The Role of Forkhead Box O in Pathogenesis and Therapy of Diabetes Mellitus

Marchelek-Myśliwiec, Małgorzata; Nalewajska, Magdalena; Turoń-Skrzypińska, Agnieszka; Kotrych, Katarzyna; Dziedziejko, Violetta; Sulikowski, Tadeusz; Pawlik, Andrzej

doi:10.3390/ijms231911611

Cited by 11 publications

(9 citation statements)

References 74 publications

(76 reference statements)

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“…FoxO proteins are transcription factors involved in numerous physiological processes and various pathological conditions, including diabetes. In particular, FoxO1 is an important regulator of pancreatic β-cell function, improving cell compensation under metabolic stress, and it also regulates α-cell mass by controlling Arx expression [ 43 , 44 ]. Furthermore, the loss of FoxO1 signaling in response to metabolic stress promotes the dedifferentiation of β-cells to a cell type similar to endocrine progenitors.…”

Section: Discussionmentioning

confidence: 99%

Gene expression analysis reveals diabetes-related gene signatures

Farrim,

Gomes,

Milenkovic

et al. 2024

Hum Genomics

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Background Diabetes is a spectrum of metabolic diseases affecting millions of people worldwide. The loss of pancreatic β-cell mass by either autoimmune destruction or apoptosis, in type 1-diabetes (T1D) and type 2-diabetes (T2D), respectively, represents a pathophysiological process leading to insulin deficiency. Therefore, therapeutic strategies focusing on restoring β-cell mass and β-cell insulin secretory capacity may impact disease management. This study took advantage of powerful integrative bioinformatic tools to scrutinize publicly available diabetes-associated gene expression data to unveil novel potential molecular targets associated with β-cell dysfunction. Methods A comprehensive literature search for human studies on gene expression alterations in the pancreas associated with T1D and T2D was performed. A total of 6 studies were selected for data extraction and for bioinformatic analysis. Pathway enrichment analyses of differentially expressed genes (DEGs) were conducted, together with protein–protein interaction networks and the identification of potential transcription factors (TFs). For noncoding differentially expressed RNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which exert regulatory activities associated with diabetes, identifying target genes and pathways regulated by these RNAs is fundamental for establishing a robust regulatory network. Results Comparisons of DEGs among the 6 studies showed 59 genes in common among 4 or more studies. Besides alterations in mRNA, it was possible to identify differentially expressed miRNA and lncRNA. Among the top transcription factors (TFs), HIPK2, KLF5, STAT1 and STAT3 emerged as potential regulators of the altered gene expression. Integrated analysis of protein-coding genes, miRNAs, and lncRNAs pointed out several pathways involved in metabolism, cell signaling, the immune system, cell adhesion, and interactions. Interestingly, the GABAergic synapse pathway emerged as the only common pathway to all datasets. Conclusions This study demonstrated the power of bioinformatics tools in scrutinizing publicly available gene expression data, thereby revealing potential therapeutic targets like the GABAergic synapse pathway, which holds promise in modulating α-cells transdifferentiation into β-cells.

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Section: Discussionmentioning

confidence: 99%

Gene expression analysis reveals diabetes-related gene signatures

Farrim,

Gomes,

Milenkovic

et al. 2024

Hum Genomics

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“…In this study, we found that FKBP5 depletion by siRNAs promotes FOXO1 phosphorylation at Ser 256 in human islets, and so did its inhibitor SAFit2. Previous studies have reported that FOXO1 protein can be modi ed by phosphorylation or acetylation in β cells, which precisely regulates Foxo1's transcriptional activity, subcellular localization, and turnover [35,39] . The phosphorylation of Foxo1 at Ser 256 promotes its unclear localization and activation under oxidative stress, which also elevates expression of transcription factors involved in promoting β-cell function [23,24] .…”

Section: Discussionmentioning

confidence: 99%

The inhibition of FKBP5 protects β cell survival under inflammation stress via AKT/FOXO1 signaling.

