scholarly journals Liraglutide Increases the Catabolism of Apolipoprotein B100–Containing Lipoproteins in Patients With Type 2 Diabetes and Reduces Proprotein Convertase Subtilisin/Kexin Type 9 Expression

2021 ◽  
Author(s):  
Bruno Vergès ◽  
Laurence Duvillard ◽  
Jean Paul Pais de Barros ◽  
Benjamin Bouillet ◽  
Sabine Baillot-Rudoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Kinetic Study ◽  
Receptor Protein ◽  
Proprotein Convertase ◽  
Positive Effects ◽  
Ldl Particles ◽  
Expression Of Genes ◽  
Apolipoprotein B100

<a><b>OBJECTIVE:</b></a> Dyslipidemia observed in type 2 diabetes (T2DM) is atherogenic. Important features of diabetic dyslipidemia are increased levels of triglyceride-rich lipoproteins and small dense LDL particles which, all have apolipoprotein B100 (apoB100) as major apolipoprotein. This prompted us to study the effect of the GLP1 agonist, liraglutide, on the metabolism of apoB100 containing lipoproteins. <p><b>RESEARCH DESIGN AND METHODS</b>: We performed an <i>in vivo</i> kinetic study with stable isotopes (L-[1-<sup>13</sup>C] leucine) in 10 T2DM patients before and after 6-month treatment with liraglutide (1.2 mg/day). We also evaluated, in mice, the effect of liraglutide on the expression of genes involved in apoB100 containing lipoprotein clearance.</p> <p><b>RESULTS</b>: In T2DM patients, liraglutide treatment significantly reduced plasma apoB100 (0.93±0.13 vs. 1.09±0.11 g/L, p=0.011) and fasting triglycerides (1.76±0.37 vs. 2.48±0.69 mmol/L, p=0.005). The kinetic study showed a significant increase in indirect catabolism of VLDL<sub>1</sub>-apoB100 (4.11±1.91 vs. 2.96±1.61 day<sup>-1</sup>,p=0.005), VLDL<sub>2</sub>-apoB100 (5.17±2.53 vs. 2.84±1.65 day<sup>-1</sup>,p=0.008), IDL-apoB100 (5.27±2.77 vs. 3.74±1.85 day<sup>-1</sup>,p=0.017) and in catabolism of LDL-apoB100 (0.72±0.22 vs. 0.56±0.22 day<sup>-1</sup>,p=0.005). In mice, liraglutide increased lipoprotein lipase (LPL) gene expression and reduced Proprotein convertase subtilisin/kexin type 9 (PCSK9), Retinol Binding Protein 4 (RBP4) and Tumor Necrosis Factor alpha (TNF alpha) gene expression in adipose tissue, and decreased PCSK9 mRNA and increased LDL-receptor protein expression, in liver. In vitro, liraglutide directly reduced the expression of PCSK9 in the liver.</p> <p><b>CONCLUSIONS</b>: Treatment with liraglutide induces a significant acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL<sub>1</sub>, VLDL<sub>2</sub>, IDL) and LDL. Liraglutide modifies the expression of genes involved in apoB100 containing lipoprotein catabolism. These positive effects on lipoprotein metabolism may reduce cardiovascular risk in T2DM.</p>

scholarly journals Liraglutide Increases the Catabolism of Apolipoprotein B100–Containing Lipoproteins in Patients With Type 2 Diabetes and Reduces Proprotein Convertase Subtilisin/Kexin Type 9 Expression

2021 ◽  
Author(s):  
Bruno Vergès ◽  
Laurence Duvillard ◽  
Jean Paul Pais de Barros ◽  
Benjamin Bouillet ◽  
Sabine Baillot-Rudoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Kinetic Study ◽  
Receptor Protein ◽  
Proprotein Convertase ◽  
Positive Effects ◽  
Ldl Particles ◽  
Expression Of Genes ◽  
Apolipoprotein B100

