{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T16:30:43Z","timestamp":1777566643585,"version":"3.51.4"},"reference-count":38,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,5,1]]},"abstract":"<jats:p>Antecedent hypoglycemia suppresses the counterregulatory responses to subsequent hypoglycemic episodes, which can be prevented by normalizing portal-mesenteric vein (PMV) glycemia alone during the antecedent bout. Since the sodium\u2013glucose transporter 3 receptor has been implicated in PMV glucosensing, we hypothesized that PMV infusion of the sodium\u2013glucose cotransporter 3 receptor agonist N-hydroxyethyl-1-deoxynojirimycin (miglitol) would rescue the sympathoadrenal response to subsequent hypoglycemia. Rats underwent hyperinsulinemic-hypoglycemic clamps on 2 consecutive days without miglitol infusion (antecedent hypoglycemia without miglitol [HYPO]) or with miglitol infused upstream in the PMV, perfusing the glucosensors, or adjacent to the liver, bypassing PMV glucosensors, on day 1 or day 2. Control animals underwent day 1 euglycemic clamps, followed by hypoglycemic clamps on day 2. Peak epinephrine (EPI) responses for HYPO on day 2 were significantly blunted when compared with controls. Miglitol infusion on day 1 proved ineffective in restoring the EPI response following antecedent hypoglycemia, but day 2 miglitol infusion restored EPI responses to control levels. As norepinephrine and glucagon demonstrated similar responses, day 2 administration of miglitol effectively restored the counterregulatory response following antecedent hypoglycemia. In subsequent experiments, we demonstrate similar results with reduced miglitol infusion doses, approaching those currently prescribed for type 2 diabetes (correcting for rodent size), as well as the efficacy of oral miglitol administration in restoring the counterregulatory responses following antecedent hypoglycemia.<\/jats:p>","DOI":"10.2337\/db21-0859","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T16:36:34Z","timestamp":1645202194000},"page":"1063-1072","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":3,"title":["<i>N<\/i>-Hydroxyethyl-1-Deoxynojirimycin (Miglitol) Restores the Counterregulatory Response to Hypoglycemia Following Antecedent Hypoglycemia"],"prefix":"10.2337","volume":"71","author":[{"given":"Anne J.","family":"Jokiaho","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Southern California, Los Angeles, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Winchester","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Southern California, Los Angeles, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5257-735X","authenticated-orcid":false,"given":"Casey M.","family":"Donovan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Southern California, Los Angeles, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"2022042018451854200_B1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/B978-0-444-53491-0.00023-7","article-title":"Hypoglycemia-associated autonomic failure in diabetes","volume":"117","author":"Cryer","year":"2013","journal-title":"Handb Clin Neurol"},{"key":"2022042018451854200_B2","doi-asserted-by":"crossref","first-page":"3592","DOI":"10.2337\/diabetes.54.12.3592","article-title":"Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes","volume":"54","author":"Cryer","year":"2005","journal-title":"Diabetes"},{"key":"2022042018451854200_B3","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.2337\/dc15-0102","article-title":"Interventions that restore awareness of hypoglycemia in adults with type 1 diabetes: a systematic review and meta-analysis","volume":"38","author":"Yeoh","year":"2015","journal-title":"Diabetes Care"},{"key":"2022042018451854200_B4","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.2337\/db08-0236","article-title":"Effects of a selective serotonin reuptake inhibitor, fluoxetine, on counterregulatory responses to hypoglycemia in healthy individuals","volume":"57","author":"Briscoe","year":"2008","journal-title":"Diabetes"},{"key":"2022042018451854200_B5","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.2337\/db08-1000","article-title":"Effects of the selective serotonin reuptake inhibitor fluoxetine on counterregulatory responses to hypoglycemia in individuals with type 1 diabetes","volume":"57","author":"Briscoe","year":"2008","journal-title":"Diabetes"},{"key":"2022042018451854200_B6","doi-asserted-by":"crossref","first-page":"3372","DOI":"10.1210\/jc.2009-0882","article-title":"Hypoglycemia-associated autonomic failure is prevented by opioid receptor blockade","volume":"94","author":"Leu","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"2022042018451854200_B7","doi-asserted-by":"crossref","first-page":"3424","DOI":"10.1210\/jc.2011-1723","article-title":"Opioid receptor blockade improves hypoglycemia-associated autonomic failure in type 1 diabetes