Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses

2001 ◽  
Vol 281 (4) ◽  
pp. E649-E654 ◽  
Author(s):  
Charles V. Mobbs ◽  
Lee-Ming Kow ◽  
Xue-Jun Yang
Keyword(s):  
Glucose Concentration ◽  
Glucose Sensing ◽  
Hypothalamic Neurons ◽  
Brain Glucose ◽  
Malonyl Coa ◽  
Extracellular Glucose Concentration ◽  
Extracellular Glucose ◽  
Neuroendocrine Responses ◽  
Metabolic Signal

Interest in brain glucose-sensing mechanisms is motivated by two distinct neuronal responses to changes in glucose concentrations. One mechanism is global and ubiquitous in response to profound hypoglycemia, whereas the other mechanism is largely confined to specific hypothalamic neurons that respond to changes in glucose concentrations in the physiological range. Although both mechanisms use intracellular metabolism as an indicator of extracellular glucose concentration, the two mechanisms differ in key respects. Global hyperpolarization (inhibition) in response to 0 mM glucose can be reversed by pyruvate, implying that the reduction in ATP levels acting through ATP-dependent potassium (K-ATP) channels is the key metabolic signal for the global silencing in response to 0 mM glucose. In contrast, neuroendocrine hypothalamic responses in glucoresponsive and glucose-sensitive neurons (either excitation or inhibition, respectively) to physiological changes in glucose concentration appear to depend on glucokinase; neuroendocrine responses also depend on K-ATP channels, although the role of ATP itself is less clear. Lactate can substitute for glucose to produce these neuroendocrine effects, but pyruvate cannot, implying that NADH (possibly leading to anaplerotic production of malonyl-CoA) is a key metabolic signal for effects of glucose on glucoresponsive and glucose-sensitive hypothalamic neurons.

PKC-mediated toxicity of elevated glucose concentration on cardiomyocyte function

2014 ◽  
Vol 307 (4) ◽  
pp. H587-H597 ◽  
Author(s):  
Mark W. Sims ◽  
James Winter ◽  
Sean Brennan ◽  
Robert I. Norman ◽  
G. André Ng ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Concentration ◽  
Contractile Function ◽  
Blood Glucose Concentration ◽  
Specific Inhibitor ◽  
Wistar Rat ◽  
Patch Clamp Recording ◽  
Electrical Stability ◽  
Extracellular Glucose Concentration ◽  
Extracellular Glucose

While it is well established that mortality risk after myocardial infarction (MI) increases in proportion to blood glucose concentration at the time of admission, it is unclear whether there is a direct, causal relationship. We investigated potential mechanisms by which increased blood glucose may exert cardiotoxicity. Using a Wistar rat or guinea-pig isolated cardiomyocyte model, we investigated the effects on cardiomyocyte function and electrical stability of alterations in extracellular glucose concentration. Contractile function studies using electric field stimulation (EFS), patch-clamp recording, and Ca2+ imaging were used to determine the effects of increased extracellular glucose concentration on cardiomyocyte function. Increasing glucose from 5 to 20 mM caused prolongation of the action potential and increased both basal Ca2+ and variability of the Ca2+ transient amplitude. Elevated extracellular glucose concentration also attenuated the protection afforded by ischemic preconditioning (IPC), as assessed using a simulated ischemia and reperfusion model. Inhibition of PKCα and β, using Gö6976 or specific inhibitor peptides, attenuated the detrimental effects of glucose and restored the cardioprotected phenotype to IPC cells. Increased glucose concentration did not attenuate the cardioprotective role of PKCε, but rather activation of PKCα and β masked its beneficial effect. Elevated extracellular glucose concentration exerts acute cardiotoxicity mediated via PKCα and β. Inhibition of these PKC isoenzymes abolishes the cardiotoxic effects and restores IPC-mediated cardioprotection. These data support a direct link between hyperglycemia and adverse outcome after MI. Cardiac-specific PKCα and β inhibition may be of clinical benefit in this setting.

scholarly journals Long-term effects of glucose on insulin release and glucose oxidation by mouse pancreatic islets maintained in tissue culture

