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.
Highlights
Optimal management of type 2 diabetes (T2D) with stricter glucose control increases the risk and frequency of hypoglycemic episodes [1], and hypoglycemia has been directly linked to diabetes-related complications such as cognitive dysfunction [2]
The heat shock proteins and the inflammatory proteins are shown separately and combined. These data show that baseline Heat shock proteins (HSPs) differed between T2D and control subjects, with further differences following hypoglycemia that correlated with inflammatory protein changes, suggesting that the inflammatory response may be driving the HSP changes
We have previously reported that inflammatory regulators are increased at the time of hypoglycemia, are exaggerated in T2D, and that all apart from C-reactive protein return to normal at 24 h [21]
Summary
Optimal management of type 2 diabetes (T2D) with stricter glucose control increases the risk and frequency of hypoglycemic episodes [1], and hypoglycemia has been directly linked to diabetes-related complications such as cognitive dysfunction [2]. Diabetes progression and the development of diabetes-related complications have been associated with intracellular protein misfolding [3,4]. Heat shock proteins (HSPs) help to maintain cellular homeostasis and prevent the endoplasmic reticulum stress that results from protein misfolding through endogenous or exogenous inflammatory insults and oxidative stress generation [5]. Tein misfolding through endogenous or exogenous inflammatory insults and oxidative stress generation [5]. HSPs are constitutively expressed and rapidly respond to cellular stress [5] and may be post-translationally modified including phosphorylation, acetylation, ubiquitination, AMPylation, and ADP-ribosylation that may modulate their function [6,7,8]. Proteins that are damaged or misfolded and that may result in cellular catastrophe are chaperoned by HSPs to the ubiquitin proteasome system (UPS) that functions as the mainPmroetcehinasntihsmat aforer dparmotaegoelydsiosr, mefifsefcotlidnegddaengdratdhaattimonayofresshuolrtti-nlivceeldlu, ldaarmcaatgasetdro, pohr emairsefcohladpeedropnreodtebinysH[4S]P. HatSinPgs aenrezyinmveol(vEe1d), uinbibqiunidtiinn-gcoannjdugmatoindguleantizoynmoef(sEe2v),earanldcuribtiicqauliteinnz-pyrmoteesininlvigoalsveed(Ei3n);ifnoflllaomw-mingatuiobniq, uapitoinpattoisoins,, tmheet2a6bSolpisromte, aasnodmceelelfsfeigctnsaplirnogte[o1l0y]s.iHs [S9P]s(Fairgeuirme p1)l.icHatSePdsianreβ-icnevlol ldvyesdfinunbcintidoinnganadndinmsuoldinulraetisoisntaonf cseev[e1r1a]l, carsitwicaellleanszypmlaeysiningvaolrvoelde iinnidnfliaabmetmesatcioomn,palpicoapttioosniss., Dmieatbaebtoiclisnmeu, aronpdactehlyl saignndalninepgh[r1o0p].aHthSyPsaraereaismsopcliiactaetdedwinithβ-ecleelvl adtyesdfuHnSctPi2o7n [a1n2d],inwshuillisnt
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