mellitus","volume":"96","author":"Vele","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2022042018451854200_B8","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.2337\/db16-0406","article-title":"Acute effects of oral dehydroepiandrosterone on counterregulatory responses during repeated hypoglycemia in healthy humans","volume":"65","author":"Mikeladze","year":"2016","journal-title":"Diabetes"},{"key":"2022042018451854200_B9","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1089\/dia.2005.7.849","article-title":"Quantifying temporal glucose variability in diabetes via continuous glucose monitoring: mathematical methods and clinical application","volume":"7","author":"Kovatchev","year":"2005","journal-title":"Diabetes Technol Ther"},{"key":"2022042018451854200_B10","doi-asserted-by":"crossref","first-page":"317","DOI":"10.4158\/EP11215.OR","article-title":"Characterizing glucose changes antecedent to hypoglycemic events in the intensive care unit","volume":"18","author":"Cook","year":"2012","journal-title":"Endocr Pract"},{"key":"2022042018451854200_B11","doi-asserted-by":"crossref","first-page":"E96","DOI":"10.1152\/ajpendo.00415.2006","article-title":"Hypoglycemic detection at the portal vein is mediated by capsaicin-sensitive primary sensory neurons","volume":"293","author":"Fujita","year":"2007","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2022042018451854200_B12","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":"2022042018451854200_B13","first-page":"A146","article-title":"Hypoglycemic detection at the portal vein is impaired after antecedent hypoglycemia","volume":"51","author":"Fujita","year":"2002","journal-title":"Diabetes"},{"key":"2022042018451854200_B14","doi-asserted-by":"crossref","first-page":"E857","DOI":"10.1152\/ajpendo.00283.2007","article-title":"Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia","volume":"293","author":"Matveyenko","year":"2007","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2022042018451854200_B15","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.molmet.2012.11.003","article-title":"The role of sodium-coupled glucose co-transporter 3 in the satiety effect of portal glucose sensing","volume":"2","author":"Delaere","year":"2012","journal-title":"Mol Metab"},{"key":"2022042018451854200_B16","doi-asserted-by":"crossref","first-page":"3258","DOI":"10.2337\/diabetes.54.11.3258","article-title":"Celiac-superior mesenteric ganglionectomy, but not vagotomy, suppresses the sympathoadrenal response to insulin-induced hypoglycemia","volume":"54","author":"Fujita","year":"2005","journal-title":"Diabetes"},{"key":"2022042018451854200_B17","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.2337\/db13-1600","article-title":"Activation of hindbrain neurons is mediated by portal-mesenteric vein glucosensors during slow-onset hypoglycemia","volume":"63","author":"Bohland","year":"2014","journal-title":"Diabetes"},{"key":"2022042018451854200_B18","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1124\/mol.106.030288","article-title":"Imino sugars are potent agonists of the human glucose sensor SGLT3","volume":"71","author":"Voss","year":"2007","journal-title":"Mol Pharmacol"},{"key":"2022042018451854200_B19","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.2337\/diab.46.9.1521","article-title":"Novel glucosensor for hypoglycemic detection localized to the portal vein","volume":"46","author":"Hevener","year":"1997","journal-title":"Diabetes"},{"key":"2022042018451854200_B20","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"},{"key":"2022042018451854200_B21","volume-title":"Brain Maps: Structure of the Rat Brain","author":"Swanson","year":"2004","edition":"3rd ed."},{"key":"2022042018451854200_B22","doi-asserted-by":"crossref","first-page":"C58","DOI":"10.1152\/ajpcell.00030.2010","article-title":"Functional characterization of mouse sodium\/glucose transporter type 3b","volume":"299","author":"Aljure","year":"2010","journal-title":"Am J Physiol Cell Physiol"},{"key":"2022042018451854200_B23","doi-asserted-by":"crossref","first-page":"C1073","DOI":"10.1152\/ajpcell.00436.2011","article-title":"Mouse SGLT3a generates proton-activated currents but does not transport sugar","volume":"302","author":"Barcelona","year":"2012","journal-title":"Am J Physiol Cell Physiol"},{"key":"2022042018451854200_B24","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1476-5381.2011.01357.x","article-title":"Both stimulation of GLP-1 receptors and inhibition of glycogenolysis additively contribute to a protective effect of oral miglitol against ischaemia-reperfusion injury in rabbits","volume":"164","author":"Iwasa","year":"2011","journal-title":"Br J Pharmacol"},{"key":"2022042018451854200_B25","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1743-7075-11-14","article-title":"Miglitol increases energy expenditure by upregulating uncoupling protein 