1974 ◽  
Vol 140 (3) ◽  
pp. 377-382 ◽  
Author(s):  
Arne Andersson
Keyword(s):  
Tissue Culture ◽  
B Cells ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
High Glucose ◽  
Glucose Concentration ◽  
Glucose Oxidation ◽  
Extracellular Glucose Concentration ◽  
Extracellular Glucose ◽  
Mouse Pancreatic Islets

Rates of glucose oxidation and insulin release in response to a wide range of glucose concentrations were studied in short-term experiments in isolated mouse pancreatic islets maintained in tissue culture for 6 days at either a physiological glucose concentration (6.7mm) or at a high glucose concentration (28mm). The curves relating glucose oxidation or insulin release to the extracellular glucose concentration obtained with islets cultured in 6.7mm-glucose displayed a sigmoid shape similar to that observed for freshly isolated non-cultured islets. By contrast islets that had been cultured in 28mm-glucose showed a linear relationship between the rate of glucose oxidation and the extracellular glucose concentration up to about 8mm-glucose. The maximal oxidative rate was twice that of the non-cultured islets and the glucose concentration associated with the half-maximal rate considerably decreased. In islets cultured at 28mm-glucose there was only a small increase in the insulin release in response to glucose, probably due to a depletion of stored insulin in those B cells that had been cultured in a high-glucose medium. It is concluded that exposure of B cells for 6 days to a glucose concentration comparable with that found in diabetic individuals causes adaptive metabolic alterations rather than degeneration of these cells.

Glucose metabolism in rat hypothalamus

1981 ◽  
Vol 98 (4) ◽  
pp. 481-487 ◽  
Author(s):  
Pentti Lautala ◽  
Julio M. Martin
Keyword(s):  
Glucose Metabolism ◽  
Glucose Transport ◽  
Glucose Concentration ◽  
Glucose Oxidation ◽  
Glucose Utilization ◽  
Rat Hypothalamus ◽  
Extracellular Glucose Concentration ◽  
Extracellular Glucose ◽  
Phenazine Methosulphate

Abstract. In vitro glucose oxidation and glucose transport in the rat medial (MH) and lateral (LH) hypothalamic areas was measured. Glucose oxidation was calculated from the conversion of [U-14C]glucose to 14C02 and glucose transport from 14C02 produced from [114C]glucose in the presence of phenazine methosulphate and NaF. Increasing glucose in the medium from 1 him to 20 mm enhanced glucose oxidation two-fold in MH and 40% in LH. Addition of insulin, 100 (iU/ml, to the medium decreased glucose oxidation 30% both in MH and LH at both 4 mm and 20 mm glucose. Fasting did not affect glucose oxidation in either of these hypothalamic areas. Glucose transport was not affected by insulin, but was increased significantly when glucose was raised from 0.25 mm to 1.0 mm. Fasting also increased glucose transport in both hypothalamic areas. In conclusion, extracellular glucose concentration seems to be the major regulator of glucose utilization by the rat hypothalamus. Insulin, rather than increasing, seems to decrease glucose oxidation while having no effect on glucose transport.

Periodic high extracellular glucose enhances production of collagens III and IV by mesangial cells

1995 ◽  
Vol 268 (1) ◽  
pp. F13-F19 ◽  
Author(s):  
A. Takeuchi ◽  
D. C. Throckmorton ◽  
A. P. Brogden ◽  
N. Yoshizawa ◽  
H. Rasmussen ◽  
...  
Keyword(s):  
Glucose Concentration ◽  
Cellular Proliferation ◽  
Type I Collagen ◽  
Mesangial Cells ◽  
Blood Glucose Concentration ◽  
Type Iii Collagen ◽  
Type I ◽  
Extracellular Glucose Concentration ◽  
Extracellular Glucose ◽  
Matrix Production

