CB4211 Is a Potential Treatment for Metabolic Diseases with a Novel Mechanism of Action—Sensitization of the Insulin Receptor

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 233-LB ◽  
Author(s):  
KENT GRINDSTAFF ◽  
REMI MAGNAN ◽  
ROBIN SHANG ◽  
EMILY STENGER ◽  
JENNA S. HOLLAND ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Mechanism Of Action ◽  
Metabolic Diseases ◽  
Potential Treatment

scholarly journals Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance

2016 ◽  
Vol 36 (16) ◽  
pp. 2168-2181 ◽  
Author(s):  
Lucie Popineau ◽  
Lucille Morzyglod ◽  
Nadège Carré ◽  
Michèle Caüzac ◽  
Pascale Bossard ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Metabolic Diseases ◽  
De Novo ◽  
Liver Steatosis ◽  
Growth Factor Receptor ◽  
Glucose Production ◽  
Acid Synthesis ◽  
Related Factor ◽  
Insulin Resistant

A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, whilede novolipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood. Here, we established a model of selective insulin resistance in mice by silencing an inhibitor of insulin receptor catalytic activity, the growth factor receptor binding protein 14 (Grb14) in liver. Indeed, Grb14 knockdown enhanced hepatic insulin signaling but also dramatically inhibitedde novofatty acid synthesis. In the liver of obese and insulin-resistant mice, downregulation of Grb14 markedly decreased blood glucose and improved liver steatosis. Mechanistic analyses showed that upon Grb14 knockdown, the release of p62/sqstm1, a partner of Grb14, activated the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn repressed the lipogenic nuclear liver X receptor (LXR). Our study reveals that Grb14 acts as a new signaling node that regulates lipogenesis and modulates insulin sensitivity in the liver by acting at a crossroad between the insulin receptor and the p62-Nrf2-LXR signaling pathways.

scholarly journals Rapid molecular evolution across amniotes of the IIS/TOR network

2015 ◽  
Vol 112 (22) ◽  
pp. 7055-7060 ◽  
Author(s):  
Suzanne E. McGaugh ◽  
Anne M. Bronikowski ◽  
Chih-Horng Kuo ◽  
Dawn M. Reding ◽  
Elizabeth A. Addis ◽  
...  
Keyword(s):  
Molecular Evolution ◽  
Positive Selection ◽  
Insulin Receptor ◽  
Metabolic Diseases ◽  
Vital Role ◽  
Evolutionary Rates ◽  
Evolutionary Analysis ◽  
Binding Surface ◽  
Tor Network ◽  
Positively Selected Sites

The insulin/insulin-like signaling and target of rapamycin (IIS/TOR) network regulates lifespan and reproduction, as well as metabolic diseases, cancer, and aging. Despite its vital role in health, comparative analyses of IIS/TOR have been limited to invertebrates and mammals. We conducted an extensive evolutionary analysis of the IIS/TOR network across 66 amniotes with 18 newly generated transcriptomes from nonavian reptiles and additional available genomes/transcriptomes. We uncovered rapid and extensive molecular evolution between reptiles (including birds) and mammals: (i) the IIS/TOR network, including the critical nodes insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3K), exhibit divergent evolutionary rates between reptiles and mammals; (ii) compared with a proxy for the rest of the genome, genes of the IIS/TOR extracellular network exhibit exceptionally fast evolutionary rates; and (iii) signatures of positive selection and coevolution of the extracellular network suggest reptile- and mammal-specific interactions between members of the network. In reptiles, positively selected sites cluster on the binding surfaces of insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and insulin receptor (INSR); whereas in mammals, positively selected sites clustered on the IGF2 binding surface, suggesting that these hormone-receptor binding affinities are targets of positive selection. Further, contrary to reports that IGF2R binds IGF2 only in marsupial and placental mammals, we found positively selected sites clustered on the hormone binding surface of reptile IGF2R that suggest that IGF2R binds to IGF hormones in diverse taxa and may have evolved in reptiles. These data suggest that key IIS/TOR paralogs have sub- or neofunctionalized between mammals and reptiles and that this network may underlie fundamental life history and physiological differences between these amniote sister clades.

