Impact of severe hypoglycemia on the heat shock and related protein response

Abstract Heat shock proteins contribute to diabetes-induced complications and are affected by glycemic control. Our hypothesis was that hypoglycemia-induced heat shock and related protein changes would be amplified in type 2 diabetes (T2D). This prospective, case–control study enrolled 23 T2D patien...

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Autores principales:	Alexander S. Atkin, Abu Saleh Md Moin, Manjula Nandakumar, Ahmed Al-Qaissi, Thozhukat Sathyapalan, Stephen L. Atkin, Alexandra E. Butler
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a5987cfffa694d3688bc0a2df912dfef
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spelling	oai:doaj.org-article:a5987cfffa694d3688bc0a2df912dfef2021-12-02T19:02:35ZImpact of severe hypoglycemia on the heat shock and related protein response10.1038/s41598-021-96642-82045-2322https://doaj.org/article/a5987cfffa694d3688bc0a2df912dfef2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96642-8https://doaj.org/toc/2045-2322Abstract Heat shock proteins contribute to diabetes-induced complications and are affected by glycemic control. Our hypothesis was that hypoglycemia-induced heat shock and related protein changes would be amplified in type 2 diabetes (T2D). This prospective, case–control study enrolled 23 T2D patients and 23 control subjects who underwent hyperinsulinemic-induced hypoglycemia (≤ 2.0 mmol/L (36 mg/dl)) with blood sampling at baseline, at hypoglycemia and after a 24-h post-hypoglycemia follow-up period. Proteomic analysis of heat shock-related and pro-inflammatory proteins was performed. At baseline, MAPKAPK5 (p = 0.02) and UBE2G2 (p = 0.003) were elevated and STUB1 decreased (p = 0.007) in T2D. At hypoglycemia: PPP3CA (p < 0.03) was increased and EPHA2 (p = 0.01) reduced in T2D; by contrast, three proteins were reduced in controls [HSPA1A (p = 0.007), HSPB1 (p < 0.02), SMAD3 (p = 0.005)] while only MAPKAPK5 was elevated (p = 0.02). In the post-hypoglycemia follow-up period, most proteins normalized to baseline by 24-h; however, STIP1 (p = 0.003), UBE2N (p = 0.004) and UBE2L3 (p < 0.04) were decreased in controls at 24-h. No protein differed from baseline at 24-h in T2D. Pro-inflammatory interleukin-6 increased at 4-h post-hypoglycemia in controls and T2D (p < 0.05 and p < 0.003, respectively) and correlated with HSPA1A; anti-inflammatory IL-10 decreased 2-h post-hypoglycemia in T2D only. Other pro-inflammatory proteins, IL-1α, IFN-γ and TNF-α, were unchanged. Heat shock and related proteins differed at baseline between T2D and controls, with an exaggerated response of heat shock and related proteins to hypoglycemia that returned to baseline, though with changes at 24-h in controls alone. An increase in pro-inflammatory IL-6, with a decrease in anti-inflammatory IL-10, suggests that the HSP system is overactivated due to underlying inflammation in T2D. Trial registration: ClinicalTrials.gov NCT03102801.Alexander S. AtkinAbu Saleh Md MoinManjula NandakumarAhmed Al-QaissiThozhukat SathyapalanStephen L. AtkinAlexandra E. ButlerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alexander S. Atkin Abu Saleh Md Moin Manjula Nandakumar Ahmed Al-Qaissi Thozhukat Sathyapalan Stephen L. Atkin Alexandra E. Butler Impact of severe hypoglycemia on the heat shock and related protein response
description	Abstract Heat shock proteins contribute to diabetes-induced complications and are affected by glycemic control. Our hypothesis was that hypoglycemia-induced heat shock and related protein changes would be amplified in type 2 diabetes (T2D). This prospective, case–control study enrolled 23 T2D patients and 23 control subjects who underwent hyperinsulinemic-induced hypoglycemia (≤ 2.0 mmol/L (36 mg/dl)) with blood sampling at baseline, at hypoglycemia and after a 24-h post-hypoglycemia follow-up period. Proteomic analysis of heat shock-related and pro-inflammatory proteins was performed. At baseline, MAPKAPK5 (p = 0.02) and UBE2G2 (p = 0.003) were elevated and STUB1 decreased (p = 0.007) in T2D. At hypoglycemia: PPP3CA (p < 0.03) was increased and EPHA2 (p = 0.01) reduced in T2D; by contrast, three proteins were reduced in controls [HSPA1A (p = 0.007), HSPB1 (p < 0.02), SMAD3 (p = 0.005)] while only MAPKAPK5 was elevated (p = 0.02). In the post-hypoglycemia follow-up period, most proteins normalized to baseline by 24-h; however, STIP1 (p = 0.003), UBE2N (p = 0.004) and UBE2L3 (p < 0.04) were decreased in controls at 24-h. No protein differed from baseline at 24-h in T2D. Pro-inflammatory interleukin-6 increased at 4-h post-hypoglycemia in controls and T2D (p < 0.05 and p < 0.003, respectively) and correlated with HSPA1A; anti-inflammatory IL-10 decreased 2-h post-hypoglycemia in T2D only. Other pro-inflammatory proteins, IL-1α, IFN-γ and TNF-α, were unchanged. Heat shock and related proteins differed at baseline between T2D and controls, with an exaggerated response of heat shock and related proteins to hypoglycemia that returned to baseline, though with changes at 24-h in controls alone. An increase in pro-inflammatory IL-6, with a decrease in anti-inflammatory IL-10, suggests that the HSP system is overactivated due to underlying inflammation in T2D. Trial registration: ClinicalTrials.gov NCT03102801.
format	article
author	Alexander S. Atkin Abu Saleh Md Moin Manjula Nandakumar Ahmed Al-Qaissi Thozhukat Sathyapalan Stephen L. Atkin Alexandra E. Butler
author_facet	Alexander S. Atkin Abu Saleh Md Moin Manjula Nandakumar Ahmed Al-Qaissi Thozhukat Sathyapalan Stephen L. Atkin Alexandra E. Butler
author_sort	Alexander S. Atkin
title	Impact of severe hypoglycemia on the heat shock and related protein response
title_short	Impact of severe hypoglycemia on the heat shock and related protein response
title_full	Impact of severe hypoglycemia on the heat shock and related protein response
title_fullStr	Impact of severe hypoglycemia on the heat shock and related protein response
title_full_unstemmed	Impact of severe hypoglycemia on the heat shock and related protein response
title_sort	impact of severe hypoglycemia on the heat shock and related protein response
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a5987cfffa694d3688bc0a2df912dfef
work_keys_str_mv	AT alexandersatkin impactofseverehypoglycemiaontheheatshockandrelatedproteinresponse AT abusalehmdmoin impactofseverehypoglycemiaontheheatshockandrelatedproteinresponse AT manjulanandakumar impactofseverehypoglycemiaontheheatshockandrelatedproteinresponse AT ahmedalqaissi impactofseverehypoglycemiaontheheatshockandrelatedproteinresponse AT thozhukatsathyapalan impactofseverehypoglycemiaontheheatshockandrelatedproteinresponse AT stephenlatkin impactofseverehypoglycemiaontheheatshockandrelatedproteinresponse AT alexandraebutler impactofseverehypoglycemiaontheheatshockandrelatedproteinresponse
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Impact of severe hypoglycemia on the heat shock and related protein response

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