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PubMed Journals Articles About "Role Grb10 MTORC1 Dependent Regulation Insulin Signaling Action" RSS

13:43 EST 18th January 2020 | BioPortfolio

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Showing "Role Grb10 mTORC1 dependent regulation insulin signaling action" PubMed Articles 1–25 of 36,000+

Role of Grb10 in mTORC1-dependent regulation of insulin signaling and action in human skeletal muscle cells.

Growth factor receptor-bound 10 (Grb10) is an adaptor protein that binds to the insulin receptor, upon which insulin signaling and action is thought to be inhibited. Grb10 is also a substrate for the mechanistic target of rapamycin complex 1 (mTORC1) that mediates its feedback inhibition on phosphatidylinositide 3-kinase (PI3K)/Akt signaling. To characterize the function of Grb10 and its regulation by mTORC1 in human muscle, primary skeletal muscle cells were isolated from healthy lean young men and then in...


The Role of Androgen Excess on Insulin Sensitivity in Women.

Sex steroids, except for their primary reproductive role, exert key effects on metabolic target tissues. Androgen receptors have been detected in various tissues, participating in both central and peripheral regulation of metabolism and insulin action. The physiological role of androgens in regulating multiple aspects of female insulin signaling and energy metabolism becomes evident early in utero, thus programming how insulin-targeted tissues will behave in later life. Across lifespan, distinct effects of ...

Weak membrane interactions allow rheb to activate mTORC1 signaling without major lysosome enrichment.

Stable localization of the Rheb GTPase to lysosomes is thought to be required for activation of mTORC1 signaling. However, the lysosome targeting mechanisms for Rheb remain unclear. We therefore investigated the relationship between Rheb subcellular localization and mTORC1 activation. Surprisingly, we found that Rheb was undetectable at lysosomes. Nonetheless, functional assays in knockout human cells revealed that farnesylation of the C-terminal CaaX motif on Rheb was essential for Rheb-dependent mTORC1 ac...


Mice lacking angiotensin type 2 receptor exhibit a sex-specific attenuation of insulin sensitivity.

The renin-angiotensin system modulates insulin action. Pharmacological stimulation of angiotensin type 2 receptor (AT2R) was shown to have beneficial metabolic effects in various animal models of insulin resistance and type 2 diabetes and also to increase insulin sensitivity in wild type mice. In this study we further explored the role of the AT2R on insulin action and glucose homeostasis by investigating the glycemic profile and in vivo insulin signaling status in insulin-target tissues from both male and ...

mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes.

Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of β-cell function, we found that the control of cellular signaling in β-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critica...

Insulin and adipokine signaling and their cross-regulation in postmortem human brain.

Aberrant insulin and adipokine signaling has been implicated in cognitive decline associated with both type 2 diabetes mellitus and neurodegenerative diseases. We established methods that reliably measure insulin, adiponectin and leptin signaling, and their crosstalk, in thawed postmortem mid-frontal cortical tissue from cognitively normal older subjects with a short postmortem interval. Insulin-evoked insulin receptor (IR) activation increases activated, tyrosine-phosphorylated IRβ on tyrosine residues 96...

Cartilage ablation of Sirt1 causes inhibition of growth plate chondrogenesis by hyperactivation of mTORC1 signaling.

A growing body of evidence implied a pivotal role of Sirt1 in chondrocyte function and homeostasis, however, its underlying mechanisms mediating chondrogenesis which is an essential process for physiological skeletal growth, are still poorly understood. In the present study, we generated TamCartSirt1-/-(Sirt1 cKO) mice to explore the role of Sirt1 during postnatal endochondral ossification. Compared with control mice, cKO mice exhibited growth retardation associated with inhibited chondrocyte proliferation ...

Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer.

Signal integration has a crucial role in the cell fate decision and dysregulation of the cellular signaling pathways is a primary characteristic of cancer. As a signal integrator, mTOR shows a complex dynamical behavior which determines the cell fate at different cellular processes levels, including cell cycle progression, cell survival, cell death, metabolic reprogramming, and aging. The dynamics of the complex responses to rapamycin in cancer cells have been attributed to its differential time-dependent i...

GLUCOCORTICOID REGULATION OF AMINO ACID TRANSPORT IN PRIMARY HUMAN TROPHOBLAST CELLS.

