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Although intensive insulin therapy lowers chronic hyperglycaemia and improves cardiovascular outcomes, it also increases the frequency of hypoglycaemic episodes, an emerging but poorly understood contributor to CVD risk. The mechanisms by which recurrent hypoglycaemia exacerbates cardiovascular pathology in type 1 diabetes are unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using a C57BL\/J streptozocin-induced male mouse model of type 1 diabetes, combined with detailed physiological and molecular assessments, we investigated the impact of recurrent hypoglycaemia (&lt;3.0 mmol\/l) on cardiovascular structure and function using laser Doppler imaging with iontophoresis and ultrasound imaging.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Type 1 diabetes induces significant microvascular endothelial dysfunction, which is worsened by recurrent hypoglycaemia. Chronic exposure to hypoglycaemia (60 episodes over 20 weeks) resulted in compensatory shifts in cardiac haemodynamics, which in type 1 diabetic mice but not non-diabetic mice resulted in early dilated cardiomyopathy. In both type 1 diabetic and non-diabetic mice, recurrent hypoglycaemia resulted in impaired systolic function during a subsequent hypoglycaemic challenge, indicating increased cardiac vulnerability despite any compensatory changes. Transcriptomic profiling of left ventricular tissue revealed that recurrent hypoglycaemia induces distinct gene expression changes involving ion homeostasis, repolarisation dynamics and microvascular signalling\u2014molecular alterations characteristic of early diabetic cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>These findings provide the first in vivo evidence that recurrent hypoglycaemia synergises with hyperglycaemia to accelerate microvascular dysfunction and adverse cardiac remodelling in type 1 diabetes. This work identifies a novel mechanistic link between hypoglycaemia and diabetic heart disease, underscoring the need for therapeutic strategies that mitigate glycaemic variability without increasing the hypoglycaemic burden.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data availability<\/jats:title>\n                    <jats:p>Transcriptomic data are available as supplementary data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06574-5","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T14:35:47Z","timestamp":1762785347000},"page":"515-528","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Recurrent hypoglycaemia promotes cardiomyopathy and cardiac vulnerability in a rodent model of type 1 diabetes"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6897-6777","authenticated-orcid":false,"given":"Calum","family":"Forteath","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2233-670X","authenticated-orcid":false,"given":"Heather J.","family":"Merchant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Kocherry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0274-819X","authenticated-orcid":false,"given":"Colin E.","family":"Murdoch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Kerr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer R.","family":"Gallagher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8122-8987","authenticated-orcid":false,"given":"Mark L.","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3738-0129","authenticated-orcid":false,"given":"Bernard","family":"Thorens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0588-4880","authenticated-orcid":false,"given":"Ulrik","family":"Pedersen-Bjergaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1255-7741","authenticated-orcid":false,"given":"Bastiaan E.","family":"de Galan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3957-1981","authenticated-orcid":false,"given":"Rory J.","family":"McCrimmon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4869-178X","authenticated-orcid":false,"given":"Alison D.","family":"McNeilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of Hypo-RESOLVE Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"issue":"10397","key":"6574_CR1","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/S0140-6736(23)01301-6","volume":"402","author":"KL Ong","year":"2023","unstructured":"Ong KL, Stafford LK, McLaughlin SA et al (2023) Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. 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Transcriptomics (RNA-seq) and DESeq2 analysis was performed by Azenta Life Sciences.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Raw data are available on request to the corresponding authors. Transcriptomic data are provided in the ESM Data File.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777460. The JU receives support from the European Union\u2019s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA), T1D Exchange, Breakthrough T1D, IDF and Leona M. and Harry B. Helmsley Charitable Trust. RJM, ADM, MLE, BEdG, UP-B and BT received funding for the project (payment to respective institutions) as part of the Hypo-RESOLVE Consortium. The authors are solely responsible for the content of this work, which reflects only the authors\u2019 views, and the JU is not responsible for any use that may be made of the information it contains. The VisualSonics Fujifilm Vevo-F2 ultrasound system for echocardiography was granted to CEM as a \u2018UKRI- World Class Laboratories\u2019 award.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"BEdG and UP-B are members of the editorial board of\n                      Diabetologia\n                      . The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"RJM, ADM, CF, MLE, BT, BEdG and UP-B were responsible for the study concept and design. In vivo studies were performed by CF, ADM, JRG and JK. Microvascular assessment was performed by CF and ADM. Pressure\u2013volume loop experiments were performed by CEM and analysed by CF and JK. Echocardiography was performed by CF and analysed by CK and CF. Downstream analysis and data visualisation were performed by HJM. CF, ADM, RJM, MLE, BT, BEdG, UP-B and HJM prepared and revised the manuscript. CK, CEM, JK and JRG reviewed the manuscript. All authors approved the final version of the manuscript. RJM is responsible for the integrity of the work as a whole and is a guarantor for this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}