Aug 2026· Journal of Clinical Investigation· Vol 136· 0 citations· 22 references
Medicine
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.
Diabetes mellitus is a global metabolic disorder characterized by progressive pancreatic β-cell failure, which leads to inadequate insulin secretion, often in combination with insulin resistance, and ultimately disrupts glucose homeostasis. The Integrated Stress Response (ISR), a crucial signaling network that enables...
Yi-Jun Huang, Yu Zeng, Xin-Ying Zhong et al.· Frontiers in Endocrinology· 0 citations
PDX-1 and MafA are insulin gene transcription factors and maintain mature pancreatic β-cell function. After chronic exposure to hyperglycemia, however, the expression levels of PDX-1 and MafA are substantially suppressed by provoked oxidative stress and the activation of the JNK/c-Jun pathway, which further aggravates...
Pancreatic β-cell failure is central to the pathogenesis of type 2 diabetes (T2D), developing when chronic metabolic stress overwhelms the adaptive capacity of these cells. Because insulin biosynthesis and glucose-stimulated secretion depend on tightly coordinated organelle function, crosstalk between the endoplasmic r...
S. Niinuma, A. S. Takemoto, William Junior Khalil et al.· Cells· 0 citations
It is proposed that proteostasis functions as an active physiological signaling network that governs islet cell adaptation, plasticity, and long‐term homeostasis, extending beyond its conventional role in the response to cellular damage.
Jun Shirakawa· Journal of Diabetes Investig...· 0 citations
Two of the main intracellular signaling molecules in pancreatic β-cells are calcium (Ca2+) and reactive oxygen species (ROS). Ca2+ signaling is essential for regulating energy metabolism, insulin secretion, and the modulation of key factors involved in β-cell survival and function. In parallel, redox signaling also aff...
Lucas Rafael Pereira Camara, E. Vilas-Boas· Frontiers in Network Physiol...· 0 citations
Pancreatic β-cell dedifferentiation is a pathological mechanism that contributes to β-cell dysfunction and loss during type 2 diabetes (T2D), but the underlying mechanisms remain incompletely understood. MicroRNAs (miRNAs) are key post-transcriptional regulators of cellular identity and function. We previously identifi...