<a><b>OBJECTIVE:</b></a> Dyslipidemia observed in type 2 diabetes (T2DM) is atherogenic. Important features of diabetic dyslipidemia are increased levels of triglyceride-rich lipoproteins and small dense LDL particles which, all have apolipoprotein B100 (apoB100) as major apolipoprotein. This prompted us to study the effect of the GLP1 agonist, liraglutide, on the metabolism of apoB100 containing lipoproteins. <p><b>RESEARCH DESIGN AND METHODS</b>: We performed an <i>in vivo</i> kinetic study with stable isotopes (L-[1-<sup>13</sup>C] leucine) in 10 T2DM patients before and after 6-month treatment with liraglutide (1.2 mg/day). We also evaluated, in mice, the effect of liraglutide on the expression of genes involved in apoB100 containing lipoprotein clearance.</p> <p><b>RESULTS</b>: In T2DM patients, liraglutide treatment significantly reduced plasma apoB100 (0.93±0.13 vs. 1.09±0.11 g/L, p=0.011) and fasting triglycerides (1.76±0.37 vs. 2.48±0.69 mmol/L, p=0.005). The kinetic study showed a significant increase in indirect catabolism of VLDL<sub>1</sub>-apoB100 (4.11±1.91 vs. 2.96±1.61 day<sup>-1</sup>,p=0.005), VLDL<sub>2</sub>-apoB100 (5.17±2.53 vs. 2.84±1.65 day<sup>-1</sup>,p=0.008), IDL-apoB100 (5.27±2.77 vs. 3.74±1.85 day<sup>-1</sup>,p=0.017) and in catabolism of LDL-apoB100 (0.72±0.22 vs. 0.56±0.22 day<sup>-1</sup>,p=0.005). In mice, liraglutide increased lipoprotein lipase (LPL) gene expression and reduced Proprotein convertase subtilisin/kexin type 9 (PCSK9), Retinol Binding Protein 4 (RBP4) and Tumor Necrosis Factor alpha (TNF alpha) gene expression in adipose tissue, and decreased PCSK9 mRNA and increased LDL-receptor protein expression, in liver. In vitro, liraglutide directly reduced the expression of PCSK9 in the liver.</p> <p><b>CONCLUSIONS</b>: Treatment with liraglutide induces a significant acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL<sub>1</sub>, VLDL<sub>2</sub>, IDL) and LDL. Liraglutide modifies the expression of genes involved in apoB100 containing lipoprotein catabolism. These positive effects on lipoprotein metabolism may reduce cardiovascular risk in T2DM.</p>

Liraglutide Increases the Catabolism of Apolipoprotein B100–Containing Lipoproteins in Patients With Type 2 Diabetes and Reduces Proprotein Convertase Subtilisin/Kexin Type 9 Expression

Diabetes Care ◽  
2021 ◽  
Vol 44 (4) ◽  
pp. 1027-1037
Author(s):  
Bruno Vergès ◽  
Laurence Duvillard ◽  
Jean Paul Pais de Barros ◽  
Benjamin Bouillet ◽  
Sabine Baillot-Rudoni ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Proprotein Convertase ◽  
Apolipoprotein B100

scholarly journals H3K4 Methylation in β-cells Prevents Transcriptional Downregulation and Variance Associated with Type 2 Diabetes

2021 ◽  
Author(s):  
Ben Vanderkruk ◽  
Nina Maeshima ◽  
Daniel J Pasula ◽  
Meilin An ◽  
Priya Suresh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Cell Function ◽  
H3k4 Methylation ◽  
Β Cells ◽  
Β Cell ◽  
Genetic Mouse Model ◽  
Expression Of Genes ◽  
Β Cell Function

SummaryHistone 3 lysine 4 trimethylation (H3K4me3) is associated with promoters of actively expressed genes, with genes important for cell identity frequently having exceptionally broad H3K4me3-enriched domains at their TSS. While H3K4 methylation is implicated in contributing to transcription, maintaining transcriptional stability, facilitating enhancer-promoter interactions, and preventing irreversible silencing, some studies suggest it has little functional impact. Therefore, the function of H3K4 methylation is not resolved. Insufficient insulin release by β-cells is the primary etiology in type 2 diabetes (T2D) and is associated with the loss of expression of genes essential to normal β-cell function. We find that H3K4me3 is reduced in islets from mouse models of diabetes and from human donors with T2D. Using a genetic mouse model to impair H3K4 methyltransferase activity of TrxG complexes, we find that reduction of H3K4 methylation significantly reduces insulin production and glucose-responsiveness and increases transcriptional entropy, indicative of a loss of β-cell maturity. Genes that are downregulated by reduction to H3K4 methylation are concordantly downregulated in T2D. Loss of H3K4 methylation causes global dilution of epigenetic complexity but does not generally reduce gene expression – instead, genes related to β-cell function and/or in particular chromatin environments are specifically affected. While neither H3K4me3 nor H3K4me1 are strictly required for the expression of many genes, the expression of genes with critical roles in β-cell function becomes destabilized, with increased variance and decreased overall expression. Our data further suggests that, in absence of H3K4me3, promoter-associated H3K4me1 is sufficient to maintain expression. Together, these data implicate H3K4 methylation dysregulation as destabilizing β-cell gene expression and contributing to β-cell dysfunction in T2D.

scholarly journals Healthy glucocorticoid receptor N363S carriers dysregulate gene expression associated with metabolic syndrome

2016 ◽  
Vol 311 (4) ◽  
pp. E741-E748 ◽  
Author(s):  
Christine M. Jewell ◽  
Kevin S. Katen ◽  
Lisa M. Barber ◽  
Crystal Cannon ◽  
Stavros Garantziotis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Metabolic Syndrome ◽  
Glucocorticoid Receptor ◽  
Expression Profiles ◽  
Receptor Protein ◽  
Healthy Population ◽  
Syndrome Type

