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Young and undamaged recombinant albumin alleviates T2DM by improving hepatic glycolysis through EGFR and protecting islet β cells in mice

ABSTRACT: Type 2 Diabetes Mellitus (T2DM) is a severe disease that has reached epidemic proportions. In this study, treatment of T2DM mice with young, undamaged, and ultrapure recombinant mouse serum albumin (rMSA) increased their serum albumin levels, which resulted in a reversal of the disease including reduced fasting blood glucose levels, improved glucose tolerance, increased glucose-stimulated insulin secretion, and alleviated islet atrophy. At the cellular level, rMSA improved glucose uptake and glycolysis in hepatocytes. Mechanistically, rMSA reduced the binding between CAV1 and EGFR to increase EGFR activation leading to PI3K-AKT activation. Furthermore, rMSA extracellularly reduced the rate of fatty acid uptake by islet β-cells, which relieved the accumulation of intracellular ceramide, endoplasmic reticulum stress, and apoptosis. This study provided the first clear demonstration that injections of young, undamaged, and ultrapure recombinant serum albumin can alleviate T2DM in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE217975 | GEO | 2023/11/11

REPOSITORIES: GEO

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Vascular endothelial growth factor B regulates insulin secretion in β cells of type 2 diabetes mellitus mice via PLCγ and IP3R-evoked Ca2+/CaMK2 signal pathway

Project description:Vascular endothelial growth factor B (VEGFB) plays a crucial role in glucolipid metabolism and is highly associated with type 2 diabetes mellitus (T2DM). The role of VEGFB in the insulin secretion of β cells remains unverified. Thus, this study aims to discuss the effect of VEGFB on regulating insulin secretion in T2DM development, and its underlying mechanism. A high-fat diet and streptozocin were used for inducing T2DM in mice model, and VEGFB gene in islet cells of T2DM mice was knocked out by CRISPR Cas9 and overexpressed by Adeno-Associated Virus (AAV) injection. The effect of VEGFB and its underlying mechanism was assessed by light microscope, electron microscope, fluorescence confocal microscope, enzyme-linked immunosorbent assay, mass spectrometer, and western blot. The decrement of insulin secretion in islet β cell of T2DM mice are aggravated and blood glucose remains at a high level after VEGFB deletion. However, glucose tolerance and insulin sensitivity of T2DM mice were improved after the AAV-VEGFB186 injection. VEGFB knockout or overexpression can inhibit or activate PLCγ/IP3R in a VEGFR1-dependent manner. Then, the change of PLCγ/IP3R caused by VEGFB/VEGFR1 will alter the expression of key factors on the Ca2+/CaMK2 signal pathway such as PPP3CA. Moreover, VEGFB can cause altered insulin secretion by changing the calcium concentration in β cells of T2DM mice. These findings indicated that VEGFB activated the Ca2+/CaMK2 pathway via VEGFR1-PLCγ and IP3R pathway to regulate insulin secretion, which provides new insight into the regulatory mechanism of abnormal insulin secretion in T2DM.

2023-10-24 | PXD043843 | Pride

Effects of Electroacupuncture on the CircRNA of Plasma Exosomes in Diabetic Mice: Based on RNA Sequencing Technique

