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

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

The physiological contribution of glucose in thermoregulation is not completely established nor whether this control may involve a regulation of the melanocortin pathway. Here, we assessed thermoregulation and leptin sensitivity of hypothalamic arcuate neurons in mice with inactivation of glucose transporter type 2 (Glut2)-dependent glucose sensing. Mice with inactivation of Glut2-dependent glucose sensors are cold intolerant and show increased susceptibility to food deprivation-induced torpor and abnormal hypothermic response to intracerebroventricular administration of 2-deoxy-d-glucose compared to control mice. This is associated with a defect in regulated expression of brown adipose tissue uncoupling protein I and iodothyronine deiodinase II and with a decreased leptin sensitivity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons, as observed during the unfed-to-refed transition or following i.p. leptin injection. Sites of central Glut-2 expression were identified by a genetic tagging approach and revealed that glucose-sensitive neurons were present in the lateral hypothalamus, the dorsal vagal complex, and the basal medulla but not in the arcuate nucleus. NPY and POMC neurons were, however, connected to nerve terminals from Glut2-expressing neurons. Thus, our data suggest that glucose controls thermoregulation and the leptin sensitivity of NPY and POMC neurons through activation of Glut2-dependent glucose-sensing neurons located outside of the arcuate nucleus.

How glucose sensing by the nervous system impacts the regulation of β cell mass and function during postnatal development and throughout adulthood is incompletely understood. Here, we studied mice with inactivation of glucose transporter 2 (Glut2) in the nervous system (NG2KO mice). These mice displayed normal energy homeostasis but developed late-onset glucose intolerance due to reduced insulin secretion, which was precipitated by high-fat diet feeding. The β cell mass of adult NG2KO mice was reduced compared with that of WT mice due to lower β cell proliferation rates in NG2KO mice during the early postnatal period. The difference in proliferation between NG2KO and control islets was abolished by ganglionic blockade or by weaning the mice on a carbohydrate-free diet. In adult NG2KO mice, first-phase insulin secretion was lost, and these glucose-intolerant mice developed impaired glucagon secretion when fed a high-fat diet. Electrophysiological recordings showed reduced parasympathetic nerve activity in the basal state and no stimulation by glucose. Furthermore, sympathetic activity was also insensitive to glucose. Collectively, our data show that GLUT2-dependent control of parasympathetic activity defines a nervous system/endocrine pancreas axis that is critical for β cell mass establishment in the postnatal period and for long-term maintenance of β cell function.

Insulin-like growth factor 2 (IGF2), produced and secreted by adult b-cells, functions as an autocrine activator of the b-cell insulin-like growth factor 1 receptor signaling pathway. Whether this autocrine activity of IGF2 plays a physiological role in b-cell and whole-body physiology is not known. Here, we studied mice with b-cell-specific inactivation of Igf2 (bIGF2KO mice) and assessed b-cell mass and function in aging, pregnancy, and acute induction of insulin resistance. We showed that glucose-stimulated insulin secretion (GSIS) was markedly reduced in old female bIGF2KO mice; glucose tolerance was, however, normal because of increased insulin sensitivity. While on a high-fat diet, both male and female bIGF2KO mice displayed lower GSIS compared with control mice, but reduced b-cell mass was observed only in female bIGF2KO mice. During pregnancy, there was no increase in b-cell proliferation and mass in bIGF2KO mice. Finally, b-cell mass expansion in response to acute induction of insulin resistance was lower in bIGF2KO mice than in control mice. Thus, the autocrine action of IGF2 regulates adult b-cell mass and function to preserve in vivo GSIS in aging and to adapt b-cell mass in response to metabolic stress, pregnancy hormones, and acute induction of insulin resistance.Glucose homeostasis depends on the balance between insulin secretion by pancreatic b-cells and insulin action on peripheral tissues (1). In response to the development of insulin resistance in muscle, liver, and fat, pancreatic b-cells increase their insulin secretion capacity in order to maintain normoglycemia. This compensatory response depends not only on an enhanced secretion capacity of individual b-cells but also, at least in rodents, on an increase in their number (2). In adult life, this plasticity is essential to maintain normoglycemia in insulin resistance conditions associated with obesity, pregnancy, and aging (3-5). Failure of this b-cell compensatory response leads to the onset of type 2 diabetes.The mechanisms by which insulin resistance in peripheral tissues induces compensatory insulin secretion capacity are incompletely understood. Their identification is, however, of highest interest for the development of novel therapies for diabetes. Evidence suggests that both circulating and nervous signals are involved. Glucose was one of the first signals identified to induce b-cell proliferation (6-8) through a signaling pathway that requires glucose metabolism, insulin secretion, and activation of the insulin receptor (IR)/Akt pathway (9,10). Incompletely characterized soluble factors, distinct from glucose, are produced by insulinresistant hepatocytes to increase b-cell mass (11,12), whereas bile acids can increase b-cell secretion capacity, independent of a change in b-cell number (13). Nerve connections between the liver and the islets can also potently stimulate b-cell proliferation (14).Increased b-cell proliferation and secretion capacity is a hallmark of pregnancy both in rodents and humans (3,15). This adaptive response i...