Heat Shock-Related Protein Responses and Inflammatory Protein Changes Are Associated with Mild Prolonged Hypoglycemia

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 11; p. 3109
• Main Authors: Moin, Abu Saleh Md, Nandakumar, Manjula, Kahal, Hassan, Sathyapalan, Thozhukat, Atkin, Stephen L., Butler, Alexandra E.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.11.2021; MDPI
• Subjects: Adult; Aptamers; Biomarkers - metabolism; Case-Control Studies; Chemokines; CXCL10 protein; Cytokines; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - metabolism; Diabetic neuropathy; Diabetic retinopathy; Dinoprost - analogs & derivatives; Dinoprost - metabolism; Enzymes; Female; Glucose; Heat shock proteins; Heat-Shock Proteins - blood; Heat-Shock Response; Humans; Hypoglycemia; Hypoglycemia - blood; Hypoglycemia - metabolism; Inflammation; Inflammation - metabolism; inflammatory proteins; Interleukin 5; Kinases; Ligands; Male; Middle Aged; Oxidative Stress; Protein Interaction Mapping; Proteins - metabolism; Software; Statistical analysis; TLR4 protein; Toll-like receptors; type 2 diabetes; Ubiquitin-Conjugating Enzymes - metabolism; United Kingdom > UK; United States > US; Switzerland; inflammatory proteins; type 2 diabetes; heat shock proteins; oxidative stress; hypoglycemia
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10113109

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–control 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 < 0.05) in T2D. At hypoglycemia, UBE2N, STIP1, and UBE2L3 increased (all p < 0.05), whilst TLR4:MD-2 and HSPA8 decreased (p < 0.05) in T2D versus baseline. In follow-up after hypoglycemia, HSPs normalized to baseline by 24 h, except UBE2L3 (p < 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 < 0.01) and SIGLEC1 (p < 0.05) in controls; HSPA8 negatively correlated with IL5 (p < 0.05) in T2D. A negative correlation between urinary isoprostane 8-iso PGF2α, a marker of oxidative stress, and HSPA1A was seen at 24 h in T2D only (p < 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.