inter-dependence with calcium and calcium homeostasis sharing some of the same controlling hormones, although this is not covered in our article. We have chosen to provide a current overview of phosphate homeostasis only, focusing on the role of two major organ systems, the gastrointestinal tract and kidneys, and their contribution to the control of phosphate balance. We describe in some detail the mechanisms of intestinal and renal phosphate transport, and compare and contrast their regulation. We also consider a significant example of phosphate imbalance, with phosphate retention, which is chronic kidney disease; why consequent hyperphosphatemia is important, and some of the newer means of managing it.

Virtual clinics for glaucoma care - Patients' and clinicians' experiences and perceptions: a qualitative evaluation.

BACKGROUND: The role of glaucoma virtual clinics has developed to help meet demand for capacity within busy glaucoma services. There is limited research of patient and clinician experiences and perceptions of these clinics and the aim of this study is to provide further information to help improve patient experience and guide service delivery. METHODS: A mixed methods research design was employed comprising of a patient satisfaction survey, and patient and clinician interviews. Consultant ophthalmologists were recruited from throughout the UK, and patients and data gathering clinical staff recruited from the Manchester Royal Eye Hospital and Bristol Eye Hospital. RESULTS: We received a total of 148 patient satisfaction questionnaires with an overall response rate of 55.4%. Most respondents were diagnosed with primary open angle glaucoma (33.9%) at Manchester and glaucoma suspect status at Bristol (50.6%). Patients had high levels of confidence in the person conducting the tests (94.8% Manchester, 98.8% Bristol), and most were likely to recommend the service to family or friends (94.8% Manchester, 92.6% Bristol). We interviewed 10 consultant ophthalmologists, 10 data gathering staff and 20 patients. A number of key themes emerged from the transcribed interviews including: patient experience, clinician perception of patient experience, service delivery, staffing and staff experience, and patient safety. CONCLUSIONS: Glaucoma virtual clinics can be acceptable to both clinicians and patients, including those with a varied complexity of glaucoma and glaucoma-related disease. Dissatisfaction seemed to relate to poor communication or processes and systems within the service rather than complexity of disease.

The Complexities of Organ Crosstalk in Phosphate Homeostasis: Time to Put Phosphate Sensing Back in the Limelight.

Phosphate homeostasis is essential for health and is achieved via interaction between the bone, kidney, small intestine, and parathyroid glands and via intricate processes involving phosphate transporters, phosphate sensors, and circulating hormones. Numerous genetic and acquired disorders are associated with disruption in these processes and can lead to significant morbidity and mortality. The role of the kidney in phosphate homeostasis is well known, although it is recognized that the cellular mechanisms in murine models and humans are different. Intestinal phosphate transport also appears to differ in humans and rodents, with recent studies demonstrating a dominant role for the paracellular pathway. The existence of phosphate sensing has been acknowledged for decades; however, the underlying molecular mechanisms are poorly understood. At least three phosphate sensors have emerged. PiT2 and FGFR1c both act as phosphate sensors controlling Fibroblast Growth Factor 23 secretion in bone, whereas the calcium-sensing receptor controls parathyroid hormone secretion in response to extracellular phosphate. All three of the proposed sensors are expressed in the kidney and intestine but their exact function in these organs is unknown. Understanding organ interactions and the mechanisms involved in phosphate sensing requires significant research to develop novel approaches for the treatment of phosphate homeostasis disorders.

Diet-induced iron deficiency in rats impacts small intestinal calcium and phosphate absorption.

