Diabetes, Vol 48, Issue 9 1763-1772, Copyright © 1999 by American Diabetes Association

ARTICLES

Hypothalamic glucose sensor: similarities to and differences from pancreatic beta-cell mechanisms

XJ Yang, LM Kow, T Funabashi and CV Mobbs
Fishberg Center for Neurobiology, and Department of Geriatrics, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.

Glucose-responsive neurons in the ventromedial hypothalamus (VMH) are stimulated when glucose increases from 5 to 20 mmol/l and are thought to play an essential role in regulating metabolism. The present studies examined the role of glucose metabolism in the mechanism by which glucose-responsive neurons sense glucose. The pancreatic, but not hepatic, form of glucokinase was expressed in the VMH, but not cerebral cortex, of adult rats. In brain slice preparations, the transition from 5 to 20 mmol/l glucose stimulated approximately 17% of the neurons (as determined by single-cell extracellular recording) from VMH but none in cortex. In contrast, most cells in both VMH and cortex were silent below 1 mmol/l and active at 5 mmol/l glucose. Glucosamine, 2-deoxyglucose, phloridzin, and iodoacetic acid blocked the activation of glucose-responsive neurons by the transition from 5 to 20 mmol/l glucose. Adding 15 mmol/l mannose, galactose, glyceraldehyde, glycerol, and lactate to 5 mmol/l glucose stimulated glucose-responsive neurons. In contrast, adding 15 mmol/l pyruvate to 5 mmol/l glucose failed to activate glucose-responsive neurons, although pyruvate added to 0 mmol/l glucose permitted neurons to maintain activity. Tolbutamide activated glucose-responsive neurons; however, diazoxide only blocked the effect of glucose in a minority of neurons. These data suggest that glucose-responsive neurons sense glucose through glycolysis using a mechanism similar to the mechanism of pancreatic beta-cells, except that glucose-responsive neurons are stimulated by glycerol and lactate, and diazoxide does not generally block the effect of glucose.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. A. Gonzalez, L. T. Jensen, L. Fugger, and D. Burdakov Metabolism-Independent Sugar Sensing in Central Orexin Neurons Diabetes, October 1, 2008; 57(10): 2569 - 2576. [Abstract] [Full Text] [PDF]

				R. S. Sherwin Bringing Light to the Dark Side of Insulin: A Journey Across the Blood-Brain Barrier Diabetes, September 1, 2008; 57(9): 2259 - 2268. [Full Text] [PDF]

				B. E. Levin, T. C. Becker, J.-i. Eiki, B. B. Zhang, and A. A. Dunn-Meynell Ventromedial Hypothalamic Glucokinase Is an Important Mediator of the Counterregulatory Response to Insulin-Induced Hypoglycemia Diabetes, May 1, 2008; 57(5): 1371 - 1379. [Abstract] [Full Text] [PDF]

				R. J. McCrimmon, M. Shaw, X. Fan, H. Cheng, Y. Ding, M. C. Vella, L. Zhou, E. C. McNay, and R. S. Sherwin Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia Diabetes, February 1, 2008; 57(2): 444 - 450. [Abstract] [Full Text] [PDF]

				S. Polakof, J. M. Miguez, and J. L. Soengas In vitro evidences for glucosensing capacity and mechanisms in hypothalamus, hindbrain, and Brockmann bodies of rainbow trout Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1410 - R1420. [Abstract] [Full Text] [PDF]

				N. Marty, M. Dallaporta, and B. Thorens Brain Glucose Sensing, Counterregulation, and Energy Homeostasis Physiology, August 1, 2007; 22(4): 241 - 251. [Abstract] [Full Text] [PDF]

				M. B. Barnes and J. L. Beverly Nitric oxide's role in glucose homeostasis Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2007; 293(2): R590 - R591. [Full Text] [PDF]

				X.-j. Yang, J. Mastaitis, T. Mizuno, and C. V. Mobbs Glucokinase Regulates Reproductive Function, Glucocorticoid Secretion, Food Intake, and Hypothalamic Gene Expression Endocrinology, April 1, 2007; 148(4): 1928 - 1932. [Abstract] [Full Text] [PDF]

				O. Chan, M. Lawson, W. Zhu, J. L. Beverly, and R. S. Sherwin ATP-Sensitive K+ Channels Regulate the Release of GABA in the Ventromedial Hypothalamus During Hypoglycemia Diabetes, April 1, 2007; 56(4): 1120 - 1126. [Abstract] [Full Text] [PDF]

				S. Polakof, J. M. Miguez, T. W. Moon, and J. L. Soengas Evidence for the presence of a glucosensor in hypothalamus, hindbrain, and Brockmann bodies of rainbow trout Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1657 - R1666. [Abstract] [Full Text] [PDF]

