GLUT8 Is Dispensable for Embryonic Development but Influences Hippocampal Neurogenesis and Heart Function

Membrez, Mathieu; Hummler, Edith; Beermann, Friedrich; Haefliger, Jacques‐Antoine; Savioz, Rebecca; Pedrazzini, Thierry; Thorens, Bernard

doi:10.1128/mcb.00081-06

Cited by 50 publications

(60 citation statements)

References 24 publications

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“…The presence of the Neo cassette did not interfere with GLUT2 expression as revealed by Western blot analysis ( Figure 1B). Deletion of the last transmembrane domain and C-tail of GLUT2 suppresses glucose transport activity (14,15), as found for the deletion of the same transmembrane domain of GLUT8 (16) and GLUT4 (13).…”

Section: Resultssupporting

confidence: 67%

Hepatic glucose sensing is required to preserve β cell glucose competence

Seyer¹,

Vallois²,

et al. 2013

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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

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Section: Resultssupporting

confidence: 67%

Hepatic glucose sensing is required to preserve β cell glucose competence

Seyer¹,

Vallois²,

et al. 2013

Self Cite

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“…The eff ect of the inactivation of the Glut8 gene has been recently shown to produce mice with normal postnatal development in two studies [25,34] . One of them show mild alterations in brain and heart for knockout mice [34] , whereas in the most recent work a lower number of Glut8 -/ -off spring, associated with lower ATP levels, a reduced mitochondrial membrane potential, and a reduction of sperm motility was described [25] .…”

Section: Discussionmentioning

confidence: 99%

Expression and Regulation of Insulin and the Glucose Transporter GLUT8 in the Testes of Diabetic Rats

Gómez¹,

Ballester²,

Romero³

et al. 2009

Horm Metab Res

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Diabetes induces several malfunctions in male germ cells. The aim of this study was to analyze the levels and localization of the glucose transporter GLUT8 and insulin in the testes of rats induced to a diabetic status by a single dose of streptozotocin. One month after inducing diabetes, the GLUT8 immunoreactivity in diabetic rats was mainly located associated to the acrosomic system of spermatids, and at low levels in Leydig cells. Neither the immunohistochemical localization of this transporter nor its levels showed any difference when compared to control rats. Furthermore, it was observed that control rat testes expressed insulin, which was diffusely located in the cytoplasm of both Leydig cells and early elongated spermatids and concentrated in a cytoplasmic compartment in the more mature spermatids. Testicular insulin levels measured by western blot were reduced by more than half in diabetic rats, although the distribution of the hormone was unchanged. These results indicate that i) insulin is produced by testicular cells, ii) insulin is depleted by streptozotocin-induced diabetes, and iii) that insulin depletion and hyperglycemia do not regulate the expression of GLUT8 in testes. These results also suggest that testicular production of insulin could play a role in regulating spermatogenesis and/or glucose metabolism in these organs.

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“…It has been shown that GLUT8 mRNA levels increase dramatically during late pregnancy to early lactation in bovine and mouse mammary gland, indicating a potential role in glucose uptake for milk synthesis in this tissue [62]. GLUT8 knock-out mice were recently reported to display normal embryonic and postnatal development and glucose homeostasis, but mild defects in hippocampal neurogenesis and cardiac function [63].…”

Section: Glut8 (Slc2a8)mentioning

confidence: 99%

Functional Properties and Genomics of Glucose Transporters

Zhao

Keating²

2007

486

393

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Glucose is the major energy source for mammalian cells as well as an important substrate for protein and lipid synthesis. Mammalian cells take up glucose from extracellular fluid into the cell through two families of structurallyrelated glucose transporters. The facilitative glucose transporter family (solute carriers SLC2A, protein symbol GLUT) mediates a bidirectional and energy-independent process of glucose transport in most tissues and cells, while the Na + /glucose cotransporter family (solute carriers SLC5A, protein symbol SGLT) mediates an active, Na + -linked transport process against an electrochemical gradient. The GLUT family consists of thirteen members (GLUT1-12 and HMIT). Phylogenetically, the members of the GLUT family are split into three classes based on protein similarities. Up to now, at least six members of the SGLT family have been cloned (SGLT1-6). In this review, we report both the genomic structure and function of each transporter as well as intra-species comparative genomic analysis of some of these transporters. The affinity for glucose and transport kinetics of each transporter differs and ranges from 0.2 to 17mM. The ability of each protein to transport alternative substrates also differs and includes substrates such as fructose and galactose. In addition, the tissue distribution pattern varies between species. There are different regulation mechanisms of these transporters. Characterization of transcriptional control of some of the gene promoters has been investigated and alternative promoter usage to generate different protein isoforms has been demonstrated. We also introduce some pathophysiological roles of these transporters in human.

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GLUT8 Is Dispensable for Embryonic Development but Influences Hippocampal Neurogenesis and Heart Function

Cited by 50 publications

References 24 publications

Hepatic glucose sensing is required to preserve β cell glucose competence

Hepatic glucose sensing is required to preserve β cell glucose competence

Expression and Regulation of Insulin and the Glucose Transporter GLUT8 in the Testes of Diabetic Rats

Functional Properties and Genomics of Glucose Transporters

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