Effects of fluctuating glucose concentrations on oxidative metabolism of glucose in cultured neurons and astroglia

Shinichi Takahashi, Takato Abe, Yoshikane Izawa, Norihiro Suzuki

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Department of Neurology, School of Medicine, Keio University, Tokyo, Japan.

DOI: 10.4236/jdm.2012.21004                

Abstract

The objective of the present study was to evaluate the effects of hyperglycemia on glucose metabolism of brain cells. Not only a sustained hyperglycemic state, but also a fluctuating plasma glucose concentration has been implicated in the pathogenesis of diabetic angiopathy. Acutely increasing plasma glucose levels have not been reported to alter glucose utilization of the brain as a whole. In the present study, we examined the effects of chronic (3 weeks) or short-term (24-hour) exposure to a high glucose concentration on the oxidative metabolism of neurons and astroglia. Cells were prepared from Sprague-Dawley rats and cultured in the presence of a high (22 mM) or low (5 mM) concentration of glucose. The high or low glucose media did not alter either the rates of [¹⁴C]deoxyglucose phosphorylation (an indicator of total glucose utilization) or [¹⁴C]lactate and [¹⁴C]pyruvate oxidation (indicators of oxidative glucose metabolism) in neurons. In contrast, chronic or short-term exposure to a high glucose concentration resulted in significant decreases in oxidation of [¹⁴C]acetate, an astrocyte-specific reporter molecule, or [¹⁴C]lactate and [¹⁴C]pyruvate oxidation in the astroglia. Thus, either chronic or short-term increases in the glucose concentration suppressed oxidative metabolism only in astroglia, indicating neuro-protective roles against hyperglycemic brain cell injury in diabetes mellitus. These different responses of neurons and astroglia may also shed new light on brain energy metabolism in diabetic patients with either chronic high or fluctuating plasma glucose concentrations.

Keywords

Astrocyte; Diabetic Encephalopathy; Hyperglycemia; [¹⁴C]acetate; [¹⁴C]deoxyglucose; [¹⁴C]lactate; [¹⁴C]pyruvate

