NSD2 is downregulated in T2DM and promotes β cell proliferation and insulin secretion through the transcriptionally regulation of PDX1

Shi, Suqin; Zhao, Lu; Zheng, Lili

doi:10.3892/mmr.2018.9338

Cited by 7 publications

(12 citation statements)

References 31 publications

(40 reference statements)

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“…The present study revealed that PdX1 mrna levels decreased during the development of PDM but significantly increased following the administration of chemerin-9, which alleviated ir. This is consistent with previously published studies reporting that PdX1 expression was decreased in patients with T2dM (30,31) and that the activation of the PdX1/JaK signal transduction cascade in c57Bl/6 mice ameliorates the ir of dM (32). Thus, this supports the notion that the impaired proliferation of pancreatic β-cells resulting from decreased PdX1 expression may be causally related to the pathogenesis of PdM, and that restoring PdX1 signaling using chemerin-9 may explain the protective role against ir in PdM.…”

Section: Discussionsupporting

confidence: 94%

Regulatory effect of chemerin and therapeutic efficacy of chemerin‑9 in pancreatogenic diabetes mellitus

Tu¹,

Yang

Zhang

et al. 2020

Mol Med Report

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chemerin is a novel adipokine that regulates immune responses, adipocyte differentiation, and glucose metabolism. However, the role of chemerin in pancreatogenic diabetes mellitus (PdM) remains unknown. PdM is recognized as dM occurring secondary to chronic pancreatitis or pancreatic resection due to the loss of the loss of islet cell mass. The aim of the present study was to investigate the role of chemerin in PdM by collecting blooding samples from dM patients and establishing in vivo PdM model. The present study demonstrated that chemerin levels are decreased in the serum of patients with PdM and are negatively associated with the insulin resistance (ir) status. chemerin levels also decreased during the development of PdM in c57Bl/6 mice, together with increasing serum levels of interleukin-1 and tumor necrosis factor-α and decreasing mrna expression levels of glucose transporter 2 (GluT2) and pancreatic and duodenal homeobox 1 (PdX1). Treatment of PdM model mice with chemerin chemokine-like receptor 1 (cMKlr1) agonist, chemerin-9, elevated the serum levels of chemerin and mrna expression levels of GluT2 and PdX1, leading to the alleviation of glucose intolerance and ir in these animals. Together, the accumulated data indicated that chemerin may exert a protective function in PdM, perhaps by regulating perhaps by regulating GluT2 and PdX1 expression, and that the restoration of the chemerin/cMKlr1 pathway may represent a novel therapeutic strategy for PdM.

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Section: Discussionsupporting

confidence: 94%

Regulatory effect of chemerin and therapeutic efficacy of chemerin‑9 in pancreatogenic diabetes mellitus

Tu¹,

Yang

Zhang

et al. 2020

Mol Med Report

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“… 27 In pancreatic β-cell lines in vitro NSD2 has also been shown to promote proliferation and to regulate insulin secretion. 28 However, since diabetes has not been reported as a recurrent feature neither in our cohort nor in patients with WHS we assume that in humans, glycemic control may be maintained despite impaired NSD2 function.…”

Section: Discussionmentioning

confidence: 71%

Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

Zanoni

Steindl

Sengupta

et al. 2021

Genetics in Medicine

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Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype.

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“…The model mice were administrated with AAV-NSD2 overexpressing NSD2 to examine the function of NSD2 in DN. Since NSD2 has been reported to participate in beta-cell proliferation and result in decreased glucose concentration [ 14 ], we therefore further treated the AAV-NSD2-treated mice with glucagon to evaluate whether the effect of NSD2 on DN is glucose-dependent.…”

Section: Resultsmentioning

confidence: 99%

“…During tumor growth, reprogrammed glucose metabolism is involved to meet the demand of glycolytic intermediates for macromolecule biosynthesis, during which the NSD2 has been reported to play a role by regulating key glucose metabolism regulators, such as TIGAR, HK2, and G6PD [ 28 ]. More relevantly, NSD2 has been demonstrated to be downregulated in patients with diabetes mellitus, and its upregulation increased insulin secretion and reduced glucose concentration through promoting pancreatic β cell proliferation [ 14 ]. Moreover, NSD2-mediated H3K36 methylation has been reported to play a significant role in adipose tissue development, and NSD2 deletion was suggested to lead to lipodystrophy, which is correlated with hyperlipidemia, insulin resistance, and diabetes [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…It specifically modifies dimethylation or trimethylation of histone H3 lysine 36 (H3K36me2/me3), or dimethylation of H4K20 [ 12 , 13 ]. Interestingly, NSD2 has been demonstrated to be downregulated in patients with type 2 diabetes mellitus, and NSD2 upregulation promoted the proliferation of pancreatic β cells and increased insulin secretion, leading to reduced glucose concentration [ 14 ]. As a high-glucose condition is likely to induce glomerular lesions and renal impairment, aberrant NSD2 expression is likely to correlate with DN development as well.…”

Section: Introductionmentioning

confidence: 99%

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METTL3 enhances NSD2 mRNA stability to reduce renal impairment and interstitial fibrosis in mice with diabetic nephropathy

et al. 2022

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Background Nuclear receptor-binding SET domain protein 2 (NSD2) is a histone methyltransferase that has been demonstrated to regulate insulin secretion and glucose concentration. This study focused on the role of NSD2 in the renal impairment during diabetic nephropathy (DN). Methods Serum NSD2 level in patients with DN was examined, and its correlations with the renal impairment-related indicators were examined. A murine model of DN was established, and mouse mesangial cells (SV40-MES-13) were treated with high-glucose (HG) to mimic a DN-like condition in vitro. Overexpression of NSD2 was introduced into mice or cells for in vivo and in vitro studies. The m6A level in HG-treated SV40-MES-13 cells was analyzed. METTL3 expression and its correlation with NSD2 were determined. Results NSD2 was poorly expressed in the serum of patients with DN and was negatively correlated with the levels of fasting blood sugar (FBG), serum creatinine (SCr), serum cystatin C (S-Cys-C), the 24-h urine protein (24-h U-protein) and the urine cystatin C (U-Cys-C). NSD2 overexpression reduced the kidney weight and reduced renal impairment in mice. It also suppressed interstitial fibrosis in mouse kidney tissues and reduced fibrosis-related markers in HG-treated SV40-MES-13 cells. HG treatment reduced the m6A level in the cells. METTL3 promoted m6A modification of NDS2 mRNA and enhanced its stability by YTHDF1. METTL3 overexpression alleviated renal impairment and fibrosis in vivo and in vitro. But the protective role was blocked upon NSD2 silencing. Conclusion This study demonstrates that METTL3 promotes NSD2 mRNA stability by YTHDF1 to alleviate progression of DN.

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NSD2 is downregulated in T2DM and promotes β cell proliferation and insulin secretion through the transcriptionally regulation of PDX1

Cited by 7 publications

References 31 publications

Regulatory effect of chemerin and therapeutic efficacy of chemerin‑9 in pancreatogenic diabetes mellitus

Regulatory effect of chemerin and therapeutic efficacy of chemerin‑9 in pancreatogenic diabetes mellitus

Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

METTL3 enhances NSD2 mRNA stability to reduce renal impairment and interstitial fibrosis in mice with diabetic nephropathy

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