Liu

Cao

et al. 2023

Preprint

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The FK506-binding protein 51 (FKBP51, encoded by FKBP5 gene) has emerged as a critical regulator of mammalian endocrine stress responses and as a potential pharmacological target for metabolic disorders, including type 2 diabetes (T2D). However, in β cells, which secrete the only glucose-lowering hormone—insulin, the expression and function of FKBP5 has not been documented. Here, using human pancreatic tissue and primary human islets, we demonstrated the abundant expression of FKBP5 in β cells, which displayed an responsive induction upon acute inflammatory stress mimicked by in vitro treatment with a cocktail of inflammatory cytokines (IL-1β, IFN-γ, and TNF-α). To explore its function, siRNAs targeting FKBP5 and pharmacological inhibitor SAFit2 were applied both in clonal βTC-6 cells and primary human/mice islets. We found that FKBP5 inhibition promoted β cell survival, improved insulin secretion, and upregulated β cell functional gene expressions (Pdx1 and NKX6.1) in acute-inflammation stressed β cells. In primary human and mice islets, which constitutively suffer from inflammation stress during isolation and culture, FKBP5 inhibition also presented decent performance in improving islet function, in accordance with its protective effect against inflammation. Molecular studies found that FKBP5 is an important regulator for FOXO1 phosphorylation at Serine 256 and the subsequent nuclear translocation; Combining with the abundant expression of FKBP5 in β cells, this finding explains, as least partially, the unique constitutively cytoplasmic sub-cellular localization of FOXO1 protein. Meanwhile, silencing of FOXO1 abrogated the protective effect of FKBP5 inhibition, suggesting that it is the key downstream effector of FKBP5 in β cells. At last, taking advantage of pancreatic specimens from T2D patients and non-diabetic organ donors, we found a reduction of FKBP5 expression in β cells in T2D, which may indicate a FKBP5-inhibition mediated pro-survival mechanism against the complex stresses in T2D milieus.

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“…FoxO1 (also forkhead in rhabdomyosarcomam (FKHR)) is one of four mammalian isoforms belonging to the FoxO transcription factor family. The others include FoxO3, FoxO4, and FoxO6 ( 5 – 7 ). These FoxO proteins are mainly localized in the nucleus and exert their actions through their ability to regulate the transcription of specific genes.…”

Section: Foxo1 Structure Function and Regulationmentioning

confidence: 99%

“…Activity of all FoxOs depends on post-translational modifications. While processes such as ubiquitination, methylation, and glycosylation can alter FoxOs, phosphorylation and acetylation are the principal post-translational modifications regulating FoxO activity ( 5 , 6 ). Phosphorylation strongly regulates FoxO activity as it affects FoxO’s cellular localization, thus transcriptional capacity.…”

Section: Foxo1 Structure Function and Regulationmentioning

confidence: 99%

“…However, whether increased FoxO1 transcriptional activity exacerbates or alleviates T2D appears to be tissue-type specific and may depend on cellular conditions ( 2 , 3 ). Recent studies have called attention to these FoxO1 controversies ( 4 , 5 ). The current review describes FoxO1’s actions in T2D conditions in metabolic tissues that highly express FoxO1 and highlights some of the current progress in this field.…”

Section: Introductionmentioning

confidence: 99%

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FoxO1 as a tissue-specific therapeutic target for type 2 diabetes

Teaney,

Cyr

2023

Front. Endocrinol.

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Forkhead box O (FoxO) proteins are transcription factors that mediate many aspects of physiology and thus have been targeted as therapeutics for several diseases including metabolic disorders such as type 2 diabetes mellitus (T2D). The role of FoxO1 in metabolism has been well studied, but recently FoxO1’s potential for diabetes prevention and therapy has been debated. For example, studies have shown that increased FoxO1 activity in certain tissue types contributes to T2D pathology, symptoms, and comorbidities, yet in other tissue types elevated FoxO1 has been reported to alleviate symptoms associated with diabetes. Furthermore, studies have reported opposite effects of active FoxO1 in the same tissue type. For example, in the liver, FoxO1 contributes to T2D by increasing hepatic glucose production. However, FoxO1 has been shown to either increase or decrease hepatic lipogenesis as well as adipogenesis in white adipose tissue. In skeletal muscle, FoxO1 reduces glucose uptake and oxidation, promotes lipid uptake and oxidation, and increases muscle atrophy. While many studies show that FoxO1 lowers pancreatic insulin production and secretion, others show the opposite, especially in response to oxidative stress and inflammation. Elevated FoxO1 in the hypothalamus increases the risk of developing T2D. However, increased FoxO1 may mitigate Alzheimer’s disease, a neurodegenerative disease strongly associated with T2D. Conversely, accumulating evidence implicates increased FoxO1 with Parkinson’s disease pathogenesis. Here we review FoxO1’s actions in T2D conditions in metabolic tissues that abundantly express FoxO1 and highlight some of the current studies targeting FoxO1 for T2D treatment.

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The Role of Forkhead Box O in Pathogenesis and Therapy of Diabetes Mellitus

Cited by 11 publications

References 74 publications

Gene expression analysis reveals diabetes-related gene signatures

Gene expression analysis reveals diabetes-related gene signatures

The inhibition of FKBP5 protects β cell survival under inflammation stress via AKT/FOXO1 signaling.

FoxO1 as a tissue-specific therapeutic target for type 2 diabetes

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