AIMS: Recent reports suggest that iron deficiency impacts both intestinal calcium and phosphate absorption, although the exact transport pathways and intestinal segment responsible have not been determined. Therefore, we aimed to systematically investigate the impact of iron deficiency on the cellular mechanisms of transcellular and paracellular calcium and phosphate transport in different regions of the rat small intestine. METHODS: Adult, male Sprague-Dawley rats were maintained on a control or iron-deficient diet for 2 weeks and changes in intestinal calcium and phosphate uptake were determined using the in situ intestinal loop technique. The circulating levels of the hormonal regulators of calcium and phosphate were determined by ELISA, while the expression of transcellular calcium and phosphate transporters, and intestinal claudins were determined using qPCR and western blotting. RESULTS: Diet-induced iron deficiency significantly increased calcium absorption in the duodenum but had no impact in the jejunum and ileum. In contrast, phosphate absorption was significantly inhibited in the duodenum and to a lesser extent the jejunum, but remained unchanged in the ileum. The changes in duodenal calcium and phosphate absorption in the iron-deficient animals were associated with increased claudin 2 and 3 mRNA and protein levels, while levels of parathyroid hormone, fibroblast growth factor-23 and 1,25-dihydroxy vitamin D3 were unchanged. CONCLUSION: We propose that iron deficiency alters calcium and phosphate transport in the duodenum. This occurs via changes to the paracellular pathway, whereby upregulation of claudin 2 increases calcium absorption and upregulation of claudin 3 inhibits phosphate absorption.

1,25(OH)2 vitamin D3 stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine.

KEY POINTS: Intestinal absorption of phosphate proceeds via an active/transcellular route mostly mediated by NaPi-IIb/Slc34a2 and a poorly characterized passive/paracellular pathway. Intestinal phosphate absorption and expression of NaPi-IIb are stimulated by 1,25(OH)2 vitamin D3 but whether NaPi-IIb is the only target under hormonal control remains unknown. We report that administration of 1,25(OH)2 vitamin D3 to wild-type mice resulted in the expected increase in active transport of phosphate in jejunum, without changing paracellular fluxes. Instead, the same treatment failed to alter phosphate transport in intestinal-depleted Slc34a2-deficient mice. In both genotypes, 1,25(OH)2 vitamin D3 induced similar hyperphosphaturic responses and changes in the plasma levels of FGF23 and PTH. While urinary phosphate loss induced by administration of 1,25(OH)2 vitamin D3 did not alter plasma phosphate, further studies should investigate whether chronic administration would lead to phosphate imbalance in mice with reduced active intestinal absorption. ABSTRACT: Intestinal absorption of phosphate is stimulated by 1,25(OH)2 vitamin D3. At least two distinct mechanisms underlie phosphate absorption in the gut, an active transcellular transport requiring the Na+ /phosphate cotransporter NaPi-IIb/Slc34a2, and a poorly characterized paracellular passive pathway. 1,25(OH)2 vitamin D3 stimulates NaPi-IIb expression and function, and loss of NaPi-IIb reduces intestinal phosphate absorption. However, it is remains unknown whether NaPi-IIb is the only target for hormonal regulation by 1,25(OH)2 vitamin D3 . Here we compared the effects of intraperitoneal administration of 1,25(OH)2 vitamin D3 (2 days, once per day) in wild-type and intestinal-specific Slc34a2-deficient mice, and analysed trans- vs. paracellular routes of phosphate absorption. We found that treatment stimulated active transport of phosphate only in jejunum of wild-type mice, though NaPi-IIb protein expression was upregulated in jejunum and ileum. In contrast, 1,25(OH)2 vitamin D3 administration had no effect in Slc34a2-deficient mice, suggesting that the hormone specifically regulates NaPi-IIb expression. In both groups, 1,25(OH)2 vitamin D3 elicited the expected increase of plasma fibroblast growth factor 23 (FGF23) and reduction of parathyroid hormone (PTH). Treatment resulted in hyperphosphaturia (and hypercalciuria) in both genotypes, though mice remained normophosphataemic. While increased intestinal absorption and higher FGF23 can trigger the hyperphosphaturic response in wild types, only higher FGF23 can explain the renal response in Slc34a2-deficient mice. Thus, 1,25(OH)2 vitamin D3 stimulates intestinal phosphate absorption by acting on the active transcellular pathway mostly mediated by NaPi-IIb while the paracellular pathway appears not to be affected.

Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3.

The breakdown of the intestinal epithelial barrier and subsequent increase in intestinal permeability can lead to systemic inflammatory diseases and multiple-organ failure. Nutrition impacts the intestinal barrier, with dietary components such as gluten increasing permeability. Artificial sweeteners are increasingly consumed by the general public in a range of foods and drinks. The sweet taste receptor (T1R3) is activated by artificial sweeteners and has been identified in the intestine to play a role in incretin release and glucose transport; however, T1R3 has not been previously linked to intestinal permeability. Here, the intestinal epithelial cell line, Caco-2, was used to study the effect of commonly-consumed artificial sweeteners, sucralose, aspartame and saccharin, on permeability. At high concentrations, aspartame and saccharin were found to induce apoptosis and cell death in intestinal epithelial cells, while at low concentrations, sucralose and aspartame increased epithelial barrier permeability and down-regulated claudin 3 at the cell surface. T1R3 knockdown was found to attenuate these effects of artificial sweeteners. Aspartame induced reactive oxygen species (ROS) production to cause permeability and claudin 3 internalization, while sweetener-induced permeability and oxidative stress was rescued by the overexpression of claudin 3. Taken together, our findings demonstrate that the artificial sweeteners sucralose, aspartame, and saccharin exert a range of negative effects on the intestinal epithelium through the sweet taste receptor T1R3.

The absorbing life of bile acids.

Hyperphosphatemia increases cardiovascular complications and all-cause mortality rate in patients with chronic kidney disease. Targeting the processes involved in dietary phosphate absorption is an attractive means for reducing this phosphate burden. We do not, however, fully understand this process and how it is regulated. This commentary describes recent findings regarding the novel role of bile acids in regulating paracellular phosphate (and calcium) absorption by the small intestine and the potential cellular mechanisms involved.

Clinical effectiveness of the Manchester Glaucoma Enhanced Referral Scheme.

BACKGROUND: Glaucoma referral filtering schemes have operated in the UK for many years. However, there is a paucity of data on the false-negative (FN) rate. This study evaluated the clinical effectiveness of the Manchester Glaucoma Enhanced Referral Scheme (GERS), estimating both the false-positive (FP) and FN rates. METHOD: Outcome data were collected for patients newly referred through GERS and assessed in 'usual-care' clinics to determine the FP rate (referred patients subsequently discharged at their first visit). For the FN rate, glaucoma suspects deemed not requiring referral following GERS assessment were invited to attend for a 'reference standard' examination including all elements of assessment recommended by National Institute for Health and Care Excellence (NICE) by a glaucoma specialist optometrist. A separate 33 cases comprising randomly selected referred and non-referred cases were reviewed independently by two glaucoma specialist consultant ophthalmologists to validate the reference standard assessment. RESULTS: 1404 patients were evaluated in GERS during the study period; 651 (46.3%) were referred to the Hospital Eye Service (HES) and 753 (53.6%) were discharged. The FP rate in 307 assessable patients referred to the HES was 15.5%. This study reviewed 131 (17.4%) of those patients not referred to the HES through the GERS scheme; 117 (89.3%) were confirmed as not requiring hospital follow-up; 14 (10.7%) required follow-up, including 5 (3.8%) offered treatment. Only one patient (0.8%) in this sample met the GERS referral criteria and was not referred (true FN). There were no cases of missed glaucoma or non-glaucomatous pathology identified within our sample. CONCLUSION: The Manchester GERS is an effective glaucoma filtering scheme with a low FP and FN rate.

The role of SLC34A2 in intestinal phosphate absorption and phosphate homeostasis.

