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

Abstract

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.

Single-cell and transcriptomic analyses reveal the influence of diabetes on ovarian cancer

“…In the ovarian cancer tumor microenvironment, HSPA8 is implicated in modulating the immune response of monocytes/macrophages [61]. Furthermore, HSPA8 plays an important role in insulin secretion and insulin receptor signaling in DM [62]. Small nuclear ribonucleoprotein D2 (SNRPD2) consists of small nuclear ribonucleoproteins and small nuclear RNAs (snRNAs), playing a crucial role in the splicing process and gene expression regulation [63].…”

Plasma proteins and onset of type 2 diabetes and diabetic complications: Proteome-wide Mendelian randomization and colocalization analyses

“…Many small molecule AGER inhibitors or antagonists have been proposed to treat diabetic complications and cancer progression with a good tolerance in humans. 33 Heat shock proteins were associated with hypoglycemia 34 and diabetic foot ulcer. 35 However, the mechanisms underlying the inverse associations of HSPA1A and HSPA1B with diabetes and its complications are unclear, but possibly related to attenuation of oxidative stress.…”

Quantification of heat shock proteins in the posterior interosseous nerve among subjects with type 1 and type 2 diabetes compared to healthy controls

“…However, contrary data have been published suggesting that HSP27 levels in plasma are higher among T1D subjects with DPN than in control subjects (Gruden et al, 2008 ). Interestingly, mild and severe hypoglycemia in T2D is also associated with changes in HSPs, such as HSP70 and HSP90, with an additional related inflammatory response to mild hypoglycemia among T2D subjects (Moin et al, 2021 ). These data indicate that the pattern of HSP expression in plasma and in the nervous system is complex in diabetes.…”

“…Although the cohort is well-defined, there is a lack of data regarding insulin treatment for some of the T2D subjects. Such data could be relevant since HSPs have been shown to react to hypoglycemic events (Moin et al, 2021 ), and insulin-dependent T2D subjects are more prone to hypoglycemic events than non-insulin-dependent subjects.…”