The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity

Abstract

Apoptosis of pancreatic beta cells is a feature of type 2 diabetes and its prevention may have therapeutic benefit. High glucose concentrations induce apoptosis of islet cells, and this requires the proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins Bim and Puma. We studied the stress pathways induced by glucotoxicity in beta cells that result in apoptosis. High concentrations of glucose or ribose increased expression of the transcription factor CHOP (C/EBP homologous protein) but not endoplasmic reticulum (ER) chaperones, indicating activation of proapoptotic ER stress signaling. Inhibition of ER stress prevented ribose-induced upregulation of Chop and Puma mRNA, and partially protected islets from glucotoxicity. Loss of Bim or Puma partially protected islets from the canonical ER stressor thapsigargin. The antioxidant N -acetyl-cysteine also partially protected islets from glucotoxicity. Islets deficient in both Bim and Puma, but not Bim or Puma alone, were significantly protected from killing induced by the mitochondrial reactive oxygen species donor rotenone. Our data demonstrate that high concentrations of glucose induce ER and oxidative stress, which causes cell death mediated by Bim and Puma. We observed significantly higher Bim and Puma mRNA in islets of human donors with type 2 diabetes. This indicates that inhibition of Bim and Puma, or their inducers, may prevent beta-cell destruction in type 2 diabetes.

Cytokines Regulate β-Cell Thioredoxin-interacting Protein (TXNIP) via Distinct Mechanisms and Pathways

“…Our studies further established a critical role for Bim in IFN␥ and cytokine-induced ␤-cell apoptosis, which is consistent with recent reports implicating Bim in ␤-cell death (30,31). Although this supports the notion that cytokine-induced ␤-cell death is mediated by different pathways, some of which may act independently of TXNIP signaling, our results also indicate that for any complete protection against cytokine-induced apoptosis, effective inhibition of TXNIP expression is crucial (Fig.…”

“…Interestingly, the BH3-only BCL2 family protein Bim has recently been reported to play a critical role in IFN␥ϩTNF␣-induced ␤-cell death (30,31) and is also known to inhibit BCL2 (32), raising the possibility that Bim might mediate the observed ␤-cell apoptosis in response to IFN␥. Indeed, Bim expression was significantly induced by IFN␥ in INS-1 ␤-cells as well as in human islets (Fig.…”

Redox controls UPR to control redox

“…ER stress signals facilitate BAX and BAK oligomerization by inducing the expression of BH3-only proteins, including BIM, NOXA, PUMA, DR5 and CRK (Austgen et al, 2011;Cunha et al, 2012;Li et al, 2006;Puthalakath et al, 2007;Wali et al, 2014) and by repressing BCL2 (McCullough et al, 2001). Furthermore, the BH3-only protein BID is truncated or activated in response to ER stress in a pathway downstream of caspase-8 (Namba et al, 2013) or caspase-2 (Upton et al, 2008) -although the role of caspase-2 is debated (Sandow et al, 2014).…”

Inhibitor of differentiation proteins protect against oxidative stress by regulating the antioxidant–mitochondrial response in mouse beta cells

“…Elevated glucose or ribose levels have been shown to increase reactive oxygen species (ROS) production in beta cells [8,[14][15][16], and islets of diabetic mice exhibit higher ROS content, mitochondrial dysfunction and oxidative damage [15,[17][18][19].…”

“…Several lines of evidence underscore a role for chronic hyperglycaemia-termed 'glucotoxicity'-in increased beta cell apoptosis. Thus, elevated glucose concentrations trigger apoptosis in cultured islets and beta cell lines [4][5][6][7][8] and in animal models of type 2 diabetes [9][10][11].…”