There has recently been significant interest in the concept of directly targeting intestinal phosphate transport to control hyperphosphatemia in patients with chronic kidney disease. However, we do not have a complete understanding of the cellular mechanisms that govern dietary phosphate absorption. Studies in the 1970s documented both active and passive pathways for intestinal phosphate absorption. However, following the cloning of the intestinal SLC34 cotransporter, NaPi-IIb, much of the research focused on the role of this protein in active transcellular phosphate absorption and the factors involved in its regulation. Generation of a conditional NaPi-IIb knockout mouse has demonstrated that this protein is critical for the maintenance of skeletal integrity during periods of phosphate restriction and that under normal physiological conditions, the passive sodium-independent pathway is likely be the more dominant pathway for intestinal phosphate absorption. The review aims to summarise the most recent developments in our understanding of the role of the intestine in phosphate homeostasis, including the acute and chronic renal adaptations that occur in response to dietary phosphate intake. Evidence regarding the overall contribution of the transcellular and paracellular pathways for phosphate absorption will be discussed, together with the clinical benefit of inhibiting these pathways for the treatment of hyperphosphatemia in chronic kidney disease.

Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability.

Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia with dietary restriction and oral phosphate binders often proves inadequate. Tenapanor, a minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), acts locally in the gastrointestinal tract to inhibit sodium absorption. Because tenapanor also reduces intestinal phosphate absorption, it may have potential as a therapy for hyperphosphatemia. We investigated the mechanism by which tenapanor reduces gastrointestinal phosphate uptake, using in vivo studies in rodents and translational experiments on human small intestinal stem cell-derived enteroid monolayers to model ion transport physiology. We found that tenapanor produces its effect by modulating tight junctions, which increases transepithelial electrical resistance (TEER) and reduces permeability to phosphate, reducing paracellular phosphate absorption. NHE3-deficient monolayers mimicked the phosphate phenotype of tenapanor treatment, and tenapanor did not affect TEER or phosphate flux in the absence of NHE3. Tenapanor also prevents active transcellular phosphate absorption compensation by decreasing the expression of NaPi2b, the major active intestinal phosphate transporter. In healthy human volunteers, tenapanor (15 mg, given twice daily for 4 days) increased stool phosphorus and decreased urinary phosphorus excretion. We determined that tenapanor reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux, an effect mediated exclusively via on-target NHE3 inhibition.

Acute saccharin infusion has no effect on renal glucose handling in normal rats in vivo.

Artificial sweeteners are extensively used by the food industry to replace sugar in food and beverages and are widely considered to be a healthy alternative. However, recent data suggest that artificial sweeteners may impact intestinal glucose absorption and that they might lead to glucose intolerance. Moreover, chronic consumption of artificial sweeteners has also been linked to detrimental changes in renal function. Using an in vivo approach, our study aimed to determine if short-term infusion of the artificial sweetener saccharin can alter renal function and renal glucose absorption. We show that saccharin infusion does not induce any major change in GFR or urine flow rate at either the whole kidney or single nephron level, suggesting that any reported change in renal function with artificial sweeteners must depend on chronic consumption. As expected for a nondiabetic animal, glucose excretion was low; however, saccharin infusion caused a small, but significant, decrease in fractional glucose excretion. In contrast to the whole kidney data, our micropuncture results did not show any significant difference in fractional glucose reabsorption in either the proximal or distal tubules, indicating that saccharin does not influence renal glucose handling in vivo under euglycemic conditions. In keeping with this finding, protein levels of the renal glucose transporters SGLT1 and SGLT2 were also unchanged. In addition, saccharin infusion in rats undergoing a glucose tolerance test failed to induce a robust change in renal glucose excretion or renal glucose transporter expression. In conclusion, our results demonstrate that saccharin does not induce acute physiologically relevant changes in renal function or renal glucose handling.

Acceptability and use of glaucoma virtual clinics in the UK: a national survey of clinical leads.

