III- Cellular stress in type 2 diabetes
I. ER stress and glucolipotoxicity in the beta-cell
Prolonged high glucose exposure has been suggested to induce ER stress in beta-cells since treatment of INS-1 cells with 25 mM glucose for 24–48 h decreased insulin mRNA and protein levels and reduced the proinsulin translation rate. However, although some markers of UPR signaling were found to be elevated, hyperglycemia per se did not elicit a characteristic ER stress response as chaperone expression was not induced. Nevertheless, overexpressing GRP78 partially rescued high glucose-induced suppression of proinsulin levels and improved glucose stimulated insulin secretion (GSIS) whereas its knockdown under basal glucose conditions reduced cellular insulin levels and GSIS. This suggests that GRP78 is essential for insulin biosynthesis, and enhancing chaperone capacity can improve beta-cell function in the presence of prolonged hyperglycemia (Volchuk, Lecture).16
Treatment of beta-cells with saturated and/or unsaturated FFA leads to differential ER stress signaling. INS-1 cells exposed to palmitate for 16 to 24 h under serum-free conditions showed marked apoptosis and increased protein levels of phosphorylated eIF2α, ATF4, XBP-1, and CHOP compared with control cells, with no alteration of GRP78 levels.17 Clonal beta-cells, rat primary beta-cells, and human islets treated with palmitate also died by apoptosis caused by activation of JNK and CHOP in the IRE1 and PERK pathways, whereas ATF6 activation had antiapoptotic effects.18
Contrary to palmitate, oleate did not significantly induce the UPR and was less toxic for beta-cells.17 Interestingly, FFA-induced ER stress response was not modified by high glucose concentrations18 and FFA damaging effects were prevented by GLP-1 agonists (exendin-4 or forskolin) (Cnop and Volchuk, Lectures).19
One of the potent factors involved in glucose-mediated ER stress is mTORC1, the rapamycin-sensitive complex of mTOR (mammalian Target of Rapamycin). Bachar et al (2009)20 evidenced that glucose augments palmitate-induced beta-cell lipotoxicity by stimulating mTORC1 leading to activation of ER stress. Indeed, in beta-cells exposed in vivo and in vitro to hyperglycemia (and FFA), mTORC1 activation stimulates both the biosynthesis of proteins required for the adaptive response of beta-cell and the biosynthesis of proteins involved in the execution of the ER stress response.
This effect of mTORC1 could counteract the adaptive attenuation of protein synthesis induced by the UPR and induce beta-cell apoptosis (Leibowitz, Lecture).20 The dual effect of mTORC1 excludes its potential use as therapeutic target to treat metabolic disease.
2. Role of ER stress in hepatic insulin resistance
Besides pancreatic beta-cells, other types of cells could be sensitive to ER stress. Recent studies in humans pointed out the important role of de novo lipogenesis in the excessive accumulation of triglycerides in the liver of patients with nonalcoholic fatty liver disease (NAFLD), since one third of total triglycerides might originate from this pathway. In insulin-resistant obese rodents, hepatic steatosis is present and concomitant with active lipogenesis. Hepatic lipogenesis depends on the insulin-induced activation of the transcription factor SREBP-1c and despite prevailing insulin resistance, SREBP-1c was shown to be activated in the liver of genetically and diet-induced obese rodents. Kammoun et al (2009)21 evidenced that ER stress is a major component of the hepatic steatosis and insulin resistance observed in obese insulin-resistant rodents. Indeed, they demonstrated that GRP78 overexpression in cultured hepatocytes and in the livers of ob/ob mice reduced ER stress and inhibited both insulin- and ER stress–induced SREBP-1c cleavage and subsequent activation of target genes expression. This led to the reduction of hepatic triglyceride and cholesterol contents, thus slowing down lipogenesis and improved steatosis and insulin sensitivity (Foufelle, Lecture).
“The Stressed Beta-Cell”
I- ER and the canonical unfolded protein response (UPR)
II- When UPR leads to cell death
III- Cellular stress in type 2 diabetes
IV- The mitochondria and cellular stress
V- Therapeutic targeting of ER dysfunction