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Insulin resistance AND mtor

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https://www.readbyqxmd.com/read/29324300/hippocampal-insulin-resistance-links-maternal-obesity-with-impaired-neuronal-plasticity-in-adult-offspring
#1
Lisa Schmitz, Rebecca Kuglin, Inga Bae-Gartz, Ruth Janoschek, Sarah Appel, Andrea Mesaros, Igor Jakovcevski, Christina Vohlen, Marion Handwerk, Regina Ensenauer, Jörg Dötsch, Eva Hucklenbruch-Rother
OBJECTIVE: Maternal obesity and a disturbed metabolic environment during pregnancy and lactation have been shown to result in many long-term health consequences for the offspring. Among them, impairments in neurocognitive development and performance belong to the most dreaded ones. So far, very few mechanistic approaches have aimed to determine the responsible molecular events. METHODS: In a mouse model of maternal diet-induced obesity and perinatal hyperinsulinemia, we assessed adult offspring's hippocampal insulin signaling as well as concurrent effects on markers of hippocampal neurogenesis, synaptic plasticity and function using western blotting and immunohistochemistry...
December 28, 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/29316242/sustained-high-fat-diet-modulates-inflammation-insulin-signalling-and-cognition-in-mice-and-a-modified-xenin-peptide-ameliorates-neuropathology-in-a-chronic-high-fat-model
#2
Paul Denver, Victor A Gault, Paula L McClean
AIMS: Metabolic disease increases risk of Alzheimer's disease and cognitive dysfunction. Chronic high fat diet (HFD) feeding leads to cognitive impairment and neuroinflammation. This study demarcated pathological events in brain as a result of short-term to chronic HFD feeding. Efficacy of Xenin-25[Lys(13)PAL] was assessed in chronic HFD-fed mice. METHODS: C57BL/6 mice were fed HFD or normal diet for 18 days, 34 days, 10 and 21 weeks. Cognition was assessed using novel object recognition and Morris water maze...
January 5, 2018: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/29288408/muscle-specific-deletion-of-prkaa1-enhances-skeletal-muscle-lipid-accumulation-in-mice-fed-a-high-fat-diet
#3
Weiche Wu, Ziye Xu, Ling Zhang, Jiaqi Liu, Jie Feng, Xinxia Wang, Tizhong Shan, Yizhen Wang
Excessive intramyocellular triacylglycerols (IMTGs, muscle lipids) are associated with the abnormal energy metabolism and insulin resistance of skeletal muscle. AMP-activated protein kinase (AMPK), a crucial cellular energy sensor, consists of α, β and γ subunits. Researchers have not clearly determined whether Prkaa1 (also known as AMPKα1) affects IMTG accumulation in skeletal muscle. Here, we show an important role of Prkaa1 in skeletal muscle lipid metabolism. Deletion of muscle Prkaa1 leads to the delayed development of skeletal muscles but does not affect glucose tolerance or insulin sensitivity in animals fed a normal diet...
December 29, 2017: Journal of Physiology and Biochemistry
https://www.readbyqxmd.com/read/29276026/dueling-for-dual-inhibition-means-to-enhance-effectiveness-of-pi3k-akt-mtor-inhibitors-in-aml
#4
REVIEW
Lauren Herschbein, Jane L Liesveld
The phosphatidylinositol 3-kinase/protein kinase B (Akt)/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway is amplified in 60-80% of patients with acute myelogenous leukemia (AML). Since this complex pathway is crucial to cell functions such as growth, proliferation, and survival, inhibition of this pathway would be postulated to inhibit leukemia initiation and propagation. Inhibition of the mTORC1 pathway has met with limited success in AML due to multiple resistance mechanisms including direct insensitivity of the mTORC1 complex, feedback activation of the PI3k/Akt signaling network, insulin growth factor-1 (IGF-1) activation of PI3K, and others...
