{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T07:13:23Z","timestamp":1763968403036,"version":"3.41.2"},"reference-count":55,"publisher":"The Endocrine Society","issue":"3","license":[{"start":{"date-parts":[[2020,12,26]],"date-time":"2020-12-26T00:00:00Z","timestamp":1608940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100008871","name":"Juvenile Diabetes Research Foundation","doi-asserted-by":"crossref","award":["3-SRA-2017-487-S-B"],"award-info":[{"award-number":["3-SRA-2017-487-S-B"]}],"id":[{"id":"10.13039\/100008871","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DK099315"],"award-info":[{"award-number":["R01 DK099315"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Activation of the adrenergic system in response to hypoglycemia is important for proper recovery from low glucose levels. However, it has been suggested that repeated adrenergic stimulation may also contribute to counterregulatory failure, but the underlying mechanisms are not known. The aim of this study was to establish whether repeated activation of noradrenergic receptors in the ventromedial hypothalamus (VMH) contributes to blunting of the counterregulatory response by enhancing local lactate production. The VMH of nondiabetic rats were infused with either artificial extracellular fluid, norepinephrine (NE), or salbutamol for 3 hours\/day for 3 consecutive days before they underwent a hypoglycemic clamp with microdialysis to monitor changes in VMH lactate levels. Repeated exposure to NE or salbutamol suppressed both the glucagon and epinephrine responses to hypoglycemia compared to controls. Furthermore, antecedent NE and salbutamol treatments raised extracellular lactate levels in the VMH. To determine whether the elevated lactate levels were responsible for impairing the hormone response, we pharmacologically inhibited neuronal lactate transport in a subgroup of NE-treated rats during the clamp. Blocking neuronal lactate utilization improved the counterregulatory hormone responses in NE-treated animals, suggesting that repeated activation of VMH \u03b22-adrenergic receptors increases local lactate levels which in turn, suppresses the counterregulatory hormone response to hypoglycemia.<\/jats:p>","DOI":"10.1210\/endocr\/bqaa241","type":"journal-article","created":{"date-parts":[[2020,12,26]],"date-time":"2020-12-26T17:29:43Z","timestamp":1609003783000},"source":"Crossref","is-referenced-by-count":5,"title":["Repeated Activation of Noradrenergic Receptors in the Ventromedial Hypothalamus Suppresses the Response to Hypoglycemia"],"prefix":"10.1210","volume":"162","author":[{"given":"Anne-Sophie","family":"Sejling","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Nephrology, Nordsj\u00e6llands Hospital, Dyrehavevej, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peili","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Section of Endocrinology, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanling","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Section of Endocrinology, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rawad","family":"Farhat","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2014Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, UT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Knight","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2014Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, UT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Appadurai","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2014Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, UT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6652-1066","authenticated-orcid":false,"given":"Owen","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2014Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, UT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2020,12,26]]},"reference":[{"issue":"6","key":"2021121701473764100_CIT0001","doi-asserted-by":"crossref","first-page":"427","DOI":"10.2165\/00002018-199308060-00004","article-title":"Adverse effects of exogenous insulin. Clinical features, management and prevention","volume":"8","author":"Patrick","year":"1993","journal-title":"Drug Saf."},{"issue":"11","key":"2021121701473764100_CIT0002","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1007\/s001250051065","article-title":"Risk factors of severe hypoglycaemia in adult patients with Type I diabetes\u2013a prospective population based study","volume":"41","author":"M\u00fchlhauser","year":"1998","journal-title":"Diabetologia."},{"issue":"4","key":"2021121701473764100_CIT0003","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/j.1464-5491.2008.02413.x","article-title":"Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes","volume":"25","author":"Geddes","year":"2008","journal-title":"Diabet Med."},{"issue":"10","key":"2021121701473764100_CIT0004","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1111\/j.1464-5491.1991.tb01533.x","article-title":"Hypoglycaemia unawareness in type 1 diabetes: a lower plasma glucose is required to stimulate sympatho-adrenal activation","volume":"8","author":"Hepburn","year":"1991","journal-title":"Diabet Med."