Project description:Aim: To study the effect of electroacupuncture (EA) on circRNA expression of plasma Exosomes and signal pathway of type 2 diabetic mice (T2DM). Methods: 10 mice were randomly selected as normal group. 20 mice were for T2DM model preparation and then were randomly divided into model and model + EA group. Mice in model + EA group were given EA treatment. The changes of fasting blood glucose (FBG) and the Islet structure were evaluated. Plasma exosomes of mice were subjected to RNA sequencing. Bioinformatics analysis on differentially expressed circRNA was performed. 12 differentially expressed circRNA were confirmed for real-time quantitative PCR (qPCR). Results: EA treatment reduced the FBG, preserved islets structure and reduced the islet β cell apoptotic rate of T2DM mice. RNA-sequencing analysis showed EA treatment lead to significant change of 165 circRNA expressions. GO and KEGG revealed that the effects of EA on T2DM mainly focus on regulating the functions and pathways related to multi-link metabolism, cell growth and organ development. Especially, the thyroid hormone signaling pathway was actively regulated by EA. circRNA/miRNA interactions analysis revealed that that mmu-mir-7092-3p was closely combined with circINPP4B, suggesting phosphatidylinositol signaling pathway was affected by EA. 12 circRNAs were identified to have significant differences by qRT-PCR. Conclusion: EA intervention can significantly protect islet function and improve FBG in T2DM, which may be related to the regulation on thyroid hormone and Phosphatidylinositol signaling pathway.

2019-07-02 | GSE133665 | GEO

Insulin-stimulated glucose uptake in recombinant MMP12 treated 3T3-L1 cells

Project description:Insulin-stimulated glucose uptake in recombinant MMP12 treated 3T3-L1 cells

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Oilseed protein isolates as albumin alternatives for muscle cell culture media

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2023-03-25 | PXD036518 | Pride

HBP1 inhibits the development of type 2 diabetes mellitus through transcriptional activation of the IGFBP1 gene

Project description:Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease that is highly prevalent worldwide and characterized by glucose and lipid metabolism disorders. However, the pathogenic mechanisms have not been fully established. Here, we found that HMG-box transcription factor 1 (HBP1) is involved in T2DM and that its deficiency in mice aggravates the features of diabetes. In addition, we undertook screening by RNA sequencing and found that HBP1 activates the transcription of the insulin-like growth factor binding protein 1 (IGFBP1) gene. Moreover, Insulin and palmitic acid reduced HBP1 protein expression and inhibited its binding to the IGFBP1 promoter. Furthermore, HBP1 reduced the serum free insulin-like growth factor 1 (IGF-1) concentration through IGFBP1 and inhibited the PI3K/AKT signaling pathway. This forms an insulin/HBP1/IGFBP1 negative feedback regulatory loop to dynamically regulate blood glucose and insulin concentrations. These findings have elucidated a mechanism whereby HBP1 and its negative feedback regulatory loop influence the development of T2DM, thereby providing a new theoretical basis and potential therapeutic target for T2DM.

2022-09-26 | GSE214089 | GEO

Gene expression in Bacillus subtilis treated with human PGRP, gentamicin, and CCCP

Project description:Human Peptidoglycan Recognition Proteins (PGRPs) kill bacteria, likely by over-activating stress responses in bacteria. To gain insight into the mechanism of PGRP killing of Bacillus subtilis and bacterial defense against PGRP killing, gene expression in B. subtilis treated with a control protein (bovine serum albumin, BSA), human recombinant PGRP (PGLYRP4), gentamicin (aminoglycoside antibiotic), and CCCP (membrane potential decoupler) were compared. Each treatment induced unique and somewhat overlapping pattern of gene expression. PGRP highly increased expression of genes for oxidative and disulfide stress, detoxification and efflux of Cu, As, and Zn, several transporters, repair of damaged proteins and DNA, energy generation, histidine and cysteine synthesis, envelope lysis and remodeling, and other stress responses. PGRP also caused marked decrease in the expression of genes for phosphate uptake and utilization, Fe uptake, and motility. Gene expression microarray in B. subtilis exposed to a human bactericidal innate immunity protein, PGRP, showed induction of oxidative stress response and defense genes, with different expression pattern than B. subtilis exposed to an aminoglycoside antibiotic and a membrane potential decoupler. B. subtilis was treated with PGRP (human recombinant PGLYRP4), gentamicin, or CCCP (carbonyl cyanide 3-chlorophenylhydrazone). RNA was obtained from each culture and assayed for gene expression using custom whole genome Affymetrix 900513 GeneChip B. subtilis Genome Array. Each experiment was repeated 3 times.

