PGLP‐1, a novel long‐acting dual‐function GLP‐1 analog, ameliorates streptozotocin‐induced hyperglycemia and inhibits body weight loss

Gao, Huashan; Zhao, Qian; Song, Ziwei; Yang, Ziying; Wu, You; Tang, Shanshan; Alahdal, Murad; Zhang, Yanfeng; Jin, Liang

doi:10.1096/fj.201700002r

Cited by 14 publications

(29 citation statements)

References 48 publications

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“…In comparison, EGLP-1, GLP-1, and exendin-4 treatment preserved islet integrity. This indicated that these GLP-1R agonists had a protective effect on islet morphology, which is consistent with our previous report [17]. It has also been reported that GLP-1 can increase β-cell mass by stimulating β-cell proliferation and inhibiting apoptosis [36,37].…”

Section: Cellular Physiology and Biochemistrysupporting

confidence: 92%

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

Gao

Song

Zhao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Abnormal glucose metabolism and lipid metabolism are two key issues in Type 1 diabetes mellitus (T1DM). Insulin can control carbohydrate metabolism adequately, but cannot regulate lipid metabolism well in patients with T1DM. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have cured type 2 diabetes mellitus in clinical trials and have improved T1DM glycemic control in preclinical studies. However, previous studies have not reported whether GLP-1 can lower the serum concentration of non-esterified fatty acids (NEFAs). In this study, we examine whether GLP-1 can affect serum NEFA levels. Methods: The bioactivity of EGLP-1 (a novel GLP-1 analog) in vitro was analyzed in CG-HEK293 cells and with high-performance liquid chromatography. An intraperitoneal glucose tolerance test (IPGTT) was used to analyze the acute and sustained hypoglycemic effects of EGLP-1 in normal C57BL/6J mice. Streptozotocin-induced hyperglycemic mice were used to study the effects of EGLP-1 on blood glucose and NEFAs as well as its mechanism. Results: EGLP-1 activated GLP-1R and resisted dipeptidyl peptidase-IV digestion in vitro. Additionally, EGLP-1 had an insulinotropic action in vivo that lasted for approximately 6 h. In Streptozotocin-induced hyperglycemic mice, EGLP-1 improved hyperglycemia, inhibited food intake, and increased β-cell area. Serum physiological indexes showed that insulin and C-peptide levels were increased, while NEFA and triacylglycerol concentrations were decreased. Western blot analysis revealed that EGLP-1 significantly reduced phosphorylated-hormone sensitive lipase (pHSL) levels in white adipose tissue. Conclusions: EGLP-1 can improve hyperglycemia by increasing islet β-cell area and improving β-cell function, possibly due to reduced NEFA content in serum by lowering pHSL levels.

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Section: Cellular Physiology and Biochemistrysupporting

confidence: 92%

“…In vitro, a stability test of EGLP-1 against DPP-IV enzymolysis was carried out as described previously [17]. Briefly, GLP-1 or EGLP-1 was mixed with an isopycnic volume of recombinant human DPP-IV enzyme (R&D Systems, Minneapolis, MN) and incubated for different times at 37 ℃.…”

Section: Biological Activities In Vitromentioning

confidence: 99%

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

Gao

Song

Zhao

et al. 2018

Cell Physiol Biochem

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“…A summary of body weights and glucose readings is provided in Table 1. C57-STZ treated mice displayed a 3-fold increase in fasting blood glucose levels (BGL) and a significant decrease in body weight, mimicking body weight decline in humans with diabetes type 1 [34]. Db/db mice presented much higher BGL, 4.9-and 1.35-fold vs. C57-STZ-treated mice, respectively.…”

Section: High Blood Glucose Is Associated With Memory Impairment In Bmentioning

confidence: 99%

Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models

et al. 2018

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End organ injury in diabetes mellitus (DM) is driven by microvascular compromise (including diabetic retinopathy and nephropathy). Cognitive impairment is a well-known complication of DM types 1 and 2; however, its mechanism(s) is(are) not known. We hypothesized that blood-brain barrier (BBB) compromise plays a key role in cognitive decline in DM. Using a DM type 1 model (streptozotocin injected C57BL/6 mice) and type 2 model (leptin knockout obese db/db mice), we showed enhanced BBB permeability and memory loss (Y maze, water maze) that are associated with hyperglycemia. Gene profiling in isolated microvessels from DM type 1 animals demonstrated deregulated expression of 54 genes related to angiogenesis, inflammation, vasoconstriction/vasodilation, and platelet activation pathways by at least 2-fold (including eNOS, TNFα, TGFβ1, VCAM-1, E-selectin, several chemokines, and MMP9). Further, the magnitude of gene expression was linked to degree of cognitive decline in DM type 1 animals. Gene analysis in brain microvessels of DM type 2 db/db animals showed alterations of similar genes as in DM 1 model, some to an even greater extent. Neuropathologic analyses of brain tissue derived from DM mice showed microglial activation, expression of ICAM-1, and attenuated coverage of pericytes compared to controls. There was a significant upregulation of inflammatory genes in brain tissue in both DM models. Taken together, our findings indicate that BBB compromise in DM in vivo models and its association with memory deficits, gene alterations in brain endothelium, and neuroinflammation. Prevention of BBB injury may be a new therapeutic approach to prevent cognitive demise in DM.

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“…Western blot Western blotting was performed as described previously [25]. Results were normalised to glyceraldehyde-3-phosphate dehydrogenase (GAPDH).…”

Section: Plasmid Constructionmentioning

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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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).

show abstract

PGLP‐1, a novel long‐acting dual‐function GLP‐1 analog, ameliorates streptozotocin‐induced hyperglycemia and inhibits body weight loss

Cited by 14 publications

References 48 publications

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

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

Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models

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

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