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

Atkin, Alexander S.; Moin, Abu Saleh Md; Nandakumar, Manjula; Al-Qaissi, Ahmed; Sathyapalan, Thozhukat; Atkin, Stephen L.; Butler, Alexandra E.

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.

Citation

Atkin, A. S., Moin, A. S. M., Nandakumar, M., Al-Qaissi, A., Sathyapalan, T., Atkin, S. L., & Butler, A. E. (2021). Impact of severe hypoglycemia on the heat shock and related protein response. Scientific reports, 11(1), Article 17057. https://doi.org/10.1038/s41598-021-96642-8

• Journal Article Type: Article
• Acceptance Date: Aug 13, 2021
• Online Publication Date: Aug 23, 2021
• Publication Date: Dec 1, 2021
• Deposit Date: Sep 27, 2021
• Publicly Available Date: Sep 29, 2021
• Journal: Scientific Reports
• Print ISSN: 2045-2322
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 1
• Article Number: 17057
• DOI: https://doi.org/10.1038/s41598-021-96642-8
• Keywords: Diabetes complications; Type 2 diabetes
• Public URL: https://hull-repository.worktribe.com/output/3834716