Excess maternal glucocorticoids reduce placental amino acid transport and fetal growth, but whether these effects are mediated directly on the syncytiotrophoblast remains unknown. We hypothesised that glucocorticoids inhibit mechanistic target of rapamycin (mTOR) signaling and insulin-stimulated System A amino acid transport activity in primary human trophoblast (PHT) cells. Syncytialised PHTs, isolated from term placentas (n=15), were treated with either cortisol (1μM) or dexamethasone (1μM), ± insulin ...

Differential regulation of mTORC1 activation by leucine and β-hydroxy-β-methylbutyrate in skeletal muscle of neonatal pigs.

Leucine and its metabolite β-hydroxy-β-methylbutyrate (HMB) stimulate mTORC1-dependent protein synthesis in the skeletal muscles of neonatal pigs. The aim of this study was to determine whether HMB and leucine utilize common nutrient-sensing mechanisms to activate mTORC1. In Study 1, neonatal pigs were fed one of five diets for 24 h: low protein (LP), high protein (HP), or LP supplemented with 4 (LP+HMB4), 40 (LP+HMB40), or 80 (LP+HMB80) μmol HMB·kg body wt-1·day-1. In Study 2, neonatal pigs were fed f...

Functional Redundancy between β1 and β3 Integrin in Activating the IR/Akt/mTORC1 Signaling Axis to Promote ErbB2-Driven Breast Cancer.

Integrin receptors coordinate cell adhesion to the extracellular matrix (ECM) to facilitate many cellular processes during malignant transformation. Despite their pro-tumorigenic roles, therapies targeting integrins remain limited. Here, we provide genetic evidence supporting a functional redundancy between β1 and β3 integrin during breast cancer progression. Although ablation of β1 or β3 integrin alone has limited effects on ErbB2-driven mammary tumorigenesis, deletion of both receptors resulted in a s...

Rho-kinase activity is upregulated in the skeletal muscle of aged exercised rats.

There is a gap in the knowledge regarding the regulation of glucose uptake in skeletal muscle during the development of insulin resistance in the elderly. Rho-Kinase (Rock) signaling has been demonstrated as a crucial mechanism related to glucose metabolism and insulin sensitivity in skeletal muscle. This kinase is involved in the insulin receptor substrate 1 (IRS1) phosphorylation, leading to glucose uptake stimulation in the skeletal muscle; however, the mechanisms elucidating the role of Rock regulation ...

Phosphofructokinases Axis Controls Glucose-Dependent mTORC1 Activation Driven by E2F1.

Cancer cells rely on mTORC1 activity to coordinate mitogenic signaling with nutrients availability for growth. Based on the metabolic function of E2F1, we hypothesize that glucose catabolism driven by E2F1 could participate on mTORC1 activation. Here, we demonstrate that glucose potentiates E2F1-induced mTORC1 activation by promoting mTORC1 translocation to lysosomes, a process that occurs independently of AMPK activation. We showed that E2F1 regulates glucose metabolism by increasing aerobic glycolysis and...

CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice.

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance, metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism are not fully understood. I...

The RING-type E3 ligase RNF186 ubiquitinates Sestrin-2 and thereby controls nutrient sensing.

Nutrient sensing is a critical cellular process controlling metabolism and signaling. mTOR complex 1 (mTORC1) is the primary signaling hub for nutrient sensing and, when activated, stimulates anabolic processes while decreasing autophagic flux. mTORC1 receives nutrient status signals from intracellular amino acid sensors. One of these sensors, Sestrin-2, functions as an intracellular sensor of cytosolic leucine and inhibitor of mTORC1 activity. Genetic studies of Sestrin-2 have confirmed its critical role i...

3-Deoxyglucosone interferes with insulin signaling and attenuates insulin action on glucose-induced GLP-1 secretion in the enteroendocrine L cell line STC-1.

Maintenance of glucose homeostasis is reciprocally regulated by insulin and glucagon-like peptide-1 (GLP-1). We previously reported that GLP-1 secretion in response to an oral glucose load was impaired following an administration of 3-deoxyglucosone (3DG), an independent factor associated with the development of pre-diabetes. Here we investigated the effects of 3DG on insulin signaling and insulin-induced GLP-1 secretion under high-glucose conditions in the enteroendocrine L cell line STC-1. STC-1 cells we...

Liver and insulin resistance: New wine in old bottle!!!

