Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function

Backe, Marie Balslev; Andersson, Jan L.; Bacos, Karl; Christensen, Dan Ploug; Hansen, Jakob Bondo; Dorosz, Jerzy; Gajhede, Michael; Dahlby, Tina; Bysani, Madhusudhan; Kristensen, Line H.; Ling, Charlotte; Olsen, Lars; Mandrup-Poulsen, Thomas

doi:10.1016/j.mce.2017.07.001

Cited by 23 publications

(19 citation statements)

References 52 publications

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“…INS-1 cells (300,000) were cultured in 12-well plates (Nunc) and incubated for 2 days before being exposed to cytokine mixture (150 pg/mL IL-1b + 0.1 ng/mL IFN-g) or control medium. GSIS was performed using Krebs-Ringer buffer containing 2 or 17 mmol/L glucose as previously described (23).…”

Section: Gsismentioning

confidence: 99%

The No-Go and Nonsense-Mediated RNA Decay Pathways Are Regulated by Inflammatory Cytokines in Insulin-Producing Cells and Human Islets and Determine β-Cell Insulin Biosynthesis and Survival

et al. 2018

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Stress-related changes in β-cell mRNA levels result from a balance between gene transcription and mRNA decay. The regulation of RNA decay pathways has not been investigated in pancreatic β-cells. We found that no-go and nonsense-mediated RNA decay pathway components (RDPCs) and exoribonuclease complexes were expressed in INS-1 cells and human islets. Pelo, Dcp2, Dis3L2, Upf2, and Smg1/5/6/7 were upregulated by inflammatory cytokines in INS-1 cells under conditions where central β-cell mRNAs were downregulated. These changes in RDPC mRNA or corresponding protein levels were largely confirmed in INS-1 cells and rat/human islets. Cytokine-induced upregulation of Pelo, Xrn1, Dis3L2, Upf2, and Smg1/6 was reduced by inducible nitric oxide synthase inhibition, as were endoplasmic reticulum (ER) stress, inhibition of Ins1/2 mRNA, and accumulated insulin secretion. Reactive oxygen species inhibition or iron chelation did not affect RDPC expression. Pelo or Xrn1 knockdown (KD) aggravated, whereas Smg6 KD ameliorated, cytokine-induced INS-1 cell death without affecting ER stress; both increased insulin biosynthesis and medium accumulation but not glucose-stimulated insulin secretion in cytokine-exposed INS-1 cells. In conclusion, RDPCs are regulated by inflammatory stress in β-cells. RDPC KD improved insulin biosynthesis, likely by preventing Ins1/2 mRNA clearance. Pelo/Xrn1 KD aggravated, but Smg6 KD ameliorated, cytokine-mediated β-cell death, possibly through prevention of proapoptotic and antiapoptotic mRNA degradation, respectively.

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Section: Gsismentioning

confidence: 99%

The No-Go and Nonsense-Mediated RNA Decay Pathways Are Regulated by Inflammatory Cytokines in Insulin-Producing Cells and Human Islets and Determine β-Cell Insulin Biosynthesis and Survival

et al. 2018

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“…Accordingly, glucose-stimulated insulin secretion (GSIS) in islets from mice with beta-cell-specific deletion of the H3K4 methyltransferase Set7/9 is impaired [13]. Consistent with these findings, we recently showed that GSK-J4 improved GSIS accompanied by an increased level of the transcriptionally activating H3K4 methylation mark [9], but we did not pinpoint the precise mechanism.…”

Section: Introductionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

“…We recently demonstrated that preserving H3K27 methylation marks using the lysine demethylase (KDM) inhibitor GSK-J4 protects beta-cells from cytokine-induced apoptosis in rodent and human islets, possibly via reduction of NFkB levels and ER stress signaling [9]. GSK-J4, which targets KDM6 demethylases with the highest potency, has cross-reactivity with the demethylase KDM5B, which catalyzes demethylation of lysine 4 on histone 3 tail (H3K4) [9, 10]. In contrast to methylation of H3K27, methylation of H3K4 is associated with transcriptional activation and is of particular importance for transcription of essential beta-cell genes such as ins1/2 , MafA , and Glut2 [11, 12].…”

Section: Introductionmentioning

confidence: 99%

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The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis

Backe

Jin

Andreone

et al. 2019

Journal of Diabetes Research

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Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods. We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results. GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.

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“…Several studies have investigated whether inhibitors of epigenetic enzymes may affect insulin secretion and action. Studies from our group and Thomas Mandrup‐Poulsen’s group have used inhibitors of histone deacetylases (HDACs) and lysine demethylases and studied their impact on islet function [[77‐84]. These studies support a protective β‐cell function and show improved insulin secretion when cells are exposed to these inhibitors.…”

Section: Can Epigenetics Be Of Clinical Use In Diabetes?mentioning

confidence: 99%

Epigenetic regulation of insulin action and secretion – role in the pathogenesis of type 2 diabetes

Ling

2020

J Intern Med

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Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function

Cited by 23 publications

References 52 publications

The No-Go and Nonsense-Mediated RNA Decay Pathways Are Regulated by Inflammatory Cytokines in Insulin-Producing Cells and Human Islets and Determine β-Cell Insulin Biosynthesis and Survival

The No-Go and Nonsense-Mediated RNA Decay Pathways Are Regulated by Inflammatory Cytokines in Insulin-Producing Cells and Human Islets and Determine β-Cell Insulin Biosynthesis and Survival

The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis

Epigenetic regulation of insulin action and secretion – role in the pathogenesis of type 2 diabetes

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