Seladelpar’s mechanism of action as a potential treatment for primary biliary cholangitis and non-alcoholic steato-hepatitis

2018 ◽  
Vol 68 ◽  
pp. S235-S236
Author(s):  
P. Boudes ◽  
Y.-J. Choi ◽  
A. (Sasha) Steinberg ◽  
S. Bergheanu ◽  
C. Mcwherter
Keyword(s):  
Mechanism Of Action ◽  
Primary Biliary Cholangitis ◽  
Potential Treatment

scholarly journals Simultaneous siRNA-mediated silencing of pairs of genes coding for enzymes involved in glycosaminoglycan synthesis.

2012 ◽  
Vol 59 (2) ◽  
Author(s):  
Dariusz Dziedzic ◽  
Magdalena Narajczyk ◽  
Magdalena Gabig-Cimińska ◽  
Joanna Jakóbkiewicz-Banecka
Keyword(s):  
Potential Benefit ◽  
Metabolic Diseases ◽  
Cost Benefit ◽  
Potential Treatment ◽  
Glycosaminoglycan Synthesis ◽  
Benefit Ratio ◽  
Expression Of Genes ◽  
Cost Benefit Ratio ◽  
The Cost ◽  
In Cells

It has been demonstrated recently that it is possible to decrease expression of genes coding for enzymes involved in synthesis of glycosaminoglycans (GAGs) by using specific siRNAs which interfere with stability of particular mRNAs. This procedure has been proposed as a potential treatment for patients suffering from mucopolysaccharidoses, a group of inherited metabolic diseases caused by dysfunction of enzymes required for GAG degradation, and resultant storage of these compounds in cells of affected persons. Here, we asked if the simultaneous use two species of specific siRNAs aimed at silencing two genes involved in particular steps of GAG synthesis may be more effective than the use of single siRNA. We found that inhibition of GAG synthesis in cells treated with two siRNAs is generally more effective than using single siRNAs. However, the differences were not statistically significant, therefore the potential benefit from the use of two siRNAs over the use of a single siRNA is doubtful in the light of the cost-benefit ratio and possibly stronger side-effects of the putative therapy.

scholarly journals Chloroquine as a Potential Treatment and Prevention Measure for the 2019 Novel Coronavirus: A Review

2020 ◽  
Author(s):  
John Kearney
Keyword(s):  
Mechanism Of Action ◽  
Scientific Community ◽  
Potential Treatment ◽  
In Vivo Efficacy ◽  
Treatment And Prevention ◽  
Prevention Measure ◽  
Coronavirus Infection ◽  
Novel Coronavirus

There is a long trail of research studies testing the in vitro and in vivo efficacy of chloroquine and its derivatives in treating and preventing infection by various coronavirus species. More recent findings have highlighted the possibility of treating patients infected with the 2019 novel coronavirus, SARS-CoV-2. This review describes the mechanism of coronavirus infection, the mechanism of action of chloroquine, and summarizes the available literature highlighting the efficacy of chloroquine as an anti-coronavirus agent. These findings should encourage the wider scientific community to conduct thorough research on the possible efficacy of chloroquine and its derivatives in treating and preventing SARS-CoV-2 infection.

scholarly journals miR-378a-3p Participates in Metformin’s Mechanism of Action on C2C12 Cells under Hyperglycemia

2021 ◽  
Vol 22 (2) ◽  
pp. 541
Author(s):  
Ivo F. Machado ◽  
João S. Teodoro ◽  
Ana C. Castela ◽  
Carlos M. Palmeira ◽  
Anabela P. Rolo
Keyword(s):  
Mechanism Of Action ◽  
Metabolic Diseases ◽  
Biological Effects ◽  
C2c12 Cells ◽  
Alternative Mechanism ◽  
C2c12 Myoblasts ◽  
Atp Production ◽  
Selective Degradation ◽  
Autophagic Process

