{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T11:46:34Z","timestamp":1784202394528,"version":"3.55.0"},"reference-count":28,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2012,9,9]],"date-time":"2012-09-09T00:00:00Z","timestamp":1347148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2013,1]]},"abstract":"Abstract<\/jats:title>\n \n Aims<\/jats:title>\n \n This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamic effects of the glucokinase activator (\n GKA<\/jats:styled-content>\n )\n AZD6370<\/jats:styled-content>\n in non\u2010diabetic subjects, using the euglycaemic clamp to avoid the risk of hypoglycaemia.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Oral single ascending doses of\n AZD6370<\/jats:styled-content>\n 10\u2013650\u2009mg or subcutaneous short\u2010acting insulin 4 or 12 U were given to healthy fasting subjects.\n AZD6370<\/jats:styled-content>\n safety, tolerability and pharmacokinetics were assessed. Pharmacodynamic effects on serum (S)\u2010insulin and glucose infusion rate (\n GIR<\/jats:styled-content>\n ) were investigated with euglycaemic clamp.\n AZD6370<\/jats:styled-content>\n 10\u201320\u2009mg was also assessed when taken with food without euglycaemic clamp.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n AZD6370<\/jats:styled-content>\n was well tolerated and no safety concerns were raised.\n AZD6370<\/jats:styled-content>\n was rapidly absorbed and eliminated, and plasma concentration was proportional to dose. Both S\u2010insulin and\n GIR<\/jats:styled-content>\n increased following\n AZD6370<\/jats:styled-content>\n administration. The observed increase in\n GIR<\/jats:styled-content>\n correlated with increasing\n AZD6370<\/jats:styled-content>\n area under the plasma concentration vs. time curve, demonstrating a dose\u2010concentration\u2010dependent pharmacodynamic effect.\n AZD6370<\/jats:styled-content>\n at doses of 50 and 80\u2009mg had similar effects to short\u2010acting insulin 4\u2009U on peripheral S\u2010insulin levels but greater effects on\n GIR<\/jats:styled-content>\n , suggesting an effect beyond the increase of peripheral S\u2010insulin levels at lower doses. In the food interaction part of the study, performed without euglycaemic clamp, dose escalation was stopped at a low dose (20\u2009mg) because of hypoglycaemia.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The euglycaemic clamp was successfully used to avoid hypoglycaemia and to demonstrate pharmacodynamic effects, that is, markedly increased insulin secretion and glucose utilisation, following administration of\n AZD6370<\/jats:styled-content>\n in healthy fasting subjects. In addition to the effect on pancreatic insulin secretion, the data support an extra\u2010pancreatic (hepatic) component of\n GKA<\/jats:styled-content>\n action.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/j.1463-1326.2012.01672.x","type":"journal-article","created":{"date-parts":[[2012,9,9]],"date-time":"2012-09-09T21:29:12Z","timestamp":1347226152000},"page":"35-41","source":"Crossref","is-referenced-by-count":9,"title":["Pharmacodynamic effects of the oral glucokinase activator\n AZD6370<\/scp>\n after single doses in healthy volunteers assessed with euglycaemic clamp"],"prefix":"10.1111","volume":"15","author":[{"given":"M.","family":"Sj\u00f6strand","sequence":"first","affiliation":[{"name":"AstraZeneca R&D M\u00f6Indal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Ericsson","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D M\u00f6Indal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Hartford","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D M\u00f6Indal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Norjavaara","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D M\u00f6Indal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. W.","family":"Eriksson","sequence":"additional","affiliation":[{"name":"AstraZeneca R&D M\u00f6Indal Sweden"},{"name":"Department of Molecular and Clinical Medicine Sahlgrenska University Hospital G\u00f6teborg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,9,9]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2850"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.3.535"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0377"},{"key":"e_1_2_14_5_1","first-page":"631","article-title":"Targeting glucokinase activation for the treatment of type 2 diabetes \u2013 a status review","volume":"8","author":"Sarabu R","year":"2005","journal-title":"Curr Opin Drug Discov Devel"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-011-2439-3"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1084073"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-007-0646-8"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.17.2.145"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2011.05.009"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1990.tb19147.x"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20031414"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.24.11.1882"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-1496"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706848"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.22.9.1501"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1916-y"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2005-865806"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.49.12.2142"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2007.05.017"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00417695"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1041"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(88)90226-2"},{"key":"e_1_2_14_24_1","first-page":"307","volume-title":"Basic pharmacokinetics and pharmacodynamics: An integrated textbook and computer simulation","author":"Rosenbaum SE","year":"2011"},{"key":"e_1_2_14_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/009286159502900324"},{"key":"e_1_2_14_26_1","first-page":"395","volume-title":"Biostatistical analysis","author":"Zar JH","year":"1999"},{"key":"e_1_2_14_27_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1979.237.3.E214"},{"key":"e_1_2_14_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/00365510050185010"},{"key":"e_1_2_14_29_1","article-title":"Identification of the mechanism of action of a glucokinase activator from oral glucose tolerance test data in type 2 diabetes patients based on an integrated glucose\u2010insulin model","author":"Jauslin PM","year":"2011","journal-title":"J Clin Pharmacol"}],"container-title":["Diabetes, Obesity and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1463-1326.2012.01672.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/pdf\/10.1111\/j.1463-1326.2012.01672.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:55:52Z","timestamp":1761875752000},"score":1,"resource":{"primary":{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/10.1111\/j.1463-1326.2012.01672.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,9,9]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,1]]}},"alternative-id":["10.1111\/j.1463-1326.2012.01672.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1463-1326.2012.01672.x","archive":["Portico"],"relation":{},"ISSN":["1462-8902","1463-1326"],"issn-type":[{"value":"1462-8902","type":"print"},{"value":"1463-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,9,9]]}}}