},{"issue":"6","key":"2021121701473764100_CIT0005","doi-asserted-by":"crossref","first-page":"E1115","DOI":"10.1152\/ajpendo.2001.281.6.E1115","article-title":"Hypoglycemia-associated autonomic failure in diabetes","volume":"281","author":"Cryer","year":"2001","journal-title":"Am J Physiol Endocrinol Metab."},{"issue":"9","key":"2021121701473764100_CIT0006","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.2337\/diabetes.47.9.1472","article-title":"Brief twice-weekly episodes of hypoglycemia reduce detection of clinical hypoglycemia in type 1 diabetes mellitus","volume":"47","author":"Ovalle","year":"1998","journal-title":"Diabetes."},{"issue":"6","key":"2021121701473764100_CIT0007","doi-asserted-by":"crossref","first-page":"809","DOI":"10.2337\/diab.43.6.809","article-title":"Hypoglycemia-induced autonomic failure in IDDM is specific for stimulus of hypoglycemia and is not attributable to prior autonomic activation","volume":"43","author":"Rattarasarn","year":"1994","journal-title":"Diabetes."},{"issue":"3","key":"2021121701473764100_CIT0008","doi-asserted-by":"crossref","first-page":"663","DOI":"10.2337\/diabetes.52.3.663","article-title":"Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic counterregulation","volume":"52","author":"Borg","year":"2003","journal-title":"Diabetes."},{"issue":"3","key":"2021121701473764100_CIT0009","doi-asserted-by":"crossref","first-page":"R990","DOI":"10.1152\/ajpregu.2000.279.3.R990","article-title":"Norepinephrine mediates glucoprivic-induced increase in GABA in the ventromedial hypothalamus of rats","volume":"279","author":"Beverly","year":"2000","journal-title":"Am J Physiol Regul Integr Comp Physiol."},{"issue":"2","key":"2021121701473764100_CIT0010","doi-asserted-by":"crossref","first-page":"R563","DOI":"10.1152\/ajpregu.2001.280.2.R563","article-title":"Noradrenergic and GABAergic systems in the medial hypothalamus are activated during hypoglycemia","volume":"280","author":"Beverly","year":"2001","journal-title":"Am J Physiol Regul Integr Comp Physiol."},{"issue":"4","key":"2021121701473764100_CIT0011","doi-asserted-by":"crossref","first-page":"R977","DOI":"10.1152\/ajpregu.00403.2005","article-title":"Hypoglycemia-induced noradrenergic activation in the VMH is a result of decreased ambient glucose","volume":"289","author":"de Vries","year":"2005","journal-title":"Am J Physiol Regul Integr Comp Physiol."},{"issue":"12","key":"2021121701473764100_CIT0012","doi-asserted-by":"crossref","first-page":"3154","DOI":"10.2337\/db11-0432","article-title":"Modulation of \u03b2-adrenergic receptors in the ventromedial hypothalamus influences counterregulatory responses to hypoglycemia","volume":"60","author":"Szepietowska","year":"2011","journal-title":"Diabetes."},{"issue":"11","key":"2021121701473764100_CIT0013","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1007\/s00125-013-3009-7","article-title":"\u03b22-Adrenergic receptor agonist administration promotes counter-regulatory responses and recovery from hypoglycaemia in rats","volume":"56","author":"Szepietowska","year":"2013","journal-title":"Diabetologia."},{"issue":"5","key":"2021121701473764100_CIT0014","doi-asserted-by":"crossref","first-page":"R910","DOI":"10.1152\/ajpregu.00254.2002","article-title":"Dissociation of hypothalamic noradrenergic activity and sympathoadrenal responses to recurrent hypoglycemia","volume":"286","author":"de Vries","year":"2004","journal-title":"Am J Physiol Regul Integr Comp Physiol."},{"issue":"2","key":"2021121701473764100_CIT0015","doi-asserted-by":"crossref","first-page":"602","DOI":"10.2337\/db10-1374","article-title":"Adrenergic mediation of hypoglycemia-associated autonomic failure","volume":"60","author":"Ramanathan","year":"2011","journal-title":"Diabetes."},{"issue":"11","key":"2021121701473764100_CIT0016","doi-asserted-by":"crossref","first-page":"3416","DOI":"10.1210\/clinem\/dgaa539","article-title":"Plasma epinephrine contributes to the development of experimental hypoglycemia-associated autonomic failure","volume":"105","author":"Lontchi-Yimagou","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2021121701473764100_CIT0017","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/jnc.13630","article-title":"Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism","volume":"138","author":"Dienel","year":"2016","journal-title":"J Neurochem."},{"issue":"1-2","key":"2021121701473764100_CIT0018","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/0304-3940(94)90955-5","article-title":"Noradrenaline reduces synaptic responses in normal and tottering mouse entorhinal cortex via alpha 2 receptors","volume":"179","author":"Pralong","year":"1994","journal-title":"Neurosci Lett."},{"issue":"3 Pt 2","key":"2021121701473764100_CIT0019","first-page":"R722","article-title":"Habituation of lactate release responding to stressful stimuli in rat prefrontal cortex in vivo","volume":"263","author":"Takita","year":"1992","journal-title":"Am J Physiol."},{"issue":"8","key":"2021121701473764100_CIT0020","doi-asserted-by":"crossref","first-page":"e1006392","DOI":"10.1371\/journal.pcbi.1006392","article-title":"Norepinephrine stimulates glycogenolysis in astrocytes to fuel neurons with lactate","volume":"14","author":"Coggan","year":"2018","journal-title":"Plos Comput Biol."