Metformin is the most used biguanide drug for the treatment of type 2 diabetes mellitus. Despite being mostly known for its hepatic anti-gluconeogenic effect, it is also known to modulate microRNAs (miRNAs, miRs) associated with metabolic diseases. The latter mechanism could be relevant for better understanding metformin’s mechanisms underlying its biological effects. In the current work, we found that metformin increases miR-378a-3p expression (p < 0.002) in C2C12 myoblasts previously exposed to hyperglycemic conditions. While the inhibition of miR-378a-3p was shown to impair metformin’s effect in ATP production, PEPCK activity and the expression of Tfam. Finally, mitophagy, an autophagic process responsible for the selective degradation of mitochondria, was found to be induced by miR-378a-3p (p < 0.04). miR-378a-3p stimulated mitophagy through a process independent of sestrin-2 (SESN2), a stress-responsible protein that has been recently demonstrated to positively modulate mitophagy. Our findings provide novel insights into an alternative mechanism of action of metformin involving miR-378a-3, which can be used in the future for the development of improved therapeutic strategies against metabolic diseases.

scholarly journals Impact of Probiotic Combination in InR[E19]/TM2 Drosophila melanogaster on Longevity, Related Gene Expression, and Intestinal Microbiota: A Preliminary Study

2020 ◽  
Vol 8 (7) ◽  
pp. 1027
Author(s):  
Shuang Ma ◽  
Hao Sun ◽  
Weichao Yang ◽  
Mingfu Gao ◽  
Hui Xu
Keyword(s):  
Drosophila Melanogaster ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
High Throughput Sequencing ◽  
Metabolic Diseases ◽  
Standard Diet ◽  
Median Lifespan ◽  
Treatment Of Diabetes ◽  
Receptor Family

The insulin receptor (InR) pertains to the insulin receptor family, which plays a key role in the insulin/insulin-like growth factor (IGF)-like signaling (IIS) pathway. Insulin signaling defects may result in the development of metabolic diseases, such as type 2 diabetes, and the InR mutant has been suggested to bear insulin signaling deficiency. Numerous studies have reported that probiotics are beneficial for the treatment of diabetes; however, the effect of probiotics on patients with InR deficiency has seldom been reported. Therefore, we chose the InR[E19]/TM2 Drosophila melanogaster to investigate. The results indicated that probiotics significantly reduce the mean and median lifespan of InR[E19]/TM2 Drosophila (by 15.56% and 23.82%, respectively), but promote that of wild-type files (by 9.31% and 16.67%, respectively). Significant differences were obtained in the expression of lifespan- and metabolism-related genes, such as Imp-L2, Tor, and GstD2, between the standard diet groups and the probiotics groups. Furthermore, analysis of 16S rDNA via high throughput sequencing revealed that the gut bacterial diversity of Drosophila fed with a probiotic combination also differs from that of Drosophila fed with a standard diet. In summary, these findings indicate that a probiotic combination indeed affects InR[E19]/TM2 Drosophila, but not all of its impacts are positive.

scholarly journals Subetta Treatment Increases Adiponectin Secretion by Mature Human AdipocytesIn Vitro

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Jim Nicoll ◽  
Evgeniy A. Gorbunov ◽  
Sergey A. Tarasov ◽  
Oleg I. Epstein
Keyword(s):  
Insulin Receptor ◽  
Mechanism Of Action ◽  
Cannabinoid Receptor ◽  
Beta Subunit ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Reference Drug ◽  
Peripheral Tissues ◽  
Negative Controls

Purpose. To investigate the mechanism of action in peripheral tissues of novel complex drug containing release-active dilutions of antibodies to the beta subunit of the insulin receptor and antibodies to endothelial nitric oxide synthase (Subetta), which has shown efficacy in animal models of diabetes.Methods. Human mature adipocytes were incubated either with Subetta, with one of negative controls (placebo or vehicle), with one of nonspecific controls (release-active dilutions of antibodies to cannabinoid receptor type I or release-active dilutions of rabbit nonimmune serum), or with dimethyl sulfoxide (DMSO) at 37°C in a humidified incubator at 5% CO2for three days. Rosiglitazone was used as reference drug. Secretion of adiponectin was measured by quantitative enzyme-linked immunosorbent assay (ELISA).Results. Only Subetta significantly stimulates adiponectin production by mature human adipocytes. Nonspecific controls did not significantly affect adiponectin secretion, resulting in adiponectin levels comparable to background values of the negative controls and DMSO.Conclusion. Increasing adiponectin production in absence of insulin by Subetta probably via modulating effect on the beta subunit of the insulin receptor might serve as one of the mechanisms of the antidiabetic effect of this drug. Thesein vitroresults give first insight on possible mechanism of action of Subetta and serve as a background for further studies.

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