Elevated plasma urate levels are associated with metabolic, cardiovascular, and renal diseases. Urate may also form crystals, which can be deposited in joints causing gout and in kidney tubules inducing nephrolithiasis. In mice, plasma urate levels are controlled by hepatic breakdown, as well as, by incompletely understood renal processes of reabsorption and secretion. Here, we investigated the role of the recently identified urate transporter, Glut9, in the physiological control of urate homeostasis using mice with systemic or liver-specific inactivation of the Glut9 gene. We show that Glut9 is expressed in the basolateral membrane of hepatocytes and in both apical and basolateral membranes of the distal nephron. Mice with systemic knockout of Glut9 display moderate hyperuricemia, massive hyperuricosuria, and an early-onset nephropathy, characterized by obstructive lithiasis, tubulointerstitial inflammation, and progressive inflammatory fibrosis of the cortex, as well as, mild renal insufficiency. In contrast, liver-specific inactivation of the Glut9 gene in adult mice leads to severe hyperuricemia and hyperuricosuria, in the absence of urate nephropathy or any structural abnormality of the kidney. Together, our data show that Glut9 plays a major role in urate homeostasis by its dual role in urate handling in the kidney and uptake in the liver.gout ͉ knockout ͉ nephrolithiasis ͉ uric acid

Activation of the hepatoportal glucose sensors by portal glucose infusion leads to increased glucose clearance and induction of hypoglycemia. Here, we investigated whether glucagon-like peptide-1 (GLP-1) could modulate the activity of these sensors. Mice were therefore infused with saline (S-mice) or glucose (P-mice) through the portal vein at a rate of 25 mg/kg ⅐ min. In P-mice, glucose clearance increased to 67.5 ؎ 3.7 mg/ kg ⅐ min as compared with 24.1 ؎ 1.5 mg/kg ⅐ min in S-mice, and glycemia decreased from 5.0 ؎ 0.1 to 3.3 ؎ 0.1 mmol/l at the end of the 3-h infusion period. Coinfusion of GLP-1 with glucose into the portal vein at a rate of 5 pmol/kg ⅐ min (P-GLP-1 mice) did not increase the glucose clearance rate (57.4 ؎ 5.0 ml/kg ⅐ min) and hypoglycemia (3.8 ؎ 0.1 mmol/l) observed in P-mice. In contrast, coinfusion of glucose and the GLP-1 receptor antagonist exendin-(9-39) into the portal vein at a rate of 0.5 pmol/kg ⅐ min (P-Ex mice) reduced glucose clearance to 36.1 ؎ 2.6 ml/kg ⅐ min and transiently increased glycemia to 9.2 ؎ 0.3 mmol/l at 60 min of infusion before it returned to the fasting level (5.6 ؎ 0.3 mmol/l) at 3 h. When glucose and exendin-(9-39) were infused through the portal and femoral veins, respectively, glucose clearance increased to 70.0 ؎ 4.6 ml/kg ⅐ min and glycemia decreased to 3.1 ؎ 0.1 mmol/l, indicating that exendin-(9-39) has an effect only when infused into the portal vein. Finally, portal vein infusion of glucose in GLP-1 receptor ؊/؊ mice failed to increase the glucose clearance rate (26.7 ؎ 2.9 ml/kg ⅐ min). Glycemia increased to 8. A fter a meal, glucose is absorbed by the intestine and collected into the hepatoportal vein. A positive glucose concentration gradient between the hepatoportal vein and arterial blood is thus established. Glucose-sensitive units present in the hepatoportal vein detect this gradient (1-3) and send a signal through the hepatic branch of the vagus nerve to target tissues such as the liver (4 -8), the hypothalamus (9,10), insulin-secreting ␤-cells (11), the brain stem (12), and the adrenal glands (13,14). The specific cellular functions that are activated then participate in the adaptation of the body to the new metabolic situation. We previously described that one of the consequences of activating the hepatoportal glucose sensor was an increase in blood glucose clearance and utilization in a subset of tissues, mostly heart, soleus, and brown adipose tissue (15). We also showed that activation of this sensor was inhibited by somatostatin and that it required the presence of the glucose transporter GLUT2 (16).The best-described glucose sensing system is the insulin-secreting pancreatic ␤-cells (17). In these cells, glucose induces insulin secretion by a mechanism that depends on glucose metabolism. This secretory activity can be strongly potentiated by hormones such as the glucoincretin glucagon-like peptide-1 (GLP-1). This hormone is secreted postprandially by intestinal L-cells in the portal vein and reaches the pancreatic ␤-cells, where it binds ...

Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr -/-mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link. IntroductionHepatic glucose metabolism is highly regulated during the fed-tofast transition by changes in plasma levels of insulin and glucagon, but also by the changes in blood glucose concentrations. In the fed state, the presence of high insulin concentrations in the portal circulation favors storage of glucose in the form of glycogen and the use of glucose through the glycolytic pathway for its conversion into fatty acids. Important regulatory events activated during the absorptive phase include the transcriptional induction of glucokinase by insulin and of L-pyruvate kinase by the carbohydrate-responsive element-binding protein (ChREBP), which translocates to the nucleus following its dephosphorylation by a glucose metabolite-activated phosphatase (1). At the same time, glucose inhibits glycogen phosphorylase through inhibition of glycogen phosphorylase phosphatase, whereas glucose-6-phosphate activates glycogen synthase (2), thus favoring glycogen biosynthesis. The combination of insulin-dependent Srebp-1c and glucose-dependent ChREBP activation then induces the expression of lipogenic genes, including Acc, Fas, and Scd1 (1, 3).In the fasted state, the decrease in glycemia reduces the intracellular levels of glucose and glucose-6-phosphate, thereby favoring glycogen degradation and reducing the activation of ChREBP and the expression of L-pyruvate kinase and lipogenic genes. Higher glucagon levels favor the gluconeogenic pathway by inducing the expression of PEPCK and G6Pase that catalyzes the hydrolysis of glucose-6-phosphate into glucose, a reaction that takes place in the lumen of the ER. The last steps of glucose output

Malaria diagnosis presents a challenge to all laboratories. There is a need for rapid, sensitive, and cost-effective screening on all samples, particularly in areas where malaria is endemic. Response to malaria infection involves an increased monocyte count and production of large activated monocytes. These changes can be detected by volume, conductivity, and scatter (VCS) technology on certain automated blood cell counters (Beckman Coulter, Miami, FL). The SD of the volume of lymphocytes and monocytes demonstrates a significant difference from normal when malaria is present. By using a calculation derived from the SD volume of the lymphocytes and monocytes, herein termed the malaria factor, sensitivity of 98% and specificity 94% were demonstrated for the detection of malaria. Based on this derived discriminant, VCS technology should become a useful tool in the detection of malaria. A flag to indicate the potential presence of malaria could then be generated by the instrument if the user or manufacturer chose to do so.

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