题名：Proteasome dysfunction mediates high glucose-induced apoptosis in rodent Beta cells and human islets.
作者：BROCA C; VARIN E; ARMANET M; TOURREL-CUZIN C; BOSCO D; DALLE S; WOJTUSCISZYN A;
来源：PLoS One. 2014 Mar 18;9(3):e92066. doi: 10.1371/journal.pone.0092066. eCollection [ IF= 3.73 ] ]
摘要：The ubiquitin/proteasome system (UPS), a major cellular protein degradation
machinery, plays key roles in the regulation of many cell functions.
Glucotoxicity mediated by chronic hyperglycaemia is detrimental to the function
and survival of pancreatic beta cells. The aim of our study was to determine
whether proteasome dysfunction could be involved in beta cell apoptosis in
glucotoxic conditions, and to evaluate whether such a dysfunction might be
pharmacologically corrected. Therefore, UPS activity was measured in GK rats
islets, INS-1E beta cells or human islets after high glucose and/or UPS inhibitor
exposure. Immunoblotting was used to quantify polyubiquitinated proteins,
endoplasmic reticulum (ER) stress through CHOP expression, and apoptosis through
the cleavage of PARP and caspase-3, whereas total cell death was detected through
histone-associated DNA fragments measurement. In vitro, we found that chronic
exposure of INS-1E cells to high glucose concentrations significantly decreases
the three proteasome activities by 20% and leads to caspase-3-dependent
apoptosis. We showed that pharmacological blockade of UPS activity by 20% leads
to apoptosis in a same way. Indeed, ER stress was involved in both conditions.
These results were confirmed in human islets, and proteasome activities were also
decreased in hyperglycemic GK rats islets. Moreover, we observed that a high
glucose treatment hypersensitized beta cells to the apoptotic effect of
proteasome inhibitors. Noteworthily, the decreased proteasome activity can be
corrected with Exendin-4, which also protected against glucotoxicity-induced
apoptosis. Taken together, our findings reveal an important role of proteasome
activity in high glucose-induced beta cell apoptosis, potentially linking ER
stress and glucotoxicity. These proteasome dysfunctions can be reversed by a
GLP-1 analog. Thus, UPS may be a potent target to treat deleterious metabolic
conditions leading to type 2 diabetes.