Bax and Bak jointly control survival and dampen the early unfolded protein response in pancreatic β-cells under glucolipotoxic stress

Abstract

ER stress and apoptosis contribute to the loss of pancreatic β-cells under the pro-diabetic conditions of glucolipotoxicity. Although activation of the canonical pathway of intrinsic apoptosis is known to require Bax and Bak, their individual and combined involvement in glucolipotoxic β-cell death have not been demonstrated. It has also remained an open question if Bax and Bak in β-cells have non-apoptotic roles in mitochondrial function and ER stress signaling, as suggested in other cell types. Using mice with individual or combined β-cell deletion of Bax and Bak, we demonstrated that glucolipotoxic β-cell death in vitro happens in sequential stages; first via non-apoptotic mechanisms and later by apoptosis, which Bax and Bak were redundant in triggering. In contrast, they had non-redundant roles in mediating staurosporine-induced β-cell apoptosis. We further established that Bax and Bak do not affect normal glucose-stimulated β-cell Ca2+ responses, insulin secretion, or in vivo glucose tolerance. Finally, our experiments revealed that Bax and Bak together dampen the unfolded protein response in β-cells during the early stages of chemical- or glucolipotoxicity-induced ER stress. These findings identify novel roles of the canonical apoptosis machinery in modulating stress signals that are important for the pathobiology of β-cells in diabetes.

Mechanisms of muscle insulin resistance and the cross‐talk with liver and adipose tissue

“…The mechanisms of lipid‐induced insulin resistance have been well described as an underlying cause of obesity‐associated insulin resistance. However, an overload of other nutrients may also be implicated in the etiology of insulin resistance (Villalobos‐Labra et al., 2019), and diabetes (White et al., 2020), for instance, the unfolded protein response (UPR), activated by ER stress (Villalobos‐Labra et al., 2019). The main role of the UPR is to promote an adaptive cellular response that alleviates ER stress through different mechanisms, such as the inhibition of protein synthesis and the enhancement of protein folding and degradation (Vincenz‐Donnelly & Hipp, 2017).…”