				R. H. Balfour and S. Trapp Ionic currents underlying the response of rat dorsal vagal neurones to hypoglycaemia and chemical anoxia J. Physiol., March 15, 2007; 579(3): 691 - 702. [Abstract] [Full Text] [PDF]

				D. O'Malley, F. Reimann, A. K. Simpson, and F. M. Gribble Sodium-Coupled Glucose Cotransporters Contribute to Hypothalamic Glucose Sensing Diabetes, December 1, 2006; 55(12): 3381 - 3386. [Abstract] [Full Text] [PDF]

				B. E. Levin Orexins: neuropeptides for all seasons and functions Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R885 - R888. [Full Text] [PDF]

				C. Leloup, C. Magnan, A. Benani, E. Bonnet, T. Alquier, G. Offer, A. Carriere, A. Periquet, Y. Fernandez, A. Ktorza, et al. Mitochondrial reactive oxygen species are required for hypothalamic glucose sensing. Diabetes, July 1, 2006; 55(7): 2084 - 2090. [Abstract] [Full Text] [PDF]

				A. V. Matveyenko and C. M. Donovan Metabolic sensors mediate hypoglycemic detection at the portal vein. Diabetes, May 1, 2006; 55(5): 1276 - 1282. [Abstract] [Full Text] [PDF]

				L. Kang, A. A. Dunn-Meynell, V. H. Routh, L. D. Gaspers, Y. Nagata, T. Nishimura, J. Eiki, B. B. Zhang, and B. E. Levin Glucokinase Is a Critical Regulator of Ventromedial Hypothalamic Neuronal Glucosensing Diabetes, February 1, 2006; 55(2): 412 - 420. [Abstract] [Full Text] [PDF]

				R. H. Balfour, A. M. K. Hansen, and S. Trapp Neuronal responses to transient hypoglycaemia in the dorsal vagal complex of the rat brainstem J. Physiol., February 1, 2006; 570(3): 469 - 484. [Abstract] [Full Text] [PDF]

				G. D. Patil and K. P. Briski Lactate is a critical "sensed" variable in caudal hindbrain monitoring of CNS metabolic stasis Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1777 - R1786. [Abstract] [Full Text] [PDF]

				R. J. McCrimmon, M. L. Evans, X. Fan, E. C. McNay, O. Chan, Y. Ding, W. Zhu, D. X. Gram, and R. S. Sherwin Activation of ATP-Sensitive K+ Channels in the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses to Hypoglycemia in Normal and Recurrently Hypoglycemic Rats Diabetes, November 1, 2005; 54(11): 3169 - 3174. [Abstract] [Full Text] [PDF]

				O. Chan, K. Inouye, E. M. Akirav, E. Park, M. C. Riddell, S. G. Matthews, and M. Vranic Hyperglycemia does not increase basal hypothalamo-pituitary-adrenal activity in diabetes but it does impair the HPA response to insulin-induced hypoglycemia Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2005; 289(1): R235 - R246. [Abstract] [Full Text] [PDF]

				J. W. Mastaitis, E. Wurmbach, H. Cheng, S. C. Sealfon, and C. V. Mobbs Acute Induction of Gene Expression in Brain and Liver by Insulin-Induced Hypoglycemia Diabetes, April 1, 2005; 54(4): 952 - 958. [Abstract] [Full Text] [PDF]

				C. Ferreira, F. van Voorst, A. Martins, L. Neves, R. Oliveira, M. C. Kielland-Brandt, C. Lucas, and A. Brandt A Member of the Sugar Transporter Family, Stl1p Is the Glycerol/H+ Symporter in Saccharomyces cerevisiae Mol. Biol. Cell, April 1, 2005; 16(4): 2068 - 2076. [Abstract] [Full Text] [PDF]

				I. Gabriely and H. Shamoon Fructose Normalizes Specific Counterregulatory Responses to Hypoglycemia in Patients With Type 1 Diabetes Diabetes, March 1, 2005; 54(3): 609 - 616. [Abstract] [Full Text] [PDF]

				Z. Song and V.H. Routh Differential Effects of Glucose and Lactate on Glucosensing Neurons in the Ventromedial Hypothalamic Nucleus Diabetes, January 1, 2005; 54(1): 15 - 22. [Abstract] [Full Text] [PDF]

				J. A. Fattor, B. F. Miller, K. A. Jacobs, and G. A. Brooks Catecholamine response is attenuated during moderate-intensity exercise in response to the "lactate clamp" Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E143 - E147. [Abstract] [Full Text] [PDF]

				C. J Burns, S. J Persaud, and P. M Jones Stem cell therapy for diabetes: do we need to make beta cells? J. Endocrinol., December 1, 2004; 183(3): 437 - 443. [Abstract] [Full Text] [PDF]

