Localization and regulation of GLUTx1 glucose transporter in the hippocampus of streptozotocin diabetic rats

Reagan, Lawrence P.; Gorovits, Naira; Hoskin, Elena; Alves, Stephen E.; Katz, Ellen B.; Grillo, Claudia A.; Piroli, Gerardo G.; McEwen, Bruce S.; Charron, Maureen J.

doi:10.1073/pnas.051629798

Cited by 94 publications

(68 citation statements)

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“…non-diabetic) animals, hippocampus-dependent learning is correlated with a decrease in extracellular glucose levels, and intrahippocampal injection of glucose improves performance 41 . No studies to date have reported an effect of diabetes on learning-induced changes in hippocampal glucose metabolism, but alterations in basal hippocampal glucose transporter expression have been demonstrated in diabetic animals 42 . While we observed no difference in glucose levels in whole hippocampal homogenates from insulin resistant mice or insulin deficient rats, our results do not preclude a role for corticosterone in modulating the diabetes-induced alterations in hippocampal glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

et al. 2008

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Multiple organ systems are adversely affected by diabetes, including the brain, which undergoes changes that may increase the risk of cognitive decline. Although diabetes influences the hypothalamic-pituitary-adrenal axis, the role of this neuroendocrine system in diabetes-induced cognitive dysfunction remains unexplored. Here we demonstrate that, in both insulin-deficient rats and insulin-resistant mice, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity and adult neurogenesis, and the adrenal steroid corticosterone contributes to these adverse effects. Rats treated with streptozocin have reduced levels of insulin, and exhibit hyperglycemia, increased levels of corticosterone, and impairments in hippocampal neurogenesis, synaptic plasticity and learning. Similar deficits are observed in db/db mice, which are characterized by insulin resistance, elevated corticosterone levels and obesity. Changes in hippocampal plasticity and function in both models are reversed when normal physiological levels of corticosterone are maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoidmediated deficits in neurogenesis and synaptic plasticity. Keywords glucocorticoid; dentate gyrus; streptozotocin; water maze; object recognition As a result of high calorie diets and sedentary lifestyles, diabetes is rapidly becoming more prevalent in Western societies 1 . In addition to its well-known adverse effects on the cardiovascular and peripheral nervous systems, diabetes also appears to negatively impact the brain, increasing the risk of depression and dementia2 , 3 . Human subjects with either type 1 (caused by insulin deficiency) or type 2 (mediated by insulin resistance) diabetes typically exhibit impaired cognitive function compared to age-matched non-diabetic subjects 3,4 . Cognitive deficits have also been documented in studies of rodent models of diabetes. For Supplementary Information accompanies this paper.Competing interests statement. The authors declare that they have no competing financial interests. Conflict of Interest:The authors declare no conflict of interest. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2010 August 25. Published in final edited form as:Nat Neurosci. 2008 March ; 11(3): 309-317. doi:10.1038/nn2055. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript example, rats rendered diabetic by treatment with the pancreatic β-cell toxin streptozocin (STZ; a model of type 1 diabetes) exhibit impaired performance in tests of spatial learning ability 5, 6. Similar deficits have been reported in the db/db mouse7, a model of Type 2 diabetes in which obesity, hyperglycemia, and elevations in circulating corticosterone levels arise from a mutation that inactivates the leptin receptor 8 . However, the mechanism(s) responsible for cognitive dysfunction in diabetes has not been established.Within the hippocampus, changes in the strength of synapses between groups of neurons play a critic...

