{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T02:16:51Z","timestamp":1775873811637,"version":"3.50.1"},"reference-count":35,"publisher":"The Endocrine Society","issue":"8","license":[{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"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\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF17OC0028358"],"award-info":[{"award-number":["NNF17OC0028358"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010809","name":"Jascha Foundation","doi-asserted-by":"publisher","award":["6989"],"award-info":[{"award-number":["6989"]}],"id":[{"id":"10.13039\/100010809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>The Arg16 variant in the \u03b22-receptor gene is associated with increased risk of severe hypoglycemia in subjects with type 1 diabetes mellitus.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>We hypothesized that the Arg16 variant is associated with decreased metabolic and symptomatic responses to recurrent hypoglycemia.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Twenty-five healthy male subjects selected according to ADRB2 genotype and being homozygous for either Arg16 (AA; n\u2005=\u200513) or Gly16 (GG; n\u2005=\u200512) participated in 2 consecutive trial days with 3 periods of hypoglycemia (H1-H3) induced by a hyperinsulinemic hypoglycemic clamp. The main outcome measure was mean glucose infusion rate (GIR) during H1-H3.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>During H1-H3, there was no difference between AA or GG subjects in GIR, counter-regulatory hormones (glucagon, epinephrine, cortisol, growth hormone), or substrate levels of lactate, glycerol, and free fatty acids (FFAs), and no differences in symptom response score or cognitive performance (trail making test, Stroop test). At H3, lactate response was reduced in both genotype groups, but AA subjects had decreased response (mean\u2005\u00b1\u2005standard error of the mean of area under the curve) of glycerol (\u201313.1\u2005\u00b1\u20053.8 \u03bcmol L\u20131 hours; P\u2005=\u2005.0052), FFA (\u201330.2\u2005\u00b1\u200511.1 \u03bcmol L\u20131 hours; P\u2005=\u2005.021), and \u03b2-hydroxybutyrate (\u20130.008\u2005\u00b1\u20050.003 mmol L\u20131 hour; P\u2005=\u2005.027), while in GG subjects alanine response was increased (negative response values) (\u201353.9\u2005\u00b1\u200520.6 \u03bcmol L\u20131 hour; P\u2005=\u2005.024).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>There was no difference in GIR between genotype groups, but secondary outcomes suggest a downregulation of the lipolytic and \u03b2-hydroxybutyrate responses to recurrent hypoglycemia in AA subjects, in contrast to the responses in GG subjects.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgac297","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T16:04:53Z","timestamp":1652371493000},"page":"e3194-e3205","source":"Crossref","is-referenced-by-count":2,"title":["Impact of Polymorphism in the \u03b22-Receptor Gene on Metabolic Responses to Repeated Hypoglycemia in Healthy Humans"],"prefix":"10.1210","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4673-0888","authenticated-orcid":false,"given":"Kim Zillo","family":"Rokamp","sequence":"first","affiliation":[{"name":"Endocrine Section, Department of Endocrinology and Nephrology, Copenhagen University Hospital, Nordsj\u00e6llands Hospital , Hiller\u00f8d , Denmark"},{"name":"Department of Anaesthesia, Zealand University Hospital , K\u00f8ge , Denmark"},{"name":"Department of Neuroanaesthesia, Copenhagen University Hospital , Rigshospitalet-Glostrup, Glostrup , Denmark"},{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-3805","authenticated-orcid":false,"given":"Jens Juul","family":"Holst","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark"},{"name":"The NNF Center for Basic Metabolic Research, University of Copenhagen , Copenhagen , Denmark"},{"name":"Departments of Biomedical Science, University of Copenhagen , Copenhagen , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels V","family":"Olsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark"},{"name":"Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flemming","family":"Dela","sequence":"additional","affiliation":[{"name":"Biomedical Science, University of Copenhagen , Copenhagen , Denmark"},{"name":"Department of Geriatrics, Copenhagen University Hospital, Bispebjerg-Frederiksberg Hospital , Copenhagen , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels H","family":"Secher","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark"},{"name":"Departments of Anaesthesia, Copenhagen University Hospital, Rigshospitalet , Copenhagen , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0534-4350","authenticated-orcid":false,"given":"Anders","family":"Juul","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark"},{"name":"Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet , Copenhagen , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Faber","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark"},{"name":"Department of Endocrinology, Copenhagen University Hospital, Herlev-Gentofte Hospital , Copenhagen , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7062-7189","authenticated-orcid":false,"given":"Sebastian","family":"Wiberg","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia, Zealand University Hospital , K\u00f8ge , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birger","family":"Thorsteinsson","sequence":"additional","affiliation":[{"name":"Endocrine Section, Department of Endocrinology and Nephrology, Copenhagen University Hospital, Nordsj\u00e6llands Hospital , Hiller\u00f8d , Denmark"},{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0588-4880","authenticated-orcid":false,"given":"Ulrik","family":"Pedersen-Bjergaard","sequence":"additional","affiliation":[{"name":"Endocrine Section, Department of Endocrinology and Nephrology, Copenhagen University Hospital, Nordsj\u00e6llands Hospital , Hiller\u00f8d , Denmark"},{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"issue":"12","key":"2022071417211902800_CIT0001","doi-asserted-by":"crossref","first-page":"3169","DOI":"10.2337\/db08-1084","article-title":"The barrier of hypoglycemia in diabetes","volume":"57","author":"Cryer","year":"2008","journal-title":"Diabetes."},{"issue":"4108","key":"2022071417211902800_CIT0002","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1126\/science.182.4108.171","article-title":"Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect","volume":"182","author":"Gerich","year":"1973","journal-title":"Science."},{"issue":"1","key":"2022071417211902800_CIT0003","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1172\/JCI109464","article-title":"Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. Effects of somatostatin and combined alpha- and beta-adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin-induced hypoglycemia","volume":"64","author":"Rizza","year":"1979","journal-title":"J Clin Invest."},{"issue":"4","key":"2022071417211902800_CIT0004","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1056\/NEJMra1215228","article-title":"Mechanisms of hypoglycemia-associated autonomic failure in diabetes","volume":"369","author":"Cryer","year":"2013","journal-title":"N Engl J Med."},{"issue":"6","key":"2022071417211902800_CIT0005","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.jdiacomp.2009.07.006","article-title":"Classification of hypoglycemia awareness in people with type 1 diabetes in clinical practice","volume":"24","author":"H\u00f8i-Hansen","year":"2010","journal-title":"J Diabetes Complications."},{"issue":"7","key":"2022071417211902800_CIT0006","doi-asserted-by":"crossref","first-page":"697","DOI":"10.2337\/diacare.17.7.697","article-title":"Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia","volume":"17","author":"Gold","year":"1994","journal-title":"Diabetes Care."},{"issue":"4","key":"2022071417211902800_CIT0007","doi-asserted-by":"crossref","first-page":"517","DOI":"10.2337\/diacare.18.4.517","article-title":"Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms","volume":"18","author":"Clarke","year":"1995","journal-title":"Diabetes Care."},{"issue":"3","key":"2022071417211902800_CIT0008","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/BF00252404","article-title":"Beta-adrenergic blockade is more effective in suppressing adrenaline-induced glucose production in type 1 (insulin-dependent) diabetes","volume":"26","author":"Shamoon","year":"1984","journal-title":"Diabetologia."},{"issue":"3","key":"2022071417211902800_CIT0009","doi-asserted-by":"crossref","first-page":"243","DOI":"10.2337\/diacare.7.3.243","article-title":"Oral propranolol and metoprolol both impair glucose recovery from insulin-induced hypoglycemia in insulin-dependent diabetes mellitus","volume":"7","author":"Popp","year":"1984","journal-title":"Diabetes Care."