1 of brown adipose tissue and reduces obesity in dietary-induced obese mice","volume":"11","author":"Sugimoto","year":"2014","journal-title":"Nutr Metab (Lond)"},{"key":"2022042018451854200_B26","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/j.metabol.2008.04.027","article-title":"Miglitol suppresses the postprandial increase in interleukin 6 and enhances active glucagon-like peptide 1 secretion in viscerally obese subjects","volume":"57","author":"Arakawa","year":"2008","journal-title":"Metabolism"},{"key":"2022042018451854200_B27","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.2337\/dc09-0123","article-title":"Glucose sensing during hypoglycemia: lessons from the lab","volume":"32","author":"McCrimmon","year":"2009","journal-title":"Diabetes Care"},{"key":"2022042018451854200_B28","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.physbeh.2010.01.004","article-title":"Mini-review: impact of recurrent hypoglycemia on cognitive and brain function","volume":"100","author":"McNay","year":"2010","journal-title":"Physiol Behav"},{"key":"2022042018451854200_B29","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.2337\/db07-1559","article-title":"Increased GABAergic tone in the ventromedial hypothalamus contributes to suppression of counterregulatory responses after antecedent hypoglycemia","volume":"57","author":"Chan","year":"2008","journal-title":"Diabetes"},{"key":"2022042018451854200_B30","doi-asserted-by":"crossref","first-page":"3169","DOI":"10.2337\/diabetes.54.11.3169","article-title":"Activation of ATP-sensitive K+ channels in the ventromedial hypothalamus amplifies counterregulatory hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats","volume":"54","author":"McCrimmon","year":"2005","journal-title":"Diabetes"},{"key":"2022042018451854200_B31","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1210\/en.2005-1040","article-title":"Effects of insulin treatment without and with recurrent hypoglycemia on hypoglycemic counterregulation and adrenal catecholamine-synthesizing enzymes in diabetic rats","volume":"147","author":"Inouye","year":"2006","journal-title":"Endocrinology"},{"key":"2022042018451854200_B32","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2337\/diabetes.48.1.141","article-title":"Effects of recurrent hypoglycemia on brainstem function in diabetic BB rats: protective adaptation during acute hypoglycemia","volume":"48","author":"Jacob","year":"1999","journal-title":"Diabetes"},{"key":"2022042018451854200_B33","doi-asserted-by":"crossref","first-page":"223","DOI":"10.2337\/diab.40.2.223","article-title":"Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans","volume":"40","author":"Heller","year":"1991","journal-title":"Diabetes"},{"key":"2022042018451854200_B34","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.2337\/diabetes.49.11.1897","article-title":"Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans","volume":"49","author":"Davis","year":"2000","journal-title":"Diabetes"},{"key":"2022042018451854200_B35","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.neulet.2004.02.044","article-title":"A single episode of central glucoprivation reduces the adrenomedullary response to subsequent hypoglycemia in rats","volume":"360","author":"Marin-Spiotta","year":"2004","journal-title":"Neurosci Lett"},{"key":"2022042018451854200_B36","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.ejphar.2015.02.054","article-title":"Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research","volume":"759","author":"Graham","year":"2015","journal-title":"Eur J Pharmacol"},{"key":"2022042018451854200_B37","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1111\/j.1476-5381.2012.01911.x","article-title":"The use of animal models in diabetes research","volume":"166","author":"King","year":"2012","journal-title":"Br J Pharmacol"},{"key":"2022042018451854200_B38","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1007\/s00125-020-05369-0","article-title":"Consequences of recurrent hypoglycaemia on brain function in diabetes","volume":"64","author":"McCrimmon","year":"2021","journal-title":"Diabetologia"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/71\/5\/1063\/673202\/db210859.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/71\/5\/1063\/673202\/db210859.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:44:00Z","timestamp":1667407440000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/71\/5\/1063\/144593\/N-Hydroxyethyl-1-Deoxynojirimycin-Miglitol"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,18]]},"references-count":38,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,2,18]]},"published-print":{"date-parts":[[2022,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db21-0859","relation":{},"ISSN":["0012-1797"],"issn-type":[{"value":"0012-1797","type":"print"}],"subject":[],"published":{"date-parts":[[2022,2,18]]}}}