},{"issue":"2","key":"2021121701473764100_CIT0021","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1007\/s12031-012-9742-4","article-title":"\u03b22-adrenergic receptor and astrocyte glucose metabolism","volume":"48","author":"Dong","year":"2012","journal-title":"J Mol Neurosci."},{"issue":"1","key":"2021121701473764100_CIT0022","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.neuroscience.2008.09.058","article-title":"Robust glycogen shunt activity in astrocytes: Effects of glutamatergic and adrenergic agents","volume":"158","author":"Walls","year":"2009","journal-title":"Neuroscience."},{"issue":"2","key":"2021121701473764100_CIT0023","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/j.1471-4159.2007.04495.x","article-title":"Noradrenaline enhances the expression of the neuronal monocarboxylate transporter MCT2 by translational activation via stimulation of PI3K\/Akt and the mTOR\/S6K pathway","volume":"102","author":"Chenal","year":"2007","journal-title":"J Neurochem."},{"issue":"6","key":"2021121701473764100_CIT0024","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1046\/j.1471-4159.2003.01964.x","article-title":"Noradrenaline enhances monocarboxylate transporter 2 expression in cultured mouse cortical neurons via a translational regulation","volume":"86","author":"Pierre","year":"2003","journal-title":"J Neurochem."},{"issue":"4","key":"2021121701473764100_CIT0025","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.neuroscience.2006.10.049","article-title":"beta(2)-Adrenoceptor-mediated facilitation of glutamatergic transmission in rat ventromedial hypothalamic neurons","volume":"144","author":"Lee","year":"2007","journal-title":"Neuroscience."},{"issue":"12","key":"2021121701473764100_CIT0026","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.2337\/db13-0770","article-title":"Lactate-induced release of GABA in the ventromedial hypothalamus contributes to counterregulatory failure in recurrent hypoglycemia and diabetes","volume":"62","author":"Chan","year":"2013","journal-title":"Diabetes."},{"issue":"4","key":"2021121701473764100_CIT0027","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1177\/0310057X1404200413","article-title":"A patient with acute liver failure and extreme hypoglycaemia with lactic acidosis who was not in a coma: causes and consequences of lactate-protected hypoglycaemia","volume":"42","author":"Oldenbeuving","year":"2014","journal-title":"Anaesth Intensive Care."},{"issue":"9","key":"2021121701473764100_CIT0028","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.2337\/db13-0313","article-title":"Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals","volume":"62","author":"De Feyter","year":"2013","journal-title":"Diabetes."},{"issue":"12","key":"2021121701473764100_CIT0029","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1053\/meta.2002.36347","article-title":"Brain glucose levels are elevated in chronically hyperglycemic diabetic rats: no evidence for protective adaptation by the blood brain barrier","volume":"51","author":"Jacob","year":"2002","journal-title":"Metabolism."},{"issue":"12","key":"2021121701473764100_CIT0030","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.tem.2013.08.005","article-title":"Influence of VMH fuel sensing on hypoglycemic responses","volume":"24","author":"Chan","year":"2013","journal-title":"Trends Endocrinol Metab."},{"issue":"4","key":"2021121701473764100_CIT0031","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.2337\/diabetes.55.04.06.db05-0958","article-title":"Blockade of GABA(A) receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia","volume":"55","author":"Chan","year":"2006","journal-title":"Diabetes."},{"issue":"4","key":"2021121701473764100_CIT0032","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.2337\/db06-1102","article-title":"ATP-sensitive K(+) channels regulate the release of GABA in the ventromedial hypothalamus during hypoglycemia","volume":"56","author":"Chan","year":"2007","journal-title":"Diabetes."},{"issue":"1","key":"2021121701473764100_CIT0033","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jneumeth.2003.08.014","article-title":"From artificial cerebro-spinal fluid (aCSF) to artificial extracellular fluid (aECF): microdialysis perfusate composition effects on in vivo brain ECF glucose measurements","volume":"132","author":"McNay","year":"2004","journal-title":"J Neurosci Methods."},{"key":"2021121701473764100_CIT0034"},{"key":"2021121701473764100_CIT0035"},{"issue":"19","key":"2021121701473764100_CIT0036","doi-asserted-by":"crossref","first-page":"4888","DOI":"10.1523\/JNEUROSCI.5430-07.2008","article-title":"Inhibition of monocarboxylate transporter 2 in the retrotrapezoid nucleus in rats: a test of the astrocyte-neuron lactate-shuttle hypothesis","volume":"28","author":"Erlichman","year":"2008","journal-title":"J Neurosci."