Hepatic and systemic insulin resistance form the core of metabolic syndrome which is also associated with cardiovascular abnormalities, inflammation, and dyslipidemia. Skeletal muscles and adipose tissues are two main target organs for glucose disposal and hence have been studied for insulin resistance too. The liver is the first organ where insulin reaches after being secreted from pancreas and liver regulates glucose storage and disposal as per the body's demand in response to insulin. There are multiple ...

Diiodothyronines regulate metabolic homeostasis in primary human hepatocytes by modulating mTORC1 and mTORC2 activity.

Until three decades, ago 3,5-diiodothyronine (3,5-T) and 3,3'-diiodothyronine (3,3'-T) were considered products of thyroid hormone catabolism without biological activity. Some metabolic effects have been described in rodents, but the physiological relevance in humans and the mechanisms of action are unknown. Aim of this work was to investigate the role and the mechanisms of action of 3,5-T and 3,3'-T in the regulation of metabolic homeostasis in human liver. We used primary human hepatocytes freshly isolate...

A specific type of insulin-like peptide regulates the conditional growth of a beetle weapon.

Evolutionarily conserved insulin/insulin-like growth factor (IGF) signaling (IIS) has been identified as a major physiological mechanism underlying the nutrient-dependent regulation of sexually selected weapon growth in animals. However, the molecular mechanisms that couple nutritional state with weapon growth remain largely unknown. Here, we show that one specific subtype of insulin-like peptide (ILP) responds to nutrient status and thereby regulates weapon size in the broad-horned flour beetle Gnatocerus ...

Enhanced mTOR complex 1 signaling attenuates diabetic cardiac injury in OVE26 mice.

The protein kinase mechanistic target of rapamycin (mTOR) performs diverse cellular functions through 2 distinct multiprotein complexes, mTOR complex (mTORC)1 and 2. Numerous studies using rapamycin, an mTORC1 inhibitor, have implicated a role for mTORC1 in several types of heart disease. People with diabetes are more susceptible to heart failure. mTORC1 activity is increased in the diabetic heart, but its functional significance remains controversial. To investigate the role of mTORC1 in the diabetic heart...

Secretagogin Regulates Insulin Signaling by Direct Insulin Binding.

Secretagogin (SCGN) is a β-cell enriched, secretory/cytosolic Ca-binding protein with unknown secretory regulation and functions. Recent findings suggest that SCGN deficiency correlates with compromised insulin response and diabetes. However, the (patho)physiological SCGN-insulin nexus remains unexplored. We here report that SCGN is an insulin-interacting protein. The protein-protein interaction between SCGN and insulin regulates insulin stability and increases insulin potency in vitro and in vivo. Mutag...

Anti-insulin resistance effects of salidroside through mitochondrial quality control.

Mitochondrial quality control (MQC) and function are determinants for cellular energy metabolism and their disorders are reported to play important role in the development of insulin resistance (IR). Salidroside was reported to have beneficial effects on MQC through AMPK pathway, however, it is unknown whether salidroside exerts anti-IR effect with this action. This study sought to investigate effects of salidroside on IR with an exploration of the mechanisms of its action. Experimental IR models were adopt...

Lipid Mediators of Insulin Signaling in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) affects approximately 40% of patients with diabetes and is associated with high mortality rates. Among different cellular targets in DKD, podocytes, a highly specialized epithelial cells of the glomerular filtration barrier, are injured in the early stages of DKD. Both clinical and experimental data support the role of preserved insulin signaling as a major contributor to podocyte function and survival. However, little is known about the key modulators of podocyte insulin signa...

Hepatic nitric oxide synthase 1 adaptor protein regulates glucose homeostasis and hepatic insulin sensitivity in obese mice depending on its PDZ binding domain.

NOS1AP is an adaptor protein and its SNP rs12742393 was associated with type 2 diabetes (T2D). However, it remains uncertain whether NOS1AP plays a role in regulation of insulin sensitivity. Hepatic insulin resistance contributed to the development of T2D. Here, our investigation was focused on whether NOS1AP is involved in the regulation of hepatic insulin sensitivity and its underlying mechanisms.

Acute inhibition of protein deacetylases does not impact skeletal muscle insulin action.

Whether the histone deacetylase (HDAC) and sirtuin families of protein deacetylases regulate insulin-stimulated glucose uptake, independent of their transcriptional effects, has not been studied. Our objective herein was to determine the non-transcriptional role of HDACs and sirtuins in regulating skeletal muscle insulin action.


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