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R. Soc. Interface."],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:p>Low blood glucose, hypoglycaemia, has been implicated as a possible contributing factor to sudden cardiac death (SCD) in people with diabetes but it is challenging to investigate in clinical studies. We hypothesized the effects of hypoglycaemia on the sinoatrial node (SAN) in the heart to be a candidate mechanism and adapted a computational model of the human SAN action potential developed by Fabbri<jats:italic>et al.<\/jats:italic>, to investigate the effects of hypoglycaemia on the pacemaker rate. Using Latin hypercube sampling, we combined the effects of low glucose (LG) on the human ether-a-go-go-related gene channel with reduced blood potassium, hypokalaemia, and added sympathetic and parasympathetic stimulus. We showed that hypoglycaemia on its own causes a small decrease in heart rate but there was also a marked decrease in heart rate when combined with hypokalaemia. The effect of the sympathetic stimulus was diminished, causing a smaller increase in heart rate, with LG and hypokalaemia compared to normoglycaemia. By contrast, the effect of the parasympathetic stimulus was enhanced, causing a greater decrease in heart rate. We therefore demonstrate a potential mechanistic explanation for hypoglycaemia-induced bradycardia and show that sinus arrest is a plausible mechanism for SCD in people with diabetes.<\/jats:p>","DOI":"10.1098\/rsif.2021.0612","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T08:05:42Z","timestamp":1637741142000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Hypoglycaemia combined with mild hypokalaemia reduces the heart rate and causes abnormal pacemaker activity in a computational model of a human sinoatrial cell"],"prefix":"10.1098","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5954-8079","authenticated-orcid":true,"given":"Alan","family":"Bernjak","sequence":"first","affiliation":[{"name":"Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK"},{"name":"INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5648-0539","authenticated-orcid":true,"given":"Ahmed","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK"},{"name":"Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2425-9565","authenticated-orcid":true,"given":"Simon R.","family":"Heller","sequence":"additional","affiliation":[{"name":"Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK"},{"name":"Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8438-7518","authenticated-orcid":true,"given":"Richard H.","family":"Clayton","sequence":"additional","affiliation":[{"name":"INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK"},{"name":"Department of Computer Science, University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"175","published-online":{"date-parts":[[2021,11,24]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0059"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0802743"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/eht332"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-5491.1991.tb01516.x"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-5491.1995.tb02080.x"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.28.10.2384"},{"key":"e_1_3_5_8_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1111\/j.1464-5491.2010.03154.x","article-title":"Characterizing sudden death and dead-in-bed syndrome in type 1 diabetes: analysis from two childhood-onset type 1 diabetes registries","volume":"28","author":"Secrest AM","year":"2011","unstructured":"Secrest AM, Becker DJ, Kelsey SF, LaPorte RE, Orchard TJ. 2011 Characterizing sudden death and dead-in-bed syndrome in type 1 diabetes: analysis from two childhood-onset type 1 diabetes registries. 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