},{"issue":"11","key":"2021121701473764100_CIT0037","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1139\/y89-233","article-title":"The use of a cell-free perfusate in the perfused rat hindquarter: methodological concerns","volume":"67","author":"McDermott","year":"1989","journal-title":"Can J Physiol Pharmacol."},{"key":"2021121701473764100_CIT0038"},{"key":"2021121701473764100_CIT0039"},{"key":"2021121701473764100_CIT0040"},{"key":"2021121701473764100_CIT0041"},{"key":"2021121701473764100_CIT0042"},{"key":"2021121701473764100_CIT0043"},{"issue":"2 Pt 1","key":"2021121701473764100_CIT0044","first-page":"E145","article-title":"Catecholamine responses and their interactions with other glucoregulatory hormones","volume":"247","author":"Vranic","year":"1984","journal-title":"Am J Physiol."},{"issue":"2 Pt 1","key":"2021121701473764100_CIT0045","first-page":"E157","article-title":"Effect of epinephrine on glucose metabolism in humans: contribution of the liver","volume":"247","author":"Sherwin","year":"1984","journal-title":"Am J Physiol."},{"issue":"6","key":"2021121701473764100_CIT0046","doi-asserted-by":"crossref","first-page":"R1815","DOI":"10.1152\/ajpregu.00171.2011","article-title":"Rate of fall in blood glucose and recurrent hypoglycemia affect glucose dynamics and noradrenergic activation in the ventromedial hypothalamus","volume":"301","author":"Barnes","year":"2011","journal-title":"Am J Physiol Regul Integr Comp Physiol."},{"issue":"8","key":"2021121701473764100_CIT0047","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.2337\/db13-1753","article-title":"The rate of fall of blood glucose determines the necessity of forebrain-projecting catecholaminergic neurons for male rat sympathoadrenal responses","volume":"63","author":"Jokiaho","year":"2014","journal-title":"Diabetes."},{"issue":"5","key":"2021121701473764100_CIT0048","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.2337\/db07-1528","article-title":"The locus for hypoglycemic detection shifts with the rate of fall in glycemia: the role of portal-superior mesenteric vein glucose sensing","volume":"57","author":"Saberi","year":"2008","journal-title":"Diabetes."},{"key":"2021121701473764100_CIT0049","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.1038\/ncomms4284","article-title":"Lactate-mediated glia-neuronal signalling in the mammalian brain","volume":"5","author":"Tang","year":"2014","journal-title":"Nat Commun."},{"issue":"6","key":"2021121701473764100_CIT0050","doi-asserted-by":"crossref","first-page":"R1777","DOI":"10.1152\/ajpregu.00177.2004","article-title":"Lactate is a critical \u201csensed\u201d variable in caudal hindbrain monitoring of CNS metabolic stasis","volume":"289","author":"Patil","year":"2005","journal-title":"Am J Physiol Regul Integr Comp Physiol."},{"issue":"4","key":"2021121701473764100_CIT0051","doi-asserted-by":"crossref","first-page":"836","DOI":"10.2337\/db07-1464","article-title":"Activation of central lactate metabolism lowers glucose production in uncontrolled diabetes and diet-induced insulin resistance","volume":"57","author":"Chari","year":"2008","journal-title":"Diabetes."},{"issue":"11-12","key":"2021121701473764100_CIT0052","doi-asserted-by":"crossref","first-page":"4403","DOI":"10.1111\/j.1582-4934.2008.00596.x","article-title":"Hypothalamic sensing of circulating lactate regulates glucose production","volume":"13","author":"Kokorovic","year":"2009","journal-title":"J Cell Mol Med."},{"issue":"2","key":"2021121701473764100_CIT0053","doi-asserted-by":"crossref","first-page":"E491","DOI":"10.1152\/ajpendo.90481.2008","article-title":"Central lactate metabolism regulates food intake","volume":"295","author":"Lam","year":"2008","journal-title":"Am J Physiol Endocrinol Metab."},{"issue":"22","key":"2021121701473764100_CIT0054","doi-asserted-by":"crossref","first-page":"10625","DOI":"10.1073\/pnas.91.22.10625","article-title":"Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization","volume":"91","author":"Pellerin","year":"1994","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"4","key":"2021121701473764100_CIT0055","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1007\/s00125-018-4802-0","article-title":"Carvedilol prevents counterregulatory failure and impaired hypoglycaemia awareness in non-diabetic recurrently hypoglycaemic rats","volume":"62","author":"Farhat","year":"2019","journal-title":"Diabetologia."}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqaa241\/35173870\/bqaa241.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/162\/3\/bqaa241\/41793210\/bqaa241.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/162\/3\/bqaa241\/41793210\/bqaa241.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T01:49:42Z","timestamp":1639705782000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqaa241\/6052997"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,26]]},"references-count":55,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,3,1]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqaa241","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"type":"print","value":"0013-7227"},{"type":"electronic","value":"1945-7170"}],"subject":[],"published-other":{"date-parts":[[2021,3]]},"published":{"date-parts":[[2020,12,26]]},"article-number":"bqaa241"}}