{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:46Z","timestamp":1787027806118,"version":"build-2736575974"},"reference-count":51,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T00:00:00Z","timestamp":1636502400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mild hypoglycemia is common in clinical practice. Severe hypoglycemia results in heat shock protein and associate co-chaperone changes. Whether mild prolonged hypoglycemia elicits a similar response with inflammatory and oxidative-stress responses compared with a severe hypoglycemic event is unclear; therefore, this pilot exploratory study was undertaken. We performed a case\u2013control induced hypoglycemia clamp study, maintaining blood glucose at 2.8 mmol\/L (50 mg\/dL) for 1 h in 17 subjects (T2D (n = 10); controls (n = 7)). Blood sampling was performed at baseline, hypoglycemia, and 24 h; slow off-rate modified aptamer (SOMA)-scan plasma protein analysis of HSP-related proteins, inflammatory stress markers, and oxidative stress markers was performed. In total, 16 HSPs were analyzed. At baseline, TLR4:MD-2 complex was elevated (p = 0.01), whilst HSPA8 was lower (p &lt; 0.05) in T2D. At hypoglycemia, UBE2N, STIP1, and UBE2L3 increased (all p &lt; 0.05), whilst TLR4:MD-2 and HSPA8 decreased (p &lt; 0.05) in T2D versus baseline. In follow-up after hypoglycemia, HSPs normalized to baseline by 24 h, except UBE2L3 (p &lt; 0.05), which was decreased in controls versus baseline. Correlation of altered inflammatory markers with HSPs revealed the following: at baseline, TLR4:MD-2 correlated with CXCL10 (p &lt; 0.01) and SIGLEC1 (p &lt; 0.05) in controls; HSPA8 negatively correlated with IL5 (p &lt; 0.05) in T2D. A negative correlation between urinary isoprostane 8-iso PGF2\u03b1, a marker of oxidative stress, and HSPA1A was seen at 24 h in T2D only (p &lt; 0.05). In conclusion, the HSP changes seen for mild prolonged hypoglycemia were similar to those previously reported for a severe event. However, mild prolonged hypoglycemia appeared to elicit an increased inflammatory response that was associated with heat shock and related proteins.<\/jats:p>","DOI":"10.3390\/cells10113109","type":"journal-article","created":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T09:19:21Z","timestamp":1636535961000},"page":"3109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Heat Shock-Related Protein Responses and Inflammatory Protein Changes Are Associated with Mild Prolonged Hypoglycemia"],"prefix":"10.3390","volume":"10","author":[{"given":"Abu Saleh Md","family":"Moin","sequence":"first","affiliation":[{"name":"Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha 5825, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manjula","family":"Nandakumar","sequence":"additional","affiliation":[{"name":"Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha 5825, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Kahal","sequence":"additional","affiliation":[{"name":"Academic Endocrinology, Diabetes and Metabolism, Hull York Medical School, Hull YO10 5DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3544-2231","authenticated-orcid":false,"given":"Thozhukat","family":"Sathyapalan","sequence":"additional","affiliation":[{"name":"Academic Endocrinology, Diabetes and Metabolism, Hull York Medical School, Hull YO10 5DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Atkin","sequence":"additional","affiliation":[{"name":"Royal College of Surgeons of Ireland, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-3917","authenticated-orcid":false,"given":"Alexandra E.","family":"Butler","sequence":"additional","affiliation":[{"name":"Royal College of Surgeons of Ireland, Busaiteen P.O. Box 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1111\/j.1464-5491.2005.01501.x","article-title":"Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: A population-based study","volume":"22","author":"Donnelly","year":"2005","journal-title":"Diabet. 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