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Section: Discussionmentioning

confidence: 99%

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

et al. 2008

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“…Similarly, glucose transport is probably not a key regulator of neuronal glucosensing because the predominant neuronal transporter, GLUT-3, is ubiquitous and saturated at physiological brain glucose concentrations (34). Other brain glucose transporters (GLUT-1, -2, -4, and -8) have either inappropriate anatomic or cell type localizations (35)(36)(37)(38).…”

Section: Diabetes Vol 51 July 2002mentioning

confidence: 99%

Glucokinase Is the Likely Mediator of Glucosensing in Both Glucose-Excited and Glucose-Inhibited Central Neurons

et al. 2002

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Specialized neurons utilize glucose as a signaling molecule to alter their firing rate. Glucose-excited (GE) neurons increase and glucose-inhibited (GI) neurons reduce activity as ambient glucose levels rise. Glucoseinduced changes in the ATP-to-ADP ratio in GE neurons modulate the activity of the ATP-sensitive K ؉ channel, which determines the rate of cell firing. The GI glucosensing mechanism is unknown. We postulated that glucokinase (GK), a high-Michaelis constant (K m ) hexokinase expressed in brain areas containing populations of GE and GI neurons, is the controlling step in glucosensing. Double-label in situ hybridization demonstrated neuron-specific GK mRNA expression in locus ceruleus norepinephrine and in hypothalamic neuropeptide Y, pro-opiomelanocortin, and ␥-aminobutyric acid neurons, but it did not demonstrate this expression in orexin neurons. GK mRNA was also found in the area postrema/nucleus tractus solitarius region by RT-PCR. Intracarotid glucose infusions stimulated c-fos expression in the same areas that expressed GK. At 2.5 mmol/l glucose, fura-2 Ca 2؉ imaging of dissociated ventromedial hypothalamic nucleus neurons demonstrated GE neurons whose intracellular Ca 2؉ oscillations were inhibited and GI neurons whose Ca 2؉ oscillations were stimulated by four selective GK inhibitors. Finally, GK expression was increased in rats with impaired central glucosensing (posthypoglycemia and diet-induced obesity) but was unaffected by a 48-h fast. These data suggest a critical role for GK as a regulator of glucosensing in both GE and GI neurons in the brain. S pecialized neurons utilize glucose as a signaling molecule rather than as an energy substrate. Glucose-excited (GE) neurons increase, whereas glucose-inhibited (GI) neurons decrease, their firing rate as ambient glucose levels rise (1-3). It is unclear how GI neurons sense glucose, but GE neurons function much like the pancreatic ␤-cell, which utilizes the ATPsensitive K ϩ (K ATP ) channel to sense glucose and regulate insulin secretion (2-7). Although many neurons contain K ATP channels, few exhibit glucosensing properties (8,9). This makes control of glycolysis a major candidate as a regulator of ATP production and K ATP channel activity (6). The pancreatic form of glucokinase (GK; hexokinase IV, ATP:D-glucose 6-phosphotransferase) is selectively expressed in brain areas where glucosensing neurons reside (5,10 -12). GK has the physiological properties that would make it an ideal regulator of glucosensing in neurons (6,13). Previous studies examined a role for GK in hypothalamic glucosensing neurons in brain slice preparations, where presynaptic inputs could not be excluded, and under conditions outside the physiological range of brain glucose (4,5). The current studies provide new data on the neurotransmitter and peptide phenotype of neurons expressing GK, the regulatory role of GK in isolated hypothalamic GE and GI neuron activity, and the in vivo conditions associated with altered brain GK expression. RESEARCH DESIGN AND METHODSAnimals. All ...

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“…GLUT8 mRNA is widely expressed in tissues including brain (cerebellum, brainstem, hippocampus, and hypothalamus), adrenal gland, spleen, brown adipose tissue, white adipose tissue, placenta, muscle, heart, and liver. The concentration of GLUT8 mRNA is greatest in testis [132][133][134][135][136] where its expression has been linked to circulating gonadotropins. Estrogen treatment suppressed GLUT8 expression in testis [133], and no expression of GLUT8 mRNA could be detected in testis of prepubertal (12 days) mice.…”

Section: Glut8mentioning

confidence: 99%

“…More recently GLUT8 was immunolocalized to the acrosome in sperm suggesting that GLUT8 may be important in maintaining reproductive function and/or fertility [138]. Utilizing immunohistochemistry and emulsion autoradiographic analysis, GLUT8 has been detected in rat hippocampal neurons and localized to the cytoplasm of neuronal cell bodies [135]. The absence of other glucose transporters and increased expression of GLUT8 mRNA in STZ diabetes in this subset of neurons highlighted a possible contribution of GLUT8 in supporting glucose requirements of hippocampal neuronal cell bodies and their cognitive function [135].…”