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Kannel, W.B. and McGee, D.L. (1979) Diabetes and cardiovascular risk factors: The Framingham study. Circulation, 59, 8-13.
[2]	Biessels, G.J., Staekenborg, S., Brunner, E., Brayne, C. and Scheltens, P. (2006) Risk of dementia in diabetes mellitus: A systematic review. Lancet Neurology, 5, 64-74. doi:10.1016/S1474-4422(05)70284-2
[3]	Brownlee, M. (2001) Biochemistry and molecular cell biology of diabetic complications. Nature, 414, 13-20. doi:10.1038/414813a
[4]	Brownlee, M. (2005) The pathobiology of diabetic complications: A unifying mechanism. Diabetes, 54, 1615-1625. doi:10.2337/diabetes.54.6.1615
[5]	Monnier, L., Mas, E., Ginet, C., Michel, F., Villon, L., Cristol, J.P. and Colette, C. (2006) Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. Journal of the American Medical Association, 295, 1681-1687. doi:10.1001/jama.295.14.1681
[6]	Ge, Q.M., Dong, Y., Zhang, H.M. and Su, Q. (2010) Effects of intermittent high glucose on oxidative stress in endothelial cells. Acta Diabetologica, 47, 97-103. doi:10.1007/s00592-009-0140-5
[7]	McCall, A.L. (2004) Cerebral glucose metabolism in diabetes mellitus. European Journal of Pharmacology, 490, 147-158. doi:10.1016/j.ejphar.2004.02.052
[8]	Abbatecola, A.M., Rizzo, M.R., Barbieri, M., Grella, R., Arciello, A., Laieta, M.T., Acampora, R., Passariello, N., Cacciapuoti, F. and Paolisso, G. (2006) Postprandial plasma glucose excursions and cognitive functioning in aged type 2 diabetics. Neurology, 67, 235-240. doi:10.1212/01.wnl.0000224760.22802.e8
[9]	Cox, D.J., Kovatchev, B.P., Gonder-Frederick, L.A., Summers, K.H., McCall, A., Grimm, KJ. and Clarke, W.L. (2005) Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes. Diabetes Care, 28, 71-77. doi:10.2337/diacare.28.1.71
[10]	McCall, A.L. (2005) Altered glycemia and brain-update and potential relevance to the aging brain. Neurobiology of Aging, 26S, S70-75. doi:10.1016/j.neurobiolaging.2005.08.009
[11]	Sommerfield, A.J., Deary, I.J. and Frier, B.M. (2004) Acute hyperglycemia alters mood state and impairs cognitive performance in people with type 2 diabetes. Diabetes Care, 27, 2335-2340. doi:10.2337/diacare.27.10.2335
[12]	Duckrow, R.B. and Bryan, R.M. Jr. (1987) Regional cerebral glucose utilization during hyperglycemia. Journal of Neurochemistry, 48, 989-993. doi:10.1111/j.1471-4159.1987.tb05614.x
[13]	Orzi, F., Lucignani, G., Dow-Edwards, D., Namba, H., Nehlig, A., Patlak, C.S., Pettigrew, K., Schuier, F. and Sokoloff, L. (1988) Local cerebral glucose utilization in controlled graded levels of hyperglycemia in the conscious rat. Journal of Cerebral Blood Flow and Metabolism, 8, 346-356. doi:10.1038/jcbfm.1988.70
[14]	Duelli, R., Maurer, M.H., Staudt, R., Heiland, S., Duembgen, L. and Kuschinsky, W. (2000) Increased cerebral glucose utilization and decreased glucose transporter Glut1 during chronic hyperglycemia in rat brain. Brain Research, 858, 338-347. doi:10.1016/S0006-8993(00)01942-9
[15]	Blomqvist, G., Grill, V., Ingvar, M., Widén, L. and Stone-Elander, S. (1998) The effect of hyperglycaemia on regional cerebral glucose oxidation in humans studied with [1-11C]-D-glucose. Acta Physiologica Scandinavica, 163, 403-415. doi:10.1046/j.1365-201X.1998.t01-1-00360.x
[16]	Rosenkrantz, T.S., Knox, I., Zalneraitis, E.L., Raye, J.R., Porte, P.J., Cramer, R., Smoloski, R. and Phillipps, A.F. (1993) Cerebral metabolism and electrocortical activity in the chronically hyperglycemic fetal lamb. American Journal of Physiology, 265, R1262- R1269.
[17]	Sieber, F.E., Brown, P.R., Wu, Y., Koehler, R.C. and Traystman, R.J. (1993) Cerebral blood flow and metabolism in dogs with chronic diabetes. Anesthesiology, 79, 1013-1021. doi:10.1097/00000542-199311000-00020
[18]	Hertz, L., Peng, L. and Dienel, G.A. (2007) Energy metabolism in astrocytes: High rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogennolysis. Journal of Cerebral Blood Flow and Metabolism, 27, 219-249. doi:10.1038/sj.jcbfm.9600343
[19]	Abe, T., Takahashi, S. and Suzuki, N. (2006) Oxidative metabolism in cultured rat astroglia: Effects of reducing the glucose concentration in the culture medium and of D-aspartate or potassium stimulation. Journal of Cerebral Blood Flow and Metabolism, 26, 153-160. doi:10.1038/sj.jcbfm.9600175
[20]	Takahashi, S., Driscoll, B.F., Law, M.J. and Sokoloff, L. (1995) Role of sodium and potassium ions in regulation of glucose metabolism in cultured astroglia. Proceedings of the National Academy of Sciences of the United States of America, 92, 4616-4620. doi:10.1073/pnas.92.10.4616