OBJECTIVE: The purpose of this paper is to describe the findings of a national survey that aimed to estimate the proportion of Hospital Eye Service (HES) units using glaucoma virtual clinics, to determine how these services differ and to gauge clinicians' views and opinions on the safety and acceptability of this model of care compared with usual care. METHODS AND ANALYSIS: This 12-question survey was disseminated nationally to 92 clinical lead consultant ophthalmologists using SurveyMonkey. RESULTS: The response rate was 45.7%. There were 21 out of the total 42 respondents (50.0%) who were based at an NHS Trust where glaucoma virtual clinics were already being used and a further 9 (21.4%) were planning to establish one. Clinical leads largely rated efficiency and patient safety to be at least equivalent to usual care (92.9%) and 81.0% perceived glaucoma virtual clinics to be acceptable to patients. The main reasons for not running glaucoma virtual clinics were insufficient staff (71.4%) and inadequate space (47.6%). The majority of those running virtual clinics used this model of care for 'lower risk' patients such as ocular hypertensives (90.5%) and glaucoma suspects. CONCLUSION: Glaucoma virtual clinics are employed by a large proportion of HES units, with many seeking to develop such services. Clinical leads largely rate efficiency, patient safety and the perception of patient acceptability to be at least equivalent to usual care.

Postprandial adjustments in renal phosphate excretion do not involve a gut-derived phosphaturic factor.

NEW FINDINGS: What is the central question of this study? Does a previously hypothesized signalling mechanism, believed to detect postprandial increases in intestinal phosphate and that can stimulate the kidneys to rapidly excrete phosphate, operate under physiological conditions? What is the main finding and its importance? Contrary to earlier reports, rapid signalling between the small intestine and kidney mediated by a gut-derived phosphaturic factor in response to a physiological intestinal phosphate load is not supported by the present findings; moreover, hyperphosphataemia and increased parathyroid hormone concentrations are likely to be the underlying factors responsible for the phosphaturia following a supraphysiological intestinal phosphate load. To date, the role of the small intestine in the regulation of postprandial phosphate homeostasis has remained unclear and controversial. Previous studies have proposed the presence of a gut-derived phosphaturic factor that acts independently of changes in plasma phosphate concentration or parathyroid hormone (PTH) concentration; however, these early studies used duodenal luminal phosphate concentrations in the molar range, and therefore, the physiological relevance of this is uncertain. In the present study, we used both in vivo and in vitro approaches to investigate the presence of this putative 'intestinal phosphatonin'. Instillation of 1.3 m phosphate into the duodenum rapidly induced phosphaturia, but in contrast to previous reports, this was associated with significant hyperphosphataemia and elevated PTH concentration; however, there was not the expected decrease in abundance of the renal sodium-phosphate cotransporter NaPi-IIa. Instillation of a physiological (10 mm) phosphate load had no effect on plasma phosphate concentration, PTH concentration or phosphate excretion. Moreover, phosphate uptake by opossum kidney cells was unaffected after incubation with serosal fluid collected from intestinal segments perfused with different concentrations of phosphate. Taken together, these findings do not support the concept of a gut-derived phosphaturic factor that can mediate rapid signalling between the gut and kidney, leading to increased urinary phosphate excretion, as part of normal phosphate homeostasis.

Putative tissue location and function of the SLC5 family member SGLT3.