We examined the effects of periodic changes in extracellular glucose concentration on matrix production and proliferation using three groups of cultured rat mesangial cells (MCs): 1) MCs in medium with continuous 5 mM glucose (CL), 2) MCs in medium alternating daily between 5 and 25 mM glucose (PH), and 3) MCs in medium with continuous 25 mM glucose (CH). MCs cultured in PH for 10 days produced 329 and 110% more type III collagen protein than MCs cultured in CL and CH, respectively. MCs cultured in PH induced 31 and 14% more type IV collagen than MCs cultured in CL and CH, respectively. Extracellular glucose concentration had no effect on the amount of type I collagen produced. MCs cultured in PH or CH for 5 days also expressed increased levels of type I, III, and IV collagen mRNA compared with MCs cultured in CL. MCs cultured in PH for 8-10 days also produced significantly more DNA than MCs in CL or CH. These data suggest that the temporal pattern of exposure to high extracellular glucose plays a role in regulating matrix formation and cellular proliferation by MCs. Furthermore, periodic elevations of extracellular glucose had a greater stimulatory effect on collagen production than a sustained elevation. These results suggest that decreasing the variability of blood glucose concentration may decrease the adverse effect of elevated glucose levels on MC matrix production and the progression of diabetic glomerulopathy.

scholarly journals Glucose increases synaptic transmission from vagal afferent central nerve terminals via modulation of 5-HT3 receptors

2008 ◽  
Vol 295 (5) ◽  
pp. G1050-G1057 ◽  
Author(s):  
Shuxia Wan ◽  
Kirsteen N. Browning
Keyword(s):  
Synaptic Transmission ◽  
Glucose Concentration ◽  
Glutamate Release ◽  
Afferent Nerve ◽  
Excitatory Synaptic Transmission ◽  
Nerve Terminals ◽  
Extracellular Glucose Concentration ◽  
Extracellular Glucose ◽  
Vagal Afferent ◽  
Rat Brainstem

Acute hyperglycemia has profound effects on vagally mediated gastrointestinal functions. We have reported recently that the release of glutamate from the central terminals of vagal afferent neurons is correlated directly with the extracellular glucose concentration. The present study was designed to test the hypothesis that 5-HT3 receptors present on vagal afferent nerve terminals are involved in this glucose-dependent modulation of glutamatergic synaptic transmission. Whole-cell patch-clamp recordings were made from neurons of the nucleus tractus solitarius (NTS) in thin rat brainstem slices. Spontaneous and evoked glutamate release was decreased in a concentration-dependent manner by the 5-HT3 receptor selective antagonist, ondansetron. Alterations in the extracellular glucose concentration induced parallel shifts in the ondansetron-mediated inhibition of glutamate release. The changes in excitatory synaptic transmission induced by extracellular glucose concentration were mimicked by the serotonin uptake inhibitor, fenfluramine. These data suggest that glucose alters excitatory synaptic transmission within the rat brainstem via actions on tonically active 5-HT3 receptors, and the number of 5-HT3 receptors on vagal afferent nerve terminals is positively correlated with the extracellular glucose concentration. These data indicate that the 5-HT3 receptors present on synaptic connections between vagal afferent nerve terminals and NTS neurons are a strong candidate for consideration as one of the sites where glucose acts to modulate vagovagal reflexes.

scholarly journals ERK1/2 mediates glucose-regulated POMC gene expression in hypothalamic neurons

2015 ◽  
Vol 54 (2) ◽  
pp. 125-135 ◽  
Author(s):  
Juan Zhang ◽  
Yunting Zhou ◽  
Cheng Chen ◽  
Feiyuan Yu ◽  
Yun Wang ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Neuronal Cell ◽  
Glucose Sensing ◽  
Hypothalamic Neurons ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Low Glucose ◽  
Amp Activated Protein Kinase

Hypothalamic glucose-sensing neurons regulate the expression of genes encoding feeding-related neuropetides POMC, AgRP, and NPY – the key components governing metabolic homeostasis. AMP-activated protein kinase (AMPK) is postulated to be the molecular mediator relaying glucose signals to regulate the expression of these neuropeptides. Whether other signaling mediator(s) plays a role is not clear. In this study, we investigated the role of ERK1/2 using primary hypothalamic neurons as the model system. The primary neurons were differentiated from hypothalamic progenitor cells. The differentiated neurons possessed the characteristic neuronal cell morphology and expressed neuronal post-mitotic markers as well as leptin-regulated orexigenic POMC and anorexigenic AgRP/NPY genes. Treatment of cells with glucose dose-dependently increased POMC and decreased AgRP/NPY expression with a concurrent suppression of AMPK phosphorylation. In addition, glucose treatment dose-dependently increased the ERK1/2 phosphorylation. Blockade of ERK1/2 activity with its specific inhibitor PD98059 partially (approximately 50%) abolished glucose-induced POMC expression, but had little effect on AgRP/NPY expression. Conversely, blockade of AMPK activity with its specific inhibitor produced a partial (approximately 50%) reversion of low-glucose-suppressed POMC expression, but almost completely blunted the low-glucose-induced AgRP/NPY expression. The results indicate that ERK1/2 mediated POMC but not AgRP/NPY expression. Confirming the in vitro findings, i.c.v. administration of PD98059 in rats similarly attenuated glucose-induced POMC expression in the hypothalamus, but again had little effect on AgRP/NPY expression. The results are indicative of a novel role of ERK1/2 in glucose-regulated POMC expression and offer new mechanistic insights into hypothalamic glucose sensing.

