Pharmacological Effects of EGLP-1, a Novel Analog of Glucagon-Like Peptide-1, on Carbohydrate and Lipid Metabolism

Aims/hypothesis Although obesity is a predisposing factor for pancreatic beta cell dysfunction, the mechanisms underlying its negative effect on insulin-secreting cells is still poorly understood. The aim of this study was to identify islet long non-coding RNAs (lncRNAs) involved in obesity-mediated beta cell dysfunction. Methods RNA sequencing was performed to analyse the islets of high-fat diet (HFD)-fed mice and those of normal chow-fed mice (NCD). The function in beta cells of the selected lncRNA 1810019D21Rik (referred to in this paper as ROIT [regulator of insulin transcription]) was assessed after its overexpression or knockdown in MIN6 cells and primary islet cells, as well as in siRNA-treated mice. Then, RNA pull-down, RNA immunoprecipitation, coimmunoprecipitation and bisulphite sequencing were performed to investigate the mechanism of ROIT regulation of islet function.Results ROIT was dramatically downregulated in the islets of the obese mice, as well as in the sera of obese donors with type 2 diabetes, and was suppressed by HNF1B. Overexpression of ROIT in MIN6 cells and islets led to improved glucose homeostasis and insulin transcription. Investigation of the mechanism involved showed that ROIT bound to DNA methyltransferase 3a and caused its degradation through the ubiquitin proteasome pathway, which blocked the methylation of the Nkx6.1 promoter. Conclusions/interpretation These findings functionally suggest a novel link between obesity and beta cell dysfunction via ROIT. Elucidating a precise mechanism for the effect of obesity on lncRNA expression will broaden our understanding of the pathophysiological development of diabetes and facilitate the design of better tools for diabetes prevention and treatment. Data availability The raw RNA sequencing data are available from the NCBI Gene Expression Omnibus (GEO series accession number GSE139991).

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“…The IPGTT and GSIS tests were performed as previously described [27]. See ESM Methods for further details.…”

Section: Ipgtt and Gsis In Vivomentioning

confidence: 99%

Obesity-induced reduced expression of the lncRNA ROIT impairs insulin transcription by downregulation of Nkx6.1 methylation

et al. 2020

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“…and incubated different times at 37 ℃. Stability test for DPP-IV in vitro was performed as previously described 16 .…”

Section: Discussionmentioning

confidence: 99%

“…Food intake was measured every 3 or 4 days. Animals were euthanized by isoflurane overdose and dissected tissues were immediately frozen in liquid nitrogen, unless otherwise stated 16,35 .…”

Section: Intraperitoneal Glucose Tolerance Test (Ipgtt) and Insulin Tmentioning

confidence: 99%

Continuous stimulation of dual-function peptide PGLP-1-VP inhibits the morbidity and mortality of NOD mice through anti-inflammation and immunoregulation

Gao

Zhao

Tang

et al. 2021

Sci Rep

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Multiple animal and human studies have shown that administration of GLP-1RA can enhance β-cell recovery, reduce insulin dosage, reduce HbA1c content in the blood, reduce the risk of hypoglycemia and reduce inflammation. In the NOD mouse model, peptide VP treatment can prevent and treat type 1 diabetes through immunomodulation. Therefore, we designed a new dual-functional PGLP-1-VP, which is expected to combine the anti-inflammatory effect of PGLP-1 and the immunomodulatory effect of VP peptide. In streptozotocin-induced hyperglycemic mice model, we demonstrated that PGLP-1-VP can act as a GLP-1R agonist to improve hyperglycemia and increase insulin sensitivity. In the NOD mouse model, PGLP-1-VP treatment reduced morbidity, mortality, and pancreatic inflammation, and showed superior effect to PGLP-1 or VP treatment alone, confirming that PGLP-1-VP may act as a dual-function peptide. PGLP-1-VP provided immunomodulatory effect through increasing Th2 cell percentage and balancing the ratio of Th2/Th1 in spleen and PLN, similar to P277 and VP. Additionally, PGLP-1-VP and PGLP-1 act the anti-inflammation by increasing Treg cells and TGF-β1 content like DPP-IV inhibitor. Taken together, our data shows that the dual-functional PGLP-1-VP reduces morbidity and mortality in the NOD model, suggesting a potential role in preventing and treating type 1 diabetes.

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EGLP-1 lowers body weight better than exendin-4 by reducing food intake and increasing basal energy expenditure in diet-induced obese mice

Gao

Zhao

et al. 2021

Experimental Cell Research

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Pharmacological Effects of EGLP-1, a Novel Analog of Glucagon-Like Peptide-1, on Carbohydrate and Lipid Metabolism

Cited by 3 publications

References 49 publications

Obesity-induced reduced expression of the lncRNA ROIT impairs insulin transcription by downregulation of Nkx6.1 methylation

Obesity-induced reduced expression of the lncRNA ROIT impairs insulin transcription by downregulation of Nkx6.1 methylation

Continuous stimulation of dual-function peptide PGLP-1-VP inhibits the morbidity and mortality of NOD mice through anti-inflammation and immunoregulation

EGLP-1 lowers body weight better than exendin-4 by reducing food intake and increasing basal energy expenditure in diet-induced obese mice

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