A randomized, double‐blind, crossover study of the effect of the fluoroquinolone moxifloxacin on glucose levels and insulin sensitivity in young men and women

Juhl, Christian R.; Burgdorf, Josephine; Knudsen, Cecilie; Lubberding, Anniek F.; Veedfald, Simon; Isaksen, Jonas L.; Hartmann, Bolette; Frikke‐Schmidt, Ruth; Mandrup‐Poulsen, Thomas; Holst, Jens J.; Kanters, Jørgen K.; Jensen, Simon B K

doi:10.1111/dom.14851

Cited by 4 publications

(3 citation statements)

References 62 publications

(113 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is interesting as calcium flux is a critical determinant for insulin secretion in beta cells. These insights place RELA among a suite of factors that influence healthy metabolism, including external factors such as exercise [ 42 ], antibiotics and glucose-lowering drugs [ 43 ], as well as molecular components of glucose sensing and insulin release such as voltage-gated K + channels [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

RELA governs a network of islet-specific metabolic genes necessary for beta cell function

et al. 2023

View full text Add to dashboard Cite

Aims/hypothesis NF-κB activation unites metabolic and inflammatory responses in many diseases yet less is known about the role that NF-κB plays in normal metabolism. In this study we investigated how RELA impacts the beta cell transcriptional landscape and provides network control over glucoregulation. Methods We generated novel mouse lines harbouring beta cell-specific deletion of either the Rela gene, encoding the canonical NF-κB transcription factor p65 (βp65KO mice), or the Ikbkg gene, encoding the NF-κB essential modulator NEMO (βNEMOKO mice), as well as βA20Tg mice that carry beta cell-specific and forced transgenic expression of the NF-κB-negative regulator gene Tnfaip3, which encodes the A20 protein. Mouse studies were complemented by bioinformatics analysis of human islet chromatin accessibility (assay for transposase-accessible chromatin with sequencing [ATAC-seq]), promoter capture Hi-C (pcHi-C) and p65 binding (chromatin immunoprecipitation–sequencing [ChIP-seq]) data to investigate genome-wide control of the human beta cell metabolic programme. Results Rela deficiency resulted in complete loss of stimulus-dependent inflammatory gene upregulation, consistent with its known role in governing inflammation. However, Rela deletion also rendered mice glucose intolerant because of functional loss of insulin secretion. Glucose intolerance was intrinsic to beta cells as βp65KO islets failed to secrete insulin ex vivo in response to a glucose challenge and were unable to restore metabolic control when transplanted into secondary chemical-induced hyperglycaemic recipients. Maintenance of glucose tolerance required Rela but was independent of classical NF-κB inflammatory cascades, as blocking NF-κB signalling in vivo by beta cell knockout of Ikbkg (NEMO), or beta cell overexpression of Tnfaip3 (A20), did not cause severe glucose intolerance. Thus, basal p65 activity has an essential and islet-intrinsic role in maintaining normal glucose homeostasis. Genome-wide bioinformatic mapping revealed the presence of p65 binding sites in the promoter regions of specific metabolic genes and in the majority of islet enhancer hubs (~70% of ~1300 hubs), which are responsible for shaping beta cell type-specific gene expression programmes. Indeed, the islet-specific metabolic genes Slc2a2, Capn9 and Pfkm identified within the large network of islet enhancer hub genes showed dysregulated expression in βp65KO islets. Conclusions/interpretation These data demonstrate an unappreciated role for RELA as a regulator of islet-specific transcriptional programmes necessary for the maintenance of healthy glucose metabolism. These findings have clinical implications for the use of anti-inflammatories, which influence NF-κB activation and are associated with diabetes. Graphical Abstract

show abstract

Section: Discussionmentioning

confidence: 99%

RELA governs a network of islet-specific metabolic genes necessary for beta cell function

et al. 2023

View full text Add to dashboard Cite

show abstract

“…29,30 Also in young healthy population, taking a drug that is known to block Kv11.1 channel, moxifloxacin, decreased glucose levels with higher hypoglucaemia questionnaire scores were observed. 31 Knockout of Kcnh6 or knockin of Kcnh6 (Kv11.3) in mice has been shown changing characteristics from hyperinsulinemia to hypoinsulinemia. Kcnh6 dysfunction induces intracellular calcium and insulin secretion disorders and causing failure of β-cells in the long term.…”

Section: Insulin Secretion In Pancreatic β-Cellsmentioning

confidence: 99%

Pancreatic Beta-cell Dysfunction in Type 2 Diabetes

Khin

Lee

2023

Eur J Inflamm

View full text Add to dashboard Cite

Pancreatic β-cells produce and secrete insulin to maintain blood glucose levels within a narrow range. Defects in the function and mass of β-cells play a significant role in the development and progression of diabetes. Increased β-cell deficiency and β-cell apoptosis are observed in the pancreatic islets of patients with type 2 diabetes. At an early stage, β-cells adapt to insulin resistance, and their insulin secretion increases, but they eventually become exhausted, and the β-cell mass decreases. Various causal factors, such as high glucose, free fatty acids, inflammatory cytokines, and islet amyloid polypeptides, contribute to the impairment of β-cell function. Therefore, the maintenance of β-cell function is a logical approach for the treatment and prevention of diabetes. In this review, we provide an overview of the role of these risk factors in pancreatic β-cell loss and the associated mechanisms. A better understanding of the molecular mechanisms underlying pancreatic β-cell loss will provide an opportunity to identify novel therapeutic targets for type 2 diabetes.

show abstract

“…In one rat study, a mixture with moxifloxacin was used [ 27 ]. Interactions between insulin and fluoroquinolone antibiotics during topical application are unknown, but systemically administered fluoroquinolones can cause dysglycemia; therefore, caution is recommended when treating diabetic patients [ 38 ].…”

Section: Solvent and Storagementioning

confidence: 99%

Topical Insulin in Neurotrophic Keratopathy: A Review of Current Understanding of the Mechanism of Action and Therapeutic Approach

Jaworski,

Lorenc,

Leszczyński

et al. 2023

Pharmaceutics

View full text Add to dashboard Cite

Neurotrophic keratopathy is a corneal disease characterized by impaired corneal innervation. It can lead to corneal epithelial defects, ulcerations, and perforations. Topical insulin has been shown to be effective in treating this disorder. Insulin is a growth factor that can promote corneal epithelial cell proliferation and migration. In addition, it can also inhibit corneal epithelial cell apoptosis. Topical insulin has previously been found to enhance corneal wound healing. This article reviews the current understanding of the mechanism of action of topical insulin in the treatment of neurotrophic keratopathy.

show abstract

A randomized, double‐blind, crossover study of the effect of the fluoroquinolone moxifloxacin on glucose levels and insulin sensitivity in young men and women

Cited by 4 publications

References 62 publications

RELA governs a network of islet-specific metabolic genes necessary for beta cell function

RELA governs a network of islet-specific metabolic genes necessary for beta cell function

Pancreatic Beta-cell Dysfunction in Type 2 Diabetes

Topical Insulin in Neurotrophic Keratopathy: A Review of Current Understanding of the Mechanism of Action and Therapeutic Approach

Contact Info

Product

Resources

About