scholarly journals Long-term effects of a high glucose concentration on cyclic nucleotide phosphodiesterase activity in mouse pancreatic islets maintained in tissue culture

1976 ◽  
Vol 156 (2) ◽  
pp. 461-463 ◽  
Author(s):  
C Berne ◽  
A Andersson
Keyword(s):  
Cyclic Amp ◽  
Pancreatic Islets ◽  
Glucose Concentration ◽  
Phosphodiesterase Activity ◽  
Long Term Effects ◽  
Isolated Pancreatic Islets ◽  
Cyclic Amp Phosphodiesterase ◽  
Extracellular Glucose Concentration ◽  
Extracellular Glucose

It has been suggested that the stimulatory effect of glucose on insulin release may be mediated by the adenylate cyclase-cyclic AMP phosphodiesterase system. In this study it was found that exposure of isolated pancreatic islets to an elevated extracellular glucose concentration for 1 week in vitro caused an increase of the cyclic AMP phosphodiesterase activity in the islet cells. These and previous data indicate that there is an increased turnover of cyclic AMP in B-cells exposed for a prolonged time to a high extracellular glucose concentration, which also causes an increased turnover rate of insulin.

scholarly journals Glucose-sensing neurons of the hypothalamus

2005 ◽  
Vol 360 (1464) ◽  
pp. 2227-2235 ◽  
Author(s):  
Denis Burdakov ◽  
Simon M Luckman ◽  
Alexei Verkhratsky
Keyword(s):  
Feeding Behaviour ◽  
Arcuate Nucleus ◽  
Glucose Sensing ◽  
Β Cell ◽  
Hypothalamic Neurons ◽  
Extracellular Glucose ◽  
Hypothalamic Arcuate Nucleus ◽  
Hypothalamic Cells ◽  
Melanin Concentrating Hormone ◽  
Cell Glucose

Specialized subgroups of hypothalamic neurons exhibit specific excitatory or inhibitory electrical responses to changes in extracellular levels of glucose. Glucose-excited neurons were traditionally assumed to employ a ‘β-cell’ glucose-sensing strategy, where glucose elevates cytosolic ATP, which closes K ATP channels containing Kir6.2 subunits, causing depolarization and increased excitability. Recent findings indicate that although elements of this canonical model are functional in some hypothalamic cells, this pathway is not universally essential for excitation of glucose-sensing neurons by glucose. Thus glucose-induced excitation of arcuate nucleus neurons was recently reported in mice lacking Kir6.2, and no significant increases in cytosolic ATP levels could be detected in hypothalamic neurons after changes in extracellular glucose. Possible alternative glucose-sensing strategies include electrogenic glucose entry, glucose-induced release of glial lactate, and extracellular glucose receptors. Glucose-induced electrical inhibition is much less understood than excitation, and has been proposed to involve reduction in the depolarizing activity of the Na + /K + pump, or activation of a hyperpolarizing Cl − current. Investigations of neurotransmitter identities of glucose-sensing neurons are beginning to provide detailed information about their physiological roles. In the mouse lateral hypothalamus, orexin/hypocretin neurons (which promote wakefulness, locomotor activity and foraging) are glucose-inhibited, whereas melanin-concentrating hormone neurons (which promote sleep and energy conservation) are glucose-excited. In the hypothalamic arcuate nucleus, excitatory actions of glucose on anorexigenic POMC neurons in mice have been reported, while the appetite-promoting NPY neurons may be directly inhibited by glucose. These results stress the fundamental importance of hypothalamic glucose-sensing neurons in orchestrating sleep-wake cycles, energy expenditure and feeding behaviour.

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