as160

BACKGROUND: The basis of Age-related macular degeneration (AMD) genetic risk has been well documented; however, few studies have looked at genetic biomarkers of disease progression or treatment response within advanced AMD patients. Here we report the first genome-wide analysis of genetic determinants of low-luminance vision deficit (LLD), which is seen as predictive of visual acuity loss and anti-VEGF treatment response in neovascular AMD patients. METHODS: AMD patients were separated into small- and large-LLD groups for comparison and whole genome sequencing was performed...

Skeletal muscle plays a major role in whole-body glucose metabolism. Insulin resistance in skeletal muscle is characterized by decreased insulin-stimulated glucose uptake resulting from impaired intracellular trafficking and decreased glucose transporter 4 (GLUT4) expression. In this study, we illustrated that tilorone, a low-molecular-weight antiviral agent, improves glucose uptake in vitro and in vivo. Tilorone increased bone morphogenetic protein (BMP) signaling in C2C12 myoblasts, the transcription of multiple BMPs (BMP2, BMP4, BMP7, and BMP14), Smad4 expression, and the phosphorylation of BMP-mediated Smad1/5/8...

BACKGROUND: Type 2 Diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and associated with poor outcome after myocardial infarction (MI). In T2DM, cardiac metabolic flexibility, i.e. the switch between carbohydrates and lipids as energy source, is disturbed. The RabGTPase-activating protein TBC1D4 represents a crucial regulator of insulin-stimulated glucose uptake in skeletal muscle by controlling glucose transporter GLUT4 translocation. A human loss-of-function mutation in TBC1D4 is associated with impaired glycemic control and elevated T2DM risk...

We evaluated effects of calorie restriction (CR; consuming 65% of ad libitum [AL] intake) for 8 weeks on female wildtype (WT) and Akt substrate of 160 kDa-knockout (AS160-KO) rats. Insulin-stimulated glucose uptake (ISGU) was determined in isolated epitrochlearis muscles incubated with 0, 50, 100, or 500 μU/ml insulin. Phosphorylation of key insulin signaling proteins that control ISGU (Akt and AS160) were assessed by immunoblotting (Akt phosphorylation on Threonine-308, pAktThr308 and Serine-473, pAktSer473; AS160 phosphorylation on Serine-588, pAS160Ser588, and Threonine-642, pAS160Thr642)...

Finnish-specific gene variant p.P50T/AKT2 (MAF=1.1%), is associated with insulin resistance and increased predisposition to type 2 diabetes. Here, we have investigated in vitro the impact of the gene variant on glucose metabolism and intracellular signalling in human primary skeletal muscle cells, that were established from 14 male p.P50T/AKT2 variant carriers and 14 controls. Insulin-stimulated glucose uptake and glucose incorporation into glycogen were detected with 2-[1,2-3H]-deoxy-D-glucose and D-[14C]-glucose, respectively, and the rate of glycolysis was measured with a Seahorse XFe96 analyzer...

BACKGROUND: The aim of the present study was to determine the role of individual PHLPP isoforms in insulin signaling and insulin resistance in neuronal cells. METHODS: PHLPP isoforms were either silenced or overexpressed individually, and the effects were observed on individual Akt isoforms, AS160 and on neuronal glucose uptake, under insulin sensitive and resistant conditions. To determine PHLPP regulation itself, we tested effect of scaffold protein, Scribble, on PHLPP isoforms and neuronal glucose uptake...

Astragalus membranaceus Bunge, known as Huangqi, has been used to treat various diseases for a long time. Astragaloside IV (AS-IV) is one of the primary active ingredients of the aqueous Huangqi extract. Many experimental models have shown that AS-IV exerts broad beneficial effects on cardiovascular disease, nervous system diseases, lung disease, diabetes, organ injury, kidney disease, and gynaecological diseases. This review demonstrates and summarizes the structure, solubility, pharmacokinetics, toxicity, pharmacological effects, and autophagic mechanism of AS-IV...

Heart disease remains the leading cause of death, and mortality rates positively correlate with the presence of obesity and diabetes. Despite the correlation between cardiac and metabolic dysregulation, the mechanistic pathway(s) of interorgan crosstalk still remain undefined. This study reveals that cardiac-restricted expression of an amino-terminal peptide of GRK2 (βARKnt) preserves systemic and cardiac insulin responsiveness, and protects against adipocyte maladaptive hypertrophy in a diet-induced obesity model...

Background: Oleuropein, the main constituent of olive fruit and leaves, has been reported to protect against insulin resistance and diabetes. While many experimental investigations have examined the mechanisms by which oleuropein improves insulin resistance and diabetes, much of these investigations have been carried out in either muscle cell lines or in vivo models two scenarios with many drawbacks. Accordingly, to simplify identification of mechanisms by which oleuropein regulates specific cellular processes, we resort, in the present study, to isolated muscle preparation which enables better metabolic milieu control and permit more detailed analyses...

BACKGROUND: Therapeutic failure and drug resistance are common sequelae to insulin resistance associated with type 2 diabetes mellitus (T2DM). Consequently, there is an unmet need of alternative strategies to overcome insulin resistance associated complications. PURPOSE: To demonstrate whether Kutkin (KT), iridoid glycoside enriched fraction of Picrorhiza kurroa extract (PKE) has potential to increase the insulin sensitivity vis à vis glucose uptake in differentiated adipocytes...