2014-07-25 | E-GEOD-44212 | biostudies-arrayexpress

Whole transcriptome analysis of mouse aortas and kidneys with or without deletion of the EGFR in vascular smooth muscle cells after 18 weeks of high fat diet

Project description:Obesity causes diabetes type 2 (DMT2) leading to vascular dysfunction and finally renal end-organ damage. Vascular smooth muscle (VSM) EGF receptor (EGFR) modulates vascular wall homeostasis in part via serum response factor (SRF), a major regulator of VSM differentiation and a sensor for glucose. We investigated the role of VSM-EGFR during obesity-induced renovascular dysfunction and the EGFR-hyperglycemia crosstalk.

2020-03-01 | GSE144838 | GEO

Discovery and validation of glucose-sensitive peptides from human serum albumin as the candidate peptide biomarkers for diagnosis of type 2 diabetes mellitus

Project description:Glycation albumin(GA) has emerged as a biomarker for diagnosing prediabetes and diabetes, which is shorter than the "gold standard" reflection period of blood glucose detection. However, the GA response is the global glycation rate of albumin, individual amino acid residues might be sensitive indicators of alterations in blood glycation levels. Here we report a method to analyze the glycated peptides that might provide a better understanding of fluctuations of blood glucose concentrations. In this study, a strategy to quantify the depletion of the digestion peptides of albumin for the diagnosis of type 2 diabetes mellitus (T2DM). First of all, a combination of 13C glucose labeling and HPLC-Q-TOF M S/MS were used to screen 16 glucose-sensitive peptides from in vitro HSA and serum models, which represent glucose-sensitive sites on HSA. Furthermore, the candidate peptide biomarkers were validated in 72 clinical samples (44 diabetic patients and 28 healthy controls) using label-free LC-ESI-MRM. Finally , three putative sensitive peptides (VAHRFKDLGEE, FKPLVEEPQNLIKQNCE and NQDSISSKLKE) from the albumin exhibited good specificity and sensitivity based on receiver operating characteristic analysis. The putative peptide biomarkers were verified as the promising biomarkers for the diagnosis and assessmen of diabetes mellitus with clinical patterns.

2022-12-13 | PXD038794 | iProX

Gene expression in Bacillus subtilis treated with human PGRP, gentamicin, and CCCP

2014-07-25 | GSE44212 | GEO

An estrogen receptor α-derived peptide improves glucose homeostasis during obesity

Project description:Estrogen improves insulin sensitivity and increases energy expenditure, contributing to sexual dimorphism regarding type 2 diabetes mellitus (T2DM) susceptibility. Estrogen receptor α (ERα) plays a crucial role in mediating estrogen action on glucose and energy homeostasis. However, the underlying mechanisms remain incompletely understood. Here, we found a ligand-independent effect of ERα on the regulation of glucose homeostasis and identified an ERα-derived peptide as a potential insulin sensitizer. Deficiency of ERα but not ERβ in the liver impaired glucose homeostasis in male, female, and ovariectomized (OVX) female mice. Mechanistic studies revealed that ERα promoted hepatic insulin sensitivity by suppressing ubiquitination-induced IRS1 degradation. The ERα 1-280 domain mediated the ligand-independent effect of ERα on insulin sensitivity. Furthermore, we designed a peptide based on ERα 1-280 domain and found that ERα-derived peptide interacted with IRS1, increased IRS1 stability through suppressing its ubiquitination, and enhanced insulin sensitivity. Importantly, administration of ERα-derived peptide into obese mice significantly increased insulin sensitivity, attenuated glucose intolerance, and improved serum lipid profiles. These findings pave the way for the therapeutic intervention of T2DM by targeting the ligand-independent effect of ERα and indicate that ERα-derived peptide is a potential insulin sensitizer for the treatment of T2DM.

2024-04-05 | GSE262841 | GEO

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