},{"key":"2022071417211902800_CIT0010","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.0954-6820.1983.tb01615.x","article-title":"Adrenergic blockade and hypoglycaemia","volume":"213","author":"Lager","year":"1983","journal-title":"Acta Med Scand Suppl."},{"issue":"8","key":"2022071417211902800_CIT0011","doi-asserted-by":"crossref","first-page":"3320","DOI":"10.1111\/bcp.14754","article-title":"Beta-blocker-associated hypoglycaemia: new insights from a real-world pharmacovigilance study","volume":"87","author":"Carnovale","year":"2021","journal-title":"Br J Clin Pharmacol."},{"issue":"5","key":"2022071417211902800_CIT0012","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1097\/01213011-200505000-00001","article-title":"Beta2-adrenoceptor gene polymorphisms","volume":"15","author":"Brodde","year":"2005","journal-title":"Pharmacogenet Genomics."},{"issue":"7","key":"2022071417211902800_CIT0013","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1113\/expphysiol.2009.048330","article-title":"-Adrenoceptor gene variation and intermediate physiological traits: prediction of distant phenotype","volume":"95","author":"Eisenach","year":"2010","journal-title":"Exp Physiol."},{"issue":"3","key":"2022071417211902800_CIT0014","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1161\/01.HYP.36.3.371","article-title":"Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans","volume":"36","author":"Cockcroft","year":"2000","journal-title":"Hypertension."},{"issue":"5","key":"2022071417211902800_CIT0015","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1152\/japplphysiol.00469.2005","article-title":"Arg16\/Gly beta2-adrenergic receptor polymorphism alters the cardiac output response to isometric exercise","volume":"99","author":"Eisenach","year":"2005","journal-title":"J Appl Physiol."},{"issue":"Pt 14","key":"2022071417211902800_CIT0016","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1113\/jphysiol.2010.190058","article-title":"beta2-Adrenoceptor gene variation and systemic vasodilatation during ganglionic blockade","volume":"588","author":"Hesse","year":"2010","journal-title":"J Physiol."},{"issue":"8","key":"2022071417211902800_CIT0017","doi-asserted-by":"crossref","first-page":"2901","DOI":"10.1210\/jc.2017-02739","article-title":"Impact of genetic polymorphism in the \u03b22-receptor gene on risk of severe hypoglycemia in patients with Type 1 diabetes","volume":"103","author":"Rokamp","year":"2018","journal-title":"J Clin Endocrinol Metab."},{"issue":"21","key":"2022071417211902800_CIT0018","doi-asserted-by":"crossref","first-page":"5416","DOI":"10.3390\/ijms20215416","article-title":"Methods and guidelines for measurement of glucagon in plasma","volume":"20","author":"Holst","year":"2019","journal-title":"Int J Mol Sci ."},{"issue":"2","key":"2022071417211902800_CIT0019","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1177\/1073191115602552","article-title":"The trail making test","volume":"24","author":"Llin\u00e0s-Regl\u00e0","year":"2017","journal-title":"Assessment."},{"issue":"1","key":"2022071417211902800_CIT0020","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/0001-6918(66)90004-7","article-title":"The Stroop color-word test: a review","volume":"25","author":"Jensen","year":"1966","journal-title":"Acta Psychol."},{"issue":"11","key":"2022071417211902800_CIT0021","doi-asserted-by":"crossref","first-page":"949","DOI":"10.2337\/diacare.14.11.949","article-title":"Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach","volume":"14","author":"Hepburn","year":"1991","journal-title":"Diabetes Care."},{"issue":"5","key":"2022071417211902800_CIT0022","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.2337\/db14-1359","article-title":"Hypoglycemia-associated changes in the electroencephalogram in patients with type 1 diabetes and normal hypoglycemia awareness or unawareness","volume":"64","author":"Sejling","year":"2015","journal-title":"Diabetes."},{"key":"2022071417211902800_CIT0023","doi-asserted-by":"crossref","first-page":"661","DOI":"10.3389\/fphys.2017.00661","article-title":"The Gly(16.Allele of the G16R single nucleotide polymorphism in the \u03b2 (2) -adrenergic receptor gene augments the glycemic response to adrenaline in humans","volume":"8","author":"Rokamp","year":"2017","journal-title":"Front Physiol."