Section: Glut8mentioning

confidence: 99%

“…Utilizing immunohistochemistry and emulsion autoradiographic analysis, GLUT8 has been detected in rat hippocampal neurons and localized to the cytoplasm of neuronal cell bodies [135]. The absence of other glucose transporters and increased expression of GLUT8 mRNA in STZ diabetes in this subset of neurons highlighted a possible contribution of GLUT8 in supporting glucose requirements of hippocampal neuronal cell bodies and their cognitive function [135]. Importantly localization of GLUT8 in the hippocampus demonstrated that it is mainly an intracellular protein.…”

Section: Glut8mentioning

confidence: 99%

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What we know about facilitative glucose transporters: Lessons from cultured cells, animal models, and human studies

Gorovits

Charron

2003

Biochem Molecular Bio Educ

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Glucose uptake by all cells in the organism by glucose transport proteins is among the most essential processes in life. The process of glucose uptake into tissues is performed by glucose transporters. This review focuses on the biology of facilitative glucose transporters (GLUTs). The knowledge that has accumulated for more than a decade with respect to the regulation of GLUT expression and function in various experimental conditions points to the great potential for GLUTs to be utilized as targets for designing therapies for treatment of diseases related to impaired regulation of glucose homeostasis including type 2 diabetes.Keywords: Glucose uptake, GLUT, insulin action, diabetes.The entry of glucose into cells is a crucial step in lifesupporting processes since glucose is the main monosaccharide in nature that provides carbon and energy for almost all cells. The passage of glucose into cells depends on different parameters, including expression of the appropriate glucose transporters in the target tissues and hormonal regulation of their function. Single cell eucaryotes such as Saccharomyces cerevisiae possess 20 genes encoding glucose or glucose-like transporters and express the glucose transporters most appropriate for the amount of glucose available [1]. In mammalian cells a tight regulation of blood glucose levels is needed to meet the energetic demands of the brain, a tissue that uses glucose as its primary energy source [2,3]. Adequate glucose flux into tissues provides maintenance of glucose homeostasis that is critical in well being. Transport of glucose across the plasma membrane is accomplished by two families of glucose transporters: sodium-glucose co-transporters (SGLT 1 1-3), mainly expressed in the apical membrane of renal and intestinal absorptive epithelial cells that transport glucose against its concentration gradient and utilize ATP (for a review, see Ref. 4), and facilitative glucose transporters (GLUTs) that are expressed in all cells that transport glucose down a concentration gradient [5][6][7]. Until now the search for the mammalian facilitative glucose transporters has yielded 12 carriers including GLUT1-5 and the recently discovered GLUT6 -12. GLUT1-4 share greater than 40% homology [8], and GLUT5, which is a fructose transporter, exhibits 42, 40, 38, and 41.6% identity with GLUT1, GLUT2, GLUT3, and GLUT4, respectively [9]. All GLUTs have been predicted to have 12 membrane-spanning domains (helices) connected by hydrophilic loops, the first of which is exofacial and contains an N-glycosylation site in GLUT1-5 (Fig. 1) [8,10]. Both the amino and carboxyl termini of GLUTs reside on the cytoplasmic side of the cell membrane [11]. The carboxyl termini of all GLUTs have unique amino acid sequences that have been utilized for development of reagents. The common sensitivity of the GLUT family to the inhibitory action of the fungal metabolite cytochalasin B has been reported widely and is utilized in studies of hexose transporters [12]. Substrate selectivity of GLUTs is dictated by conserve...

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Localization and regulation of GLUTx1 glucose transporter in the hippocampus of streptozotocin diabetic rats

Cited by 94 publications

References 35 publications

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

Glucokinase Is the Likely Mediator of Glucosensing in Both Glucose-Excited and Glucose-Inhibited Central Neurons

What we know about facilitative glucose transporters: Lessons from cultured cells, animal models, and human studies

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