Myocardial ischemia/reperfusion injury (I/RI) is closely associated with energy substrate metabolism. Fibronectin 1 (Fn1) was markedly elevated in the heart of I/R pigs and ischemic patients, but its role in myocardial I/RI is controversial and the precise mechanism involved remains elusive. Herein, we tested whether blockage of Fn1 with its inhibitor (fibronectin tetrapeptide, RGDS) would alleviate myocardial I/RI. Wild-type (WT) mice were administered with RGDS once 3 h before I/R operation and once at 24 or 48 h postreperfusion, and sacrificed at 24 or 72 h post-I/R, respectively...

The health benefits of probiotics have been known for decades, but there has only been limited use of probiotics in the treatment of obesity. In this study, we describe, for the first time, the role of cell-free metabolites (CM) from Bacillus ginsengihumi -RO6 (CMRO6) in adipogenesis and lipogenesis in 3T3-L1 pre-adipocytes. The experimental results show that CMRO6 treatment effectively reduced lipid droplet accumulation and the expression of CCAAT/enhancer-binding protein α and β (C/EBPα and C/EBPβ), peroxisome proliferator-activated receptor γ (PPAR-γ), serum regulatory binding protein 1c (SREBP-1c), fatty acid-binding protein 4 (FABP4), fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), phosphorylated p38MAPK, and Erk44/42...

Quantitative features of GLUT4 glucose transporter's behavior deep inside cells remain largely unknown. Our previous analyses with live-cell imaging of intracellular GLUT4 trafficking demonstrated two crucial early events responsible for triggering insulin-responsive translocation processes, namely, heterotypic fusion and liberation. To quantify the regulation, interrelationships, and dynamics of the initial events more accurately and comprehensively, we herein applied three analyses, each based on our distinct dual-color live-cell imaging approaches...

BACKGROUND: Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of MSCs, resulting in failure of MSC therapy. This study investigated whether the combination of melatonin and human umbilical cord mesenchymal stem cells (hUC-MSCs) was superior to hUC-MSCs alone in ameliorating high-fat diet and streptozocin (STZ)-induced type II diabetes mellitus (T2DM) in a mouse model. METHODS: Mice were divided into four groups: normal control (NC) group; T2DM group; hUC-MSCs treatment alone (UCMSC) group and pretreatment of hUC-MSCs with melatonin (UCMSC/Mel) group...

High glucose (HG) is one of the basic factors of diabetic nephropathy (DN), which leads to high morbidity and disability. During DN, the expression of glomerular glucose transporter 1 (GLUT1) increases, but the relationship between HG and GLUT1 is unclear. Glomerular mesangial cells (GMCs) have multiple roles in HG-induced DN. Here, we report prominent glomerular dysfunction, especially GMC abnormalities, in DN mice, which is closely related to GLUT1 alteration. In vivo studies have shown that BBR can alleviate pathological changes and abnormal renal function indicators of DN mice...

BACKGROUND: Type 2 diabetes mellitus is a complex metabolic disorder associated with obesity, glucose intolerance and insulin resistance. Activation of GALR2 has been proposed as a therapeutic target for the treatment of insulin resistance. The previous studies showed that baicalin could mitigate insulin resistance, but the detailed mechanism of baicalin on insulin resistance has not been fully explored yet. PURPOSE: In the present study, we evaluated whether baicalin mitigated insulin resistance via activation of GALR2 signaling pathway...

Previous studies demonstrated that acute exercise can enhance glucose uptake (GU), γ3-AMPK activity, and Akt Substrate of 160 kDa (AS160) phosphorylation in skeletal muscles from low fat diet (LFD) and high fat diet (HFD) fed male rats. Because little is known about exercise-effects on these outcomes in females, we assessed postexercise GU by muscles incubated ±insulin, delta-insulin GU (GU of muscles incubated with insulin minus GU uptake of paired muscles incubated without insulin), and muscle signaling proteins from female rats fed a LFD or brief-HFD (2wk)...

Small molecule inhibition of with no lysine kinase 1 (WNK1) (WNK463) signaling activates adenosine monophosphate-activated protein kinase signaling and mitigates membrane enrichment of glucose transporters 1 and 4, which decreases protein O-GlcNAcylation and glycation. Quantitative proteomics of right ventricular (RV) mitochondrial enrichments shows WNK463 prevents down-regulation of several mitochondrial metabolic enzymes. and metabolomics analysis suggests multiple metabolic processes are corrected. Physiologically, WNK463 augments RV systolic and diastolic function independent of pulmonary arterial hypertension severity...

Transforming growth factor (TGF)-β signalling commences with the engagement of TGF-β ligand to cell surface TGF-β receptors (TGFBR) stimulating Smad2 carboxyl-terminal phosphorylation (phospho-Smad2C) and downstream biological responses. In several cell models, G protein-coupled receptors (GPCRs) transactivate the TGF-β receptors type-1 (TGFBR1) leading to phospho-Smad2C, however, we have recently published that in keratinocytes thrombin did not transactivate the TGFBR1. The bulk of TGFBRs reside in the cytosol and in response to protein kinase B (Akt phosphorylation) can translocate to the cell surface increasing the cell's responsiveness to TGF-β...

One exercise session can elevate insulin-stimulated glucose uptake (ISGU) in skeletal muscle, but the mechanisms remain elusive. Circumstantial evidence suggests a role for Akt substrate of 160 kDa (AS160 or TBC1D4). We used genetic approaches to rigorously test this idea. The initial experiment evaluated AS160's role for the postexercise increase in ISGU using muscles from male wildtype (WT) and AS160-knockout (AS160-KO) rats. The next experiment used AS160-KO rats with an adeno-associated virus (AAV) approach to determine if rescuing muscle AS160 deficiency could restore exercise's ability to improve ISGU...