},{"issue":"7","key":"2022071417211902800_CIT0024","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1172\/JCI106989","article-title":"Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus","volume":"51","author":"Wahren","year":"1972","journal-title":"J Clin Invest."},{"issue":"5","key":"2022071417211902800_CIT0025","first-page":"411","article-title":"Regulation of gluconeogenesis and ketogenesis during rest and exercise in diabetic subjects and normal men","volume":"53","author":"Sestoft","year":"1977","journal-title":"Clin Sci Mol Med."},{"issue":"6","key":"2022071417211902800_CIT0026","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/BF01220631","article-title":"On gluconeogenesis of human liver. Accelerated hepatic glucose formation induced by increased precursor supply","volume":"12","author":"Dietze","year":"1976","journal-title":"Diabetologia."},{"key":"2022071417211902800_CIT0027","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.0954-6820.1983.tb01612.x","article-title":"Adrenergic control of lipid metabolism","volume":"213","author":"Smith","year":"1983","journal-title":"Acta Med Scand Suppl."},{"issue":"8114","key":"2022071417211902800_CIT0028","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/S0140-6736(79)90821-3","article-title":"Effect of cardioselective and non-selective beta-blockade on the hypoglycaemic response in insulin-dependent diabetics","volume":"1","author":"Lager","year":"1979","journal-title":"Lancet."},{"issue":"6","key":"2022071417211902800_CIT0029","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1097\/00005344-199424060-00001","article-title":"Effects of carvedilol on the metabolic, hemodynamic, and electrocardiographic responses to increased plasma epinephrine in normal subjects","volume":"24","author":"Hansen","year":"1994","journal-title":"J Cardiovasc Pharmacol."},{"issue":"2","key":"2022071417211902800_CIT0030","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1042\/cs0620131","article-title":"Beta-adrenoceptor blockade and recovery from hypoglycaemia in diabetic subjects: normalization after lactate and glycerol infusions","volume":"62","author":"Lager","year":"1982","journal-title":"Clin Sci (Lond)."},{"issue":"11","key":"2022071417211902800_CIT0031","doi-asserted-by":"crossref","first-page":"875","DOI":"10.2337\/diab.29.11.875","article-title":"Epinephrine-induced hypoaminoacidemia in normal and diabetic human subjects: effect of beta blockade","volume":"29","author":"Shamoon","year":"1980","journal-title":"Diabetes."},{"issue":"7","key":"2022071417211902800_CIT0032","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.2337\/db08-0276","article-title":"Effect of oral amino acids on counterregulatory responses and cognitive function during insulin-induced hypoglycemia in nondiabetic and type 1 diabetic people","volume":"57","author":"Rossetti","year":"2008","journal-title":"Diabetes."},{"issue":"5","key":"2022071417211902800_CIT0033","first-page":"299","article-title":"Regulation of in vivo ketogenesis: role of free fatty acids and control by epinephrine, thyroid hormones, insulin and glucagon","volume":"22","author":"Beylot","year":"1996","journal-title":"Diabetes Metab."},{"issue":"9","key":"2022071417211902800_CIT0034","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.2337\/diab.40.9.1177","article-title":"Higher glycemic thresholds for symptoms during beta-adrenergic blockade in IDDM","volume":"40","author":"Hirsch","year":"1991","journal-title":"Diabetes."},{"issue":"1","key":"2022071417211902800_CIT0035","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/01.fjc.0000198519.28674.cc","article-title":"Effect of sex on the cardiovascular response to adrenaline in humans","volume":"47","author":"Schouwenberg","year":"2006","journal-title":"J Cardiovasc Pharmacol."}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgac297\/43887354\/dgac297.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/107\/8\/e3194\/44886182\/dgac297.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/107\/8\/e3194\/44886182\/dgac297.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T17:21:57Z","timestamp":1657819317000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/107\/8\/e3194\/6584881"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,12]]},"references-count":35,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,5,12]]},"published-print":{"date-parts":[[2022,7,14]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgac297","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,8,1]]},"published":{"date-parts":[[2022,5,12]]}}}