				N. C. Tkacs and B. E. Levin Obesity-prone rats have preexisting defects in their counterregulatory response to insulin-induced hypoglycemia Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1110 - R1115. [Abstract] [Full Text] [PDF]

				X. Fioramonti, A. Lorsignol, A. Taupignon, and L. Penicaud A New ATP-Sensitive K+ Channel-Independent Mechanism Is Involved in Glucose-Excited Neurons of Mouse Arcuate Nucleus Diabetes, November 1, 2004; 53(11): 2767 - 2775. [Abstract] [Full Text] [PDF]

				B. E. Levin, V. H. Routh, L. Kang, N. M. Sanders, and A. A. Dunn-Meynell Neuronal Glucosensing: What Do We Know After 50 Years? Diabetes, October 1, 2004; 53(10): 2521 - 2528. [Abstract] [Full Text] [PDF]

				M. L. Evans, R. J. McCrimmon, D. E. Flanagan, T. Keshavarz, X. Fan, E. C. McNay, R. J. Jacob, and R. S. Sherwin Hypothalamic ATP-sensitive K + Channels Play a Key Role in Sensing Hypoglycemia and Triggering Counterregulatory Epinephrine and Glucagon Responses Diabetes, October 1, 2004; 53(10): 2542 - 2551. [Abstract] [Full Text] [PDF]

				B. Perras, B. Schultes, B. Behn, C. Dodt, J. Born, and H. L. Fehm Intranasal Atrial Natriuretic Peptide Acts as Central Nervous Inhibitor of the Hypothalamo-Pituitary-Adrenal Stress System in Humans J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4642 - 4648. [Abstract] [Full Text] [PDF]

				R. J. McCrimmon, X. Fan, Y. Ding, W. Zhu, R. J. Jacob, and R. S. Sherwin Potential Role for AMP-Activated Protein Kinase in Hypoglycemia Sensing in the Ventromedial Hypothalamus Diabetes, August 1, 2004; 53(8): 1953 - 1958. [Abstract] [Full Text] [PDF]

				N. M. Sanders, A. A. Dunn-Meynell, and B. E. Levin Third Ventricular Alloxan Reversibly Impairs Glucose Counterregulatory Responses Diabetes, May 1, 2004; 53(5): 1230 - 1236. [Abstract] [Full Text] [PDF]

				R. Moriyama, H. Tsukamura, M. Kinoshita, H. Okazaki, Y. Kato, and K.-i. Maeda In Vitro Increase in Intracellular Calcium Concentrations Induced by Low or High Extracellular Glucose Levels in Ependymocytes and Serotonergic Neurons of the Rat Lower Brainstem Endocrinology, May 1, 2004; 145(5): 2507 - 2515. [Abstract] [Full Text] [PDF]

				L. Kang, V. H. Routh, E. V. Kuzhikandathil, L. D. Gaspers, and B. E. Levin Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons Diabetes, March 1, 2004; 53(3): 549 - 559. [Abstract] [Full Text] [PDF]

				X.-J. Yang, L.-M. Kow, D. W. Pfaff, and C. V. Mobbs Metabolic Pathways That Mediate Inhibition of Hypothalamic Neurons by Glucose Diabetes, January 1, 2004; 53(1): 67 - 73. [Abstract] [Full Text] [PDF]

				N. Fujita, H. Sakamaki, S. Uotani, R. Takahashi, H. Kuwahara, A. Kita, K. Oshima, H. Yamasaki, Y. Yamaguchi, and K. Eguchi Intracerebroventricular Administration of Insulin and Glucose Inhibits the Anorectic Action of Leptin in Rats Experimental Biology and Medicine, November 1, 2003; 228(10): 1156 - 1161. [Abstract] [Full Text] [PDF]

				R. Burcelin, B. Thorens, M. Glauser, R. C. Gaillard, and F. P. Pralong Gonadotropin-Releasing Hormone Secretion from Hypothalamic Neurons: Stimulation by Insulin and Potentiation by Leptin Endocrinology, October 1, 2003; 144(10): 4484 - 4491. [Abstract] [Full Text] [PDF]

				A. Diez-Sampedro, B. A. Hirayama, C. Osswald, V. Gorboulev, K. Baumgarten, C. Volk, E. M. Wright, and H. Koepsell A glucose sensor hiding in a family of transporters PNAS, September 30, 2003; 100(20): 11753 - 11758. [Abstract] [Full Text] [PDF]

				J. Zhou, D. S. Roane, X. Xi, I. Bogacka, B. Li, D. H. Ryan, and R. J. Martin Short-Term Food Restriction and Refeeding Alter Expression of Genes Likely Involved in Brain Glucosensing Experimental Biology and Medicine, September 1, 2003; 228(8): 943 - 950. [Abstract] [Full Text] [PDF]