[21]	Sokoloff, L., Reivich, M., Kennedy, C., Des Rosiers, M.H., Patlak, C.S., Pettigrew, K.D., Sakurada, O. and Shinohara, M. (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: Theory, procedure, and normal values in the conscious and anesthetized albino rat. Journal of Neurochemistry, 28, 897-916. doi:10.1111/j.1471-4159.1977.tb10649.x
[22]	Smith, P.K., Krohn, R.I., Hermanson, G.T., Mallia, A.K.,Gartner, F.H., Provenzano, M.D., Fujimoto, E.K., Goeke, N.M., Olson, B.J. and Klenk, D.C. (1985) Measurement of protein using bicinchoninic acid. Analytical Biochemistry, 150, 76-85. doi:10.1016/0003-2697(85)90442-7
[23]	Waniewski, R.A. and Martin, D.L. (1998) Preferential utilization of acetate by astrocytes is attributable to transport. Journal of Neuroscience, 18, 5225-5233.
[24]	Waniewski R.A. and Martin, D.L. (2004) Astrocytes and synaptosomes transport and metabolize lactate and acetate differently. Neurochemical Research, 29, 209-217. doi:10.1023/B:NERE.0000010450.21586.a6
[25]	Clarke, D.D. and Sokoloff, L. (1999) Circulation and energy metabolism of the brain. In: Siegel, G.J., Agranoff, B.W., Albers, R.W., Fisher, S.K. and Uhler, M.D., Eds., Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 6th Edition, Lippincott-Raven, New York, 637- 669.
[26]	McKenna, M.C., Gruetter, R., Sonnewald, U., Waagepetersen, H.S. and Schousboe, A. (2006) Energy metabolism of the brain. In: Siegel, G.J., Albers, R.W., Brady, S.T. and Price, D.L. Eds., Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 7th Edition, Elsevier Academic Press, Burlington, 531-557.
[27]	Madsen, P.L., Cruz, N.F., Sokoloff, L. and Dienel, G.A. (1999) Cerebral oxygen/glucose ratio is low during sensory stimulation and rises above normal during recovery: Excess glucose consumption during stimulation is not accounted for by lactate efflux from or accumulation in brain tissue. Journal of Cerebral Blood Flow and Metabolism, 19, 393-400. doi:10.1097/00004647-199904000-00005
[28]	Chih, C.P. and Roberts, E.L. Jr. (2003) Energy substrates for neurons and during neural activity: A critical review of the astrocyte-neuron lactate shuttle hypothesis. Journal of Cerebral Blood Flow and Metabolism, 23, 1263-1281. doi:10.1097/01.WCB.0000081369.51727.6F
[29]	Hertz, L. (2004) The astrocyte-neuron lactate shuttle: A challenge of a challenge. Journal of Cerebral blood Flow and Metabolism, 24, 1241-1248. doi:10.1097/00004647-200411000-00008
[30]	Pellerin, L. and Magistretti, P.J. (2003) Food for thought: Challenging the dogmas. Journal of Cerebral Blood Flow and Metabolism, 23, 1282-1286. doi:10.1097/01.WCB.0000096064.12129.3D
[31]	McNay, E.C. and Gold, P.E. (1999) Extracellular glucose concentrations in the rat hippocampus measured by zeronetflux: Effects of microdialysis flow rate, strain, and age. Journal of Neurochemistry, 72, 785-790. doi:10.1046/j.1471-4159.1999.720785.x
[32]	Silver, I.A. and Erecinska, M. (1994) Extracellular glucose concentration in mammalian brain: Continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals. Journal of Neuroscience, 14, 5068-5076.
[33]	Jacob, R.J., Fan, X., Evans, M.L., Dziura, J. and Sherwin, R.S. (2002) Brain glucose levels are elevated in chronically hyperglycemic diabetic rats: No evidence for protective adaptation by the blood brain barrier. Metabolism, 51, 1522-1524. doi:10.1053/meta.2002.36347
[34]	Schousboe, A., Westergaard, N., Waagepetersen, H.S., Larsson, O.M., Bakken, I.J. and Sonnewald, U. (1997) Trafficking between glia and neurons of TCA cycle intermediates and related metabolites. Glia, 21, 99-105. doi:10.1002/(SICI)1098-1136(199709)21:1<99::AID-GLIA11>3.0.CO;2-W
[35]	Walz, W. and Mukerji, S. (1988) Lactate release from cultured astrocytes and neurons: A comparison. Glia, 1, 366-370. doi:10.1002/glia.440010603
[36]	Cruz, N.F., Lasater, A., Zielke, H.R. and Dienel, G.A. (2005) Activation of astrocytes in brain of conscious rats during acoustic stimulation: Acetate utilization in working brain. Journal of Neurochemistry, 92, 934-947. doi:10.1111/j.1471-4159.2004.02935.x
[37]	Dienel, G.A. and Cruz, N.F. (2006) Astrocyte activation in working brain: Energy supplied by minor substrate. Neurochemistry International, 48, 586-595. doi:10.1016/j.neuint.2006.01.004
[38]	Hosoi, R., Okada, M., Hatazawa, J., Gee, A. and Inoue, O. (2004) Effect of astrocytic energy metabolism depressant on 14C-acetate uptake in intact rat brain. Journal of Cerebral Blood Flow and Metabolism. 24, 188-190. doi:10.1097/01.WCB.0000098606.42140.02
[39]	Bolanos, J.P., Almeida, A. and Moncada, S. (2010) Glycolysis: A bioenergetic or a survival pathway? Trends in Biochemical Sciences, 35, 145-149. doi:10.1016/j.tibs.2009.10.006
[40]	Gibbs, M.E., O’Dowd, B.S., Hertz, E. and Hertz, L. (2006) Astrocytic energy metabolism consolidates memory in young chicks. Neuroscience, 141, 9-13.