The glucocorticoid receptor single-nucleotide polymorphism (SNP) N363S has been reported to be associated with metabolic syndrome, type 2 diabetes, and cardiovascular disease. Our aim was to determine how the N363S SNP modifies glucocorticoid receptor signaling in a healthy population of individuals prior to the onset of disease. We examined the function of the N363S SNP in a cohort of subjects from the general population of North Carolina. Eighteen N363S heterozygous carriers and 36 noncarrier, control subjects were examined for clinical and biochemical parameters followed by a low-dose dexamethasone suppression test to evaluate glucocorticoid responsiveness. Serum insulin measurements revealed that N363S carriers have higher levels of insulin, although not statistically significant, compared with controls. Glucocorticoid receptor protein levels evaluated in peripheral blood mononuclear cells from each clinical subject showed no difference between N363S and control. However, investigation of gene expression profiles in macrophages isolated from controls and N363S carriers using microarray, quantitative RT-PCR, and NanoString analyses revealed that the N363S SNP had an altered profile compared with control. These changes in gene expression occurred in both the absence and the presence of glucocorticoids. Thus, our observed difference in gene regulation between normal N363S SNP carriers and noncarrier controls may underlie the emergence of metabolic syndrome, type 2 diabetes, and cardiovascular disease associated with the N363S polymorphism.

Recreational Running Training Favourably Affects Antioxidants Gene Expression in Type 2 Diabetes Patients

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 52-LB
Author(s):  
MAYSA SOUSA ◽  
ARITANIA SANTOS ◽  
MARIA ELIZABETH R. SILVA
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Running Training ◽  
Diabetes Patients

Novel coumarin containing dithiocarbamate derivatives as potent α-glucosidase inhibitors for management of type 2 diabetes

2020 ◽  
Vol 16 ◽  
Author(s):  
Marjan Mollazadeh ◽  
Maryam Mohammadi-Khanaposhtani ◽  
Yousef Valizadeh ◽  
Afsaneh Zonouzi ◽  
Mohammad Ali Faramarzi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kinetic Study ◽  
Active Site ◽  
Docking Study ◽  
Secondary Amines ◽  
Molecular Docking Study ◽  
Glucosidase Inhibitors ◽  
Dithiocarbamate Derivatives

Background: α-Glucosidase is a hydrolyze enzyme that plays a crucial role in degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in the carbohydrate mediated diseases such as diabetes mellitus. Objective: In this study, novel coumarin containing dithiocarbamate derivatives 4a-n were synthesized and evaluated against α-glucosidase in vitro and in silico. Methods: These compounds were obtained of reaction between 4-(bromomethyl)-7-methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, docking study of the most potent compounds was also performed by Auto Dock Tools (version 1.5.6). Results: Obtained results showed that all the synthesized compounds exhibited prominent inhibitory activities (IC50 = 85.0 ± 4.0-566.6 ± 8.6 μM) in comparison to acarbose as standard inhibitor (IC50 = 750.0 ± 9.0 µM). Among them, secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound compete with substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Also, molecular docking study predicted that this compound as well interacted with α-glucosidase active site pocket. Conclusion: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for design potent α-glucosidase inhibitors for treatment of type 2 diabetes.

Metformin: Up to Date

2020 ◽  
Vol 20 (2) ◽  
pp. 172-181 ◽  
Author(s):  
Silvia Sciannimanico ◽  
Franco Grimaldi ◽  
Fabio Vescini ◽  
Giovanni De Pergola ◽  
Massimo Iacoviello ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Current Literature ◽  
Weight Control ◽  
Low Cost ◽  
Hepatic Glucose Production ◽  
Metabolic Effects ◽  
Hypoglycemic Agents ◽  
Positive Effects ◽  
Mesh Terms

Background: Metformin is an oral hypoglycemic agent extensively used as first-line therapy for type 2 diabetes. It improves hyperglycemia by suppressing hepatic glucose production and increasing glucose uptake in muscles. Metformin improves insulin sensitivity and shows a beneficial effect on weight control. Besides its metabolic positive effects, Metformin has direct effects on inflammation and can have immunomodulatory and antineoplastic properties. Aim: The aim of this narrative review was to summarize the up-to-date evidence from the current literature about the metabolic and non-metabolic effects of Metformin. Methods: We reviewed the current literature dealing with different effects and properties of Metformin and current recommendations about the use of this drug. We identified keywords and MeSH terms in Pubmed and the terms Metformin and type 2 diabetes, type 1 diabetes, pregnancy, heart failure, PCOS, etc, were searched, selecting only significant original articles and review in English, in particular of the last five years. Conclusion: Even if many new effective hypoglycemic agents have been launched in the market in the last few years, Metformin would always keep a place in the treatment of type 2 diabetes and its comorbidities because of its multiple positive effects and low cost.

Sign in / Sign up

Export Citation Format

Share Document