				D. A. Sandoval, L. Ping, A. R. Neill, S. Morrey, and S. N. Davis Cortisol Acts Through Central Mechanisms to Blunt Counterregulatory Responses to Hypoglycemia in Conscious Rats Diabetes, September 1, 2003; 52(9): 2198 - 2204. [Abstract] [Full Text] [PDF]

				F. M. Gribble, L. Williams, A. K. Simpson, and F. Reimann A Novel Glucose-Sensing Mechanism Contributing to Glucagon-Like Peptide-1 Secretion From the GLUTag Cell Line Diabetes, May 1, 2003; 52(5): 1147 - 1154. [Abstract] [Full Text] [PDF]

				J. Koubova and L. Guarente How does calorie restriction work? Genes & Dev., February 1, 2003; 17(3): 313 - 321. [Full Text] [PDF]

				A. B. Loucks and J. R. Thuma Luteinizing Hormone Pulsatility Is Disrupted at a Threshold of Energy Availability in Regularly Menstruating Women J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 297 - 311. [Abstract] [Full Text] [PDF]

				I. Swart, J. W. Jahng, J. M. Overton, and T. A. Houpt Hypothalamic NPY, AGRP, and POMC mRNA responses to leptin and refeeding in mice Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2002; 283(5): R1020 - R1026. [Abstract] [Full Text] [PDF]

				A. A. Dunn-Meynell, V. H. Routh, L. Kang, L. Gaspers, and B. E. Levin Glucokinase Is the Likely Mediator of Glucosensing in Both Glucose-Excited and Glucose-Inhibited Central Neurons Diabetes, July 1, 2002; 51(7): 2056 - 2065. [Abstract] [Full Text] [PDF]

				D. Dantz, J. Bewersdorf, B. Fruehwald-Schultes, W. Kern, W. Jelkmann, J. Born, H. L. Fehm, and A. Peters Vascular Endothelial Growth Factor: A Novel Endocrine Defensive Response to Hypoglycemia J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 835 - 840. [Abstract] [Full Text] [PDF]

				P. J. Havel Peripheral Signals Conveying Metabolic Information to the Brain: Short-Term and Long-Term Regulation of Food Intake and Energy Homeostasis Experimental Biology and Medicine, December 1, 2001; 226(11): 963 - 977. [Abstract] [Full Text] [PDF]

				S. B. Evans, C. W. Wilkinson, K. Bentson, P. Gronbeck, A. Zavosh, and D. P. Figlewicz PVN activation is suppressed by repeated hypoglycemia but not antecedent corticosterone in the rat Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2001; 281(5): R1426 - R1436. [Abstract] [Full Text] [PDF]

				P. Gilon and J.-C. Henquin Mechanisms and Physiological Significance of the Cholinergic Control of Pancreatic {beta}-Cell Function Endocr. Rev., October 1, 2001; 22(5): 565 - 604. [Abstract] [Full Text] [PDF]

				C. V. Mobbs, L.-M. Kow, and X.-J. Yang Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses Am J Physiol Endocrinol Metab, October 1, 2001; 281(4): E649 - E654. [Abstract] [Full Text] [PDF]

				R. Burcelin and B. Thorens Evidence That Extrapancreatic GLUT2-Dependent Glucose Sensors Control Glucagon Secretion Diabetes, June 1, 2001; 50(6): 1282 - 1289. [Abstract] [Full Text]

				H. Makimura, T. M. Mizuno, X.-J. Yang, J. Silverstein, J. Beasley, and C. V. Mobbs Cerulenin Mimics Effects of Leptin on Metabolic Rate, Food Intake, and Body Weight Independent of the Melanocortin System, but Unlike Leptin, Cerulenin Fails to Block Neuroendocrine Effects of Fasting Diabetes, April 1, 2001; 50(4): 733 - 739. [Abstract] [Full Text]

				C. V. Mobbs, G. A. Bray, R. L. Atkinson, A. Bartke, C. E. Finch, E. Maratos-Flier, J. N. Crawley, and J. F. Nelson Neuroendocrine and Pharmacological Manipulations to Assess How Caloric Restriction Increases Life Span J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2001; 56(90001): 34 - 44. [Abstract] [Full Text] [PDF]

				F. C. Schuit, P. Huypens, H. Heimberg, and D. G. Pipeleers Glucose Sensing in Pancreatic {beta}-Cells: A Model for the Study of Other Glucose-Regulated Cells in Gut, Pancreas, and Hypothalamus Diabetes, January 1, 2001; 50(1): 1 - 11. [Abstract] [Full Text]