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Helmsley Charitable Trust","doi-asserted-by":"publisher","award":["1912-03559"],"award-info":[{"award-number":["1912-03559"]}],"id":[{"id":"10.13039\/100007028","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>People with type 1 diabetes (T1D) develop an impaired glucagon response to hypoglycaemia within 5\u2009years of diagnosis, increasing their risk of severe hypoglycaemia. It is not known whether eliminating hypoglycaemia and hyperglycaemia allows recovery of this glucagon response. Hybrid closed loop (HCL) technologies improve glycaemic time in range (TIR). However, post-prandial glycaemic excursions are still evident. Consuming a low carbohydrate diet (LCD) may minimise these excursions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and analysis<\/jats:title><jats:p>This feasibility study will assess if maximising TIR (glucose \u22653.9\u2009mmol\/L\u226410\u2009mmol\/L) using HCL systems plus an LCD (defined here as &lt;130\u2009g carbohydrate\/day) for &gt;8 months, restores the glucagon response to insulin-induced hypoglycaemia. Adults (n=24) with T1D (C-peptide &lt;200\u2009pmol\/L), na\u00efve to continuous glucose monitoring (CGM) and HCL systems, will be recruited and randomised to: group 1 (non-HCL) to continue their standard diabetes care with intermittent blinded CGM; or group 2 (HCL-LCD) to use the HCL system and follow a LCD. Baseline data on diet and glycaemia will be collected from all participants. The HCL-LCD group will then enter a 2-week run-in to acclimatise to their devices. Throughout, the HCL-LCD group will have their glucose closely monitored and adjusted aiming for glycaemic TIR &gt;70%. Participants will have their glucagon response to hypoglycaemia measured at the beginning and 8 months later at the study end using a stepped hyperinsulinaemic hypoglycaemic clamp, in combination with the stable isotopes 6,6-<jats:sup>2<\/jats:sup>H<jats:sub>2<\/jats:sub>-glucose (D2-glucose) and 1,1,2,3,3-<jats:sup>2<\/jats:sup>H<jats:sub>5<\/jats:sub>-glycerol (D5-glycerol) to assess glucose and glycerol kinetics. The impact of hypoglycaemia on symptoms and cognitive function will be assessed during each clamp study. The primary outcome is the difference in the glucagon response to hypoglycaemia between and within groups at baseline versus study end.<\/jats:p><\/jats:sec><jats:sec><jats:title>Ethics and dissemination<\/jats:title><jats:p>Ethical (20\/SS\/0117)\/institutional review board (2021\/0001) approval has been obtained. The study will be disseminated by peer-reviewed publications and conference presentations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration number<\/jats:title><jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04614168\">NCT04614168<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1136\/bmjopen-2021-054958","type":"journal-article","created":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T14:56:02Z","timestamp":1671548162000},"page":"e054958","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Study protocol: a randomised controlled proof-of-concept real-world study \u2013 does maximising time in range using hybrid closed loop insulin delivery and a low carbohydrate diet restore the glucagon response to hypoglycaemia in adults with type 1 diabetes?"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct04614168","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7937-1909","authenticated-orcid":false,"given":"Faye","family":"Baxter","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1407-787X","authenticated-orcid":false,"given":"Nicola","family":"Baillie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9127-0641","authenticated-orcid":false,"given":"Shareen","family":"Forbes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2022,12,20]]},"reference":[{"key":"2022122006550982000_12.12.e054958.1","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-0465"},{"key":"2022122006550982000_12.12.e054958.2","doi-asserted-by":"crossref","DOI":"10.1111\/dme.14445","article-title":"Socioeconomic deprivation, technology use, C-peptide, smoking and other predictors of glycaemic control in adults with type 1 diabetes","volume":"38","author":"Dover","year":"2021","journal-title":"Diabet Med"},{"key":"2022122006550982000_12.12.e054958.3","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(91)90194-2"},{"key":"2022122006550982000_12.12.e054958.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-018-4548-8"},{"key":"2022122006550982000_12.12.e054958.5","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1172\/JCI134057","article-title":"High residual C-peptide likely contributes to glycemic control in type 1 diabetes","volume":"130","author":"Rickels","year":"2020","journal-title":"J Clin Invest"},{"key":"2022122006550982000_12.12.e054958.6","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1007\/s00125-020-05196-3","article-title":"Alpha cell regulation of beta cell function","volume":"63","author":"Moede","year":"2020","journal-title":"Diabetologia"},{"key":"2022122006550982000_12.12.e054958.7","doi-asserted-by":"publisher","DOI":"10.1126\/science.182.4108.171"},{"key":"2022122006550982000_12.12.e054958.8","doi-asserted-by":"publisher","DOI":"10.2337\/db10-0103"},{"key":"2022122006550982000_12.12.e054958.9","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-0871"},{"key":"2022122006550982000_12.12.e054958.10","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05099-3"},{"key":"2022122006550982000_12.12.e054958.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197007162830301"},{"key":"2022122006550982000_12.12.e054958.12","doi-asserted-by":"crossref","DOI":"10.14814\/phy2.15009","article-title":"Mini-review: Glucagon responses in type 1 diabetes - 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