NEW FINDINGS: What is the topic of this review? This review summarizes the evidence on the localization, electrophysiological properties, agonist specificity and putative physiological role of sodium-glucose transporter 3 (SGLT3). What advances does it highlight? Published information is reviewed in some detail by comparing human and rodent isoforms, as well as advances in testing hypotheses for the physiological role of SGLT3 as a glucose sensor or incretin release mediator. We provide a critical overview of available published data and discuss a putative functional role for SGLT3 in human and mouse physiology. Sodium-glucose transporter 3 (SGLT3) has attracted interest because of its putative role as a glucose sensor, rather than a sugar transporter, in contrast to its co-family members SGLT1 and SGLT2. Significant progress has been made in characterizing the electrophysiological properties in vitro of the single human SGLT3 isoform and the two mouse isoforms, SGLT3a and SGLT3b. Although early reports indicated SGLT3 expression in the small intestinal myenteric and submucosal neurones, hypothalamic neurones, portal vein and kidney, a lack of reliable antibodies has left unanswered its exact tissue and cellular localization. Several hypotheses for a role of SGLT3 in glucose sensing, gastric emptying, glucagon-like peptide-1 release and post-Roux-en-Y gastric bypass remodelling have been explored, but so far there is only limited and indirect supportive evidence using non-specific agonists/antagonists, with no firm conclusions. There are no published or available data in knockout animals, and translation is difficult because of its different isoforms in human versus rodent, as well as a lack of selective agonists or antagonists, all of which make SGLT3 challenging to study. However, its unique electrophysiological properties, ubiquitous expression at the mRNA level, enrichment in the small intestine and potential, but uncertain, physiological role demand more attention. The purpose of this overview and review of SGLT3 biology is to provide an update, highlight the gaps in our knowledge and try to signpost potential ways forward to define its likely function in vivo.

Experimental type II diabetes and related models of impaired glucose metabolism differentially regulate glucose transporters at the proximal tubule brush border membrane.

What is the central question of this study? Although SGLT2 inhibitors represent a promising treatment for patients suffering from diabetic nephropathy, the influence of metabolic disruption on the expression and function of glucose transporters is largely unknown. What is the main finding and its importance? In vivo models of metabolic disruption (Goto-Kakizaki type II diabetic rat and junk-food diet) demonstrate increased expression of SGLT1, SGLT2 and GLUT2 in the proximal tubule brush border. In the type II diabetic model, this is accompanied by increased SGLT- and GLUT-mediated glucose uptake. A fasted model of metabolic disruption (high-fat diet) demonstrated increased GLUT2 expression only. The differential alterations of glucose transporters in response to varying metabolic stress offer insight into the therapeutic value of inhibitors. SGLT2 inhibitors are now in clinical use to reduce hyperglycaemia in type II diabetes. However, renal glucose reabsorption across the brush border membrane (BBM) is not completely understood in diabetes. Increased consumption of a Western diet is strongly linked to type II diabetes. This study aimed to investigate the adaptations that occur in renal glucose transporters in response to experimental models of diet-induced insulin resistance. The study used Goto-Kakizaki type II diabetic rats and normal rats rendered insulin resistant using junk-food or high-fat diets. Levels of protein kinase C-ßI (PKC-ßI), GLUT2, SGLT1 and SGLT2 were determined by Western blotting of purified renal BBM. GLUT- and SGLT-mediated d-[(3) H]glucose uptake by BBM vesicles was measured in the presence and absence of the SGLT inhibitor phlorizin. GLUT- and SGLT-mediated glucose transport was elevated in type II diabetic rats, accompanied by increased expression of GLUT2, its upstream regulator PKC-ßI and SGLT1 protein. Junk-food and high-fat diet feeding also caused higher membrane expression of GLUT2 and its upstream regulator PKC-ßI. However, the junk-food diet also increased SGLT1 and SGLT2 levels at the proximal tubule BBM. Glucose reabsorption across the proximal tubule BBM, via GLUT2, SGLT1 and SGLT2, is not solely dependent on glycaemic status, but is also influenced by diet-induced changes in glucose metabolism. We conclude that different metabolic disturbances result in complex adaptations in renal glucose transporter protein levels and function.

Experimental and regional variations in Na+-dependent and Na+-independent phosphate transport along the rat small intestine and colon.

