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Riboseq_Acute Glucose Stimulation Drives Coordinated Translational Reprogramming in Primary Pancreatic Islets: From Global Remodeling to Fine-tuned Insulin Synthesis

ABSTRACT: Pancreatic β cells rapidly increase protein synthesis to maintain glucose homeostasis, but the immediate translational dynamics underlying this adaptive response remain poorly defined. In this study, high-resolution ribosome profiling (Ribo-seq) was performed on primary mouse pancreatic islets under acute low-glucose (2.5 mM) and high-glucose (25 mM) conditions. High glucose induced extensive translational reprogramming, including induction of immediate-early genes, suppression of stress-related genes, expansion of the cytosolic translation machinery, coordinated upregulation of secretory pathway components, and metabolic remodeling. Bulk RNA-seq was performed to support translation efficiency analysis. These data define glucose-responsive translational programs in primary islets and provide a resource for understanding β-cell function and insulin synthetic capacity.

ORGANISM(S): Mus musculus

PROVIDER: GSE334681 | GEO | 2026/06/15

REPOSITORIES: GEO

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Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).

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Riboseq_Acute Glucose Stimulation Drives Coordinated Translational Reprogramming in Primary Pancreatic Islets: From Global Remodeling to Fine-tuned Insulin Synthesis

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