Diabetic and ER-stressed pancreatic islet β cells are in need of some JNK removal
Jonathan M. Palozzi, Pere Puigserver
Jonathan M. Palozzi, Pere Puigserver
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Diabetic and ER-stressed pancreatic islet β cells are in need of some JNK removal

Abstract

Pancreatic β cells regulate glucose homeostasis through insulin secretion, but nutrient overload and genetic defects can trigger ER stress and apoptosis, contributing to type 2 diabetes. Within β cells, the kinases PERK, IRE1α, and ATF6 initiate the unfolded protein response (UPR) as a result of ER stress, a process that is constitutively suppressed under nonstress conditions by GRP78 binding to these proteins. To gain insight into the mechanisms of β cell death upon dysregulated ER stress, Sharma et al. used β cell–specific GRP78 knockout models, revealing that hyperactivation of the UPR promoted β cell death primarily through the IRE1α/JNK/p53 signaling pathway. Pharmacological inhibition of JNK improved β cell survival, increased insulin levels, and lowered blood glucose in multiple diabetic mouse models. These findings highlight JNK signaling as a promising therapeutic target for preserving β cell function.

Authors

Jonathan M. Palozzi, Pere Puigserver

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Figure 1

Pharmacological inhibition of the IRE1α-JNK-p53 signaling axis suppresses islet β cell death.

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Pharmacological inhibition of the IRE1α-JNK-p53 signaling axis suppresse...
Insulin is produced in the ER of islet β cells and is secreted to regulate circulating glucose. Dysregulation of ER stress in islet β cells can be induced by genetic factors or dietary factors, like overnutrition, leading to loss of β cell mass and impairments in insulin secretion and glucose homeostasis. (A) Under nonstressed conditions, GRP78 constitutively suppresses dimerization of IRE1α, inhibiting activation of the UPR pathway. (B) In Sharma et al.’s study (16), β cell–selective depletion of Grp78 permitted dimerization and activation of the stress kinase IRE1α, which, in turn, phosphorylated JNK, activated p53, and led to apoptosis. Systemic application of pharmacological inhibitors targeting any step in this process reduced β cell death, increased insulin secretion, and had an antidiabetic effect in these mice.