Despite the importance of extracellular phosphate in many essential biological processes, the mechanisms of phosphate transport across the epithelium of different intestinal segments remain unclear. We have used an in vitro method to investigate phosphate transport at the brush border membrane (BBM) of intact intestinal segments and an in vivo method to study transepithelial phosphate absorption. We have used micromolar phosphate concentrations known to favor NaPi-IIb-mediated transport, and millimolar concentrations that are representative of the levels we have measured in luminal contents, to compare the extent of Na(+)-dependent and Na(+)-independent phosphate transport along the rat duodenum, jejunum, ileum, and proximal and distal colon. Our findings confirm that overall the jejunum is the main site of phosphate absorption; however, at millimolar concentrations, absorption shows ~30% Na(+)-dependency, suggesting that transport is unlikely to be mediated exclusively by the Na(+)-dependent NaPi-IIb co-transporter. In the ileum, studies in vitro confirmed that relatively low levels of phosphate transport occur at the BBM of this segment, although significant Na(+)-dependent transport was detected using millimolar levels of phosphate in vivo. Since NaPi-IIb protein is not detectable at the rat ileal BBM, our data suggest the presence of an as yet unidentified Na(+)-dependent uptake pathway in this intestinal segment in vivo. In addition, we have confirmed that the colon has a significant capacity for phosphate absorption. Overall, this study highlights the complexities of intestinal phosphate absorption that can be revealed using different phosphate concentrations and experimental techniques.

Intestinal phosphate transport: a therapeutic target in chronic kidney disease and beyond?

Hyperphosphatemia is a serious complication of late-stage chronic kidney disease (CKD), contributing to the increased cardiovascular morbidity and mortality seen in this patient group. Results from retrospective studies suggest that small increases in serum phosphate concentration, within the normal or near-normal range, also correlate with increased cardiovascular morbidity and mortality and have led to the suggestion that detection and preventative treatment of positive phosphate balance is important in healthy individuals as well as in those with CKD. Phosphate homeostasis is maintained by the crosstalk between intestinal phosphate absorption and renal phosphate excretion; however, relatively little is known about the mechanisms of intestinal phosphate transport. Our current understanding is that the intestinal type II sodium phosphate cotransporter, NaPi-IIb, plays a significant role in absorption. It may also be involved in the sensing of dietary phosphate composition and the release of hormonal factors that modulate renal phosphate reabsorption to achieve phosphate balance. Interestingly, studies using NaPi-IIb knockout mice with adenine-induced CKD show only partial attenuation of hyperphosphatemia, suggesting that an additional sodium-independent pathway is involved in phosphate absorption. The aim of this review is to discuss our current knowledge of the processes and role of the intestine in phosphate homeostasis and to provide evidence that this organ could be targeted for the treatment of hypophosphatemia and hyperphosphatemia.

The role of the gastrointestinal tract in phosphate homeostasis in health and chronic kidney disease.

PURPOSE OF REVIEW: For a number of years, there has been increasing interest in the concept of directly targeting intestinal phosphate transport to control hyperphosphatemia in chronic kidney disease. However, progress has been slow due to the paucity of information on the mechanisms involved in intestinal phosphate absorption. This editorial highlights the most recent developments in our understanding of this process and the role of the intestine in the maintenance of phosphate balance. RECENT FINDINGS: Recent studies in NaPi-IIb knockout mice have confirmed that this transport protein plays a significant role in intestinal phosphate absorption and is critical in the proposed feed-forward mechanism between the small intestine and kidney, which helps to maintain normal phosphate balance and steady-state plasma phosphate concentrations. In addition, renal failure-induced hyperphosphatemia is attenuated in NaPi-IIb knockout mice, confirming that NaPi-IIb is a suitable target in the prevention and treatment of hyperphosphatemia. SUMMARY: Recent findings suggest that consumption of processed foods containing phosphate preservatives may lead to excessive phosphate exposure (if not overload), toxicity, and cardiovascular disease in the general population, as well as in patients with declining renal function. Therefore, establishing more effective ways of targeting the intestine to limit dietary phosphate absorption could have wide-reaching health benefits.