Plasma heat shock protein response to euglycemia in type 2 diabetes

Abstract

IntroductionGlucose variability is associated with mortality and macrovascular diabetes complications. The mechanisms through which glucose variability mediates tissue damage are not well understood, although cellular oxidative stress is likely involved. As heat shock proteins (HSPs) play a role in the pathogenesis of type 2 diabetes (T2D) complications and are rapidly responsive, we hypothesized that HSP-related proteins (HSPRPs) would differ in diabetes and may respond to glucose normalization.Research design and methodsA prospective, parallel study in T2D (n=23) and controls (n=23) was undertaken. T2D subjects underwent insulin-induced blood glucose normalization from baseline 7.6±0.4 mmol/L (136.8±7.2 mg/dL) to 4.5±0.07 mmol/L (81±1.2 mg/dL) for 1 hour. Control subjects were maintained at 4.9±0.1 mmol/L (88.2±1.8 mg/dL). Slow Off-rate Modified Aptamer-scan plasma protein measurement determined a panel of HSPRPs.ResultsAt baseline, E3-ubiquitin-protein ligase (carboxyl-terminus of Hsc70 interacting protein (CHIP) or HSPABP2) was lower (p=0.03) and ubiquitin-conjugating enzyme E2G2 higher (p=0.003) in T2D versus controls. Following glucose normalization, DnaJ homolog subfamily B member 1 (DNAJB1 or HSP40) was reduced (p=0.02) in T2D, with HSP beta-1 (HSPB1) and HSP-70-1A (HSP70-1A) (p=0.07 and p=0.09, respectively) also approaching significance relative to T2D baseline levels.ConclusionsKey HSPRPs involved in critical protein interactions, CHIP and UBE2G2, were altered in diabetes at baseline. DNAJB1 fell in response to euglycemia, suggesting that HSPs are reacting to basal stress that could be mitigated by tight glucose control with reduction of glucose variability.

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

“…Glucose variability may affect HSPs in T2D, so increasing their response in hypoglycemia 45 , and hypoglycemia has been reported to induce cellular stress in different in vitro studies. For example, Kato et.…”

MiRNA and associated inflammatory changes from baseline to hypoglycemia in type 2 diabetes

“…Severe hypoglycemia in type 2 diabetes (T2D) is associated with cardiovascular-related events that are a risk for increased mortality ( 1 – 6 ), observations that have been reflected in the reports from both retrospective and longitudinal cohort studies ( 7 – 10 ). Causative factors underlying the clinical observations resulting from hypoglycemia include endothelial and thrombotic dysfunction ( 11 – 13 ), oxidative and inflammatory stress ( 14 , 15 ) and the heat shock protein response ( 16 ), but the diverse range of underlying mechanistic dysfunctions resulting from hypoglycemia have not been completely clarified.…”

Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor protein response

“…Changes in haematological parameters, inflammation, oxidative stress and changes in heat shock proteins have been reported to occur within the timeline of our study for both severe transient hypoglycaemia and prolonged mild hypoglycaemia, and those changes may last for up to 24 h after the hypoglycaemic event. [15][16][17][18][19] The causative mechanism(s) leading to the changes in FGF20 at 24 h seen here need to be addressed in detailed follow-up studies.…”

“…Glycaemic control is a delicate balancing act in diabetes treatment, with stricter control increasing the risk of hypoglycaemic episodes, those patients treated with insulin having the greatest risk. 7 Severe hypoglycaemia in T2D is associated with cardiovascular-related events that are a risk for increased mortality [8][9][10][11][12][13] potentially contributed to by endothelial and thrombotic dysfunction, [14][15][16] oxidative and inflammatory stress 17,18 and the heat shock protein response, 19 but the diverse range of underlying mechanistic dysfunctions resulting from hypoglycaemia have not been completely clarified.…”