ArticleThe Journal of clinical endocrinology and metabolism2022
Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets.
Article in The Journal of clinical endocrinology and metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 14 citations in OpenAlex.
- Effect of fenofibrate on residual beta cell function in adults and adolescents with newly diagnosed type 1 diabetes: a randomised clinical trial.Diabetologia · 2025Trial
- Coordinated expression and assembly of BiP, p58Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Partial remission of type 1 diabetes: Do immunometabolic events define the honeymoon period?Diabetes, obesity & metabolism · 2025Review
- Machine Learning and Augmented Intelligence Enables Prognosis of Type 2 Diabetes Prior to Clinical Manifestation.Current diabetes reviews · 2025Review
- Optical Nanoscopy of Cytokine-Induced Structural Alterations of the Endoplasmic Reticulum and Golgi Apparatus in Insulin-Secreting Cells.International journal of molecular sciences · 2024Article
- NOD mice have distinct metabolic and immunologic profiles when compared with genetically similar MHC-matched ICR mice.American journal of physiology. Endocrinology and metabolism · 2023Article
- Unveiling nanoscale optical signatures of cytokine-induced β-cell dysfunction.Scientific reports · 2023Article
- Synchronized proinsulin trafficking reveals delayed Golgi export accompanies β-cell secretory dysfunction in rodent models of hyperglycemia.Scientific reports · 2023Article
- Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets.The Journal of clinical endocrinology and metabolism · 2022Article
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
contextAberrant biosynthesis and secretion of the insulin precursor proinsulin occurs in both type I and type II diabetes. Inflammatory cytokines are implicated in pancreatic islet stress and dysfunction in both forms of diabetes, but the mechanisms remain unclear.
objectiveWe sought to determine the effect of the diabetes-associated cytokines on proinsulin folding, trafficking, secretion, and β-cell function.
methodsHuman islets were treated with interleukin-1β and interferon-γ for 48 hours, followed by analysis of interleukin-6, nitrite, proinsulin and insulin release, RNA sequencing, and unbiased profiling of the proinsulin interactome by affinity purification-mass spectrometry.
resultsCytokine treatment induced secretion of interleukin-6, nitrites, and insulin, as well as aberrant release of proinsulin. RNA sequencing showed that cytokines upregulated genes involved in endoplasmic reticulum stress, and, consistent with this, affinity purification-mass spectrometry revealed cytokine induced proinsulin binding to multiple endoplasmic reticulum chaperones and oxidoreductases. Moreover, increased binding to the chaperone immunoglobulin binding protein was required to maintain proper proinsulin folding in the inflammatory environment. Cytokines also regulated novel interactions between proinsulin and type 1 and type 2 diabetes genome-wide association studies candidate proteins not previously known to interact with proinsulin (eg, Ataxin-2). Finally, cytokines induced proinsulin interactions with a cluster of microtubule motor proteins and chemical destabilization of microtubules with Nocodazole exacerbated cytokine induced proinsulin secretion.
conclusionTogether, the data shed new light on mechanisms by which diabetes-associated cytokines dysregulate β-cell function. For the first time, we show that even short-term exposure to an inflammatory environment reshapes proinsulin interactions with critical chaperones and regulators of the secretory pathway.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.