December 2, 2017: Blood Reviews
https://www.readbyqxmd.com/read/29245957/glipizide-sensitizes-lung-cancer-cells-to-trail-induced-apoptosis-via-akt-mtor-autophagy-pathways
#5
Uddin Md Nazim, Ji-Hong Moon, You-Jin Lee, Jae-Won Seol, Yong Ju Kim, Sang-Youel Park
The combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with subsidiary agents is a promising anticancer strategy to conquer TRAIL resistance in malignant cells. Glipizide is a second-generation oral hypoglycemic medicine for the cure of type II diabetes because of its capability to selectively stimulate insulin secretion from β-cells. In this study, we revealed that glipizide could trigger TRAIL-mediated apoptotic cell death in human lung adenocarcinoma cells. Pretreatment with glipizide downregulation of p-Akt and p-mTOR in different concentrations...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29204135/recombinant-uncarboxylated-osteocalcin-per-se-enhances-mouse-skeletal-muscle-glucose-uptake-in-both-extensor-digitorum-longus-and-soleus-muscles
#6
Xuzhu Lin, Lewan Parker, Emma Mclennan, Xinmei Zhang, Alan Hayes, Glenn McConell, Tara C Brennan-Speranza, Itamar Levinger
Emerging evidence suggests that undercarboxylated osteocalcin (ucOC) improves muscle glucose uptake in rodents. However, whether ucOC can directly increase glucose uptake in both glycolytic and oxidative muscles and the possible mechanisms of action still need further exploration. We tested the hypothesis that ucOC per se stimulates muscle glucose uptake via extracellular signal-regulated kinase (ERK), adenosine monophosphate-activated protein kinase (AMPK), and/or the mechanistic target of rapamycin complex 2 (mTORC2)-protein kinase B (AKT)-AKT substrate of 160 kDa (AS160) signaling cascade...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29128353/pyruvate-dehydrogenase-kinase-4-mediates-lipogenesis-and-contributes-to-the-pathogenesis-of-nonalcoholic-steatohepatitis
#7
Ming Zhang, Yujie Zhao, Zhen Li, Congying Wang
Nonalcoholic steatohepatitis (NASH) is a progressive disease and poses a high risk of severe liver damage. However, the pathogenesis of NASH is still unclear. Accumulation of lipid droplets and insulin resistance is the hallmark of NASH. Pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) plays key role in glucose metabolism via regulating the activity of pyruvate dehydrogenase complex (PDC). Here, we demonstrated a novel of PDK4 in NASH by regulating hepatic steatosis and insulin signaling pathway in methionine and choline deficient (MCD) diet induced NASH model...
November 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29104874/akt-mtor-role-in-human-foetoplacental-vascular-insulin-resistance-in-diseases-of-pregnancy
#8
REVIEW
Roberto Villalobos-Labra, Luis Silva, Mario Subiabre, Joaquín Araos, Rocío Salsoso, Bárbara Fuenzalida, Tamara Sáez, Fernando Toledo, Marcelo González, Claudia Quezada, Fabián Pardo, Delia I Chiarello, Andrea Leiva, Luis Sobrevia
Insulin resistance is characteristic of pregnancies where the mother shows metabolic alterations, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), or abnormal maternal conditions such as pregestational maternal obesity (PGMO). Insulin signalling includes activation of insulin receptor substrates 1 and 2 (IRS1/2) as well as Src homology 2 domain-containing transforming protein 1, leading to activation of 44 and 42 kDa mitogen-activated protein kinases and protein kinase B/Akt (Akt) signalling cascades in the human foetoplacental vasculature...
2017: Journal of Diabetes Research
https://www.readbyqxmd.com/read/29100507/inhibition-of-pi3k-akt-mtor-overcomes-cisplatin-resistance-in-the-triple-negative-breast-cancer-cell-line-hcc38
#9
Katharina Gohr, Alexandra Hamacher, Laura H Engelke, Matthias U Kassack
BACKGROUND: Widely established targeted therapies directed at triple negative breast cancer (TNBC) are missing. Classical chemotherapy remains the systemic treatment option. Cisplatin has been tested in TNBC but bears the disadvantage of resistance development. The purpose of this study was to identify resistance mechanisms in cisplatin-resistant TNBC cell lines and select targeted therapies based on these findings. METHODS: The TNBC cell lines HCC38 and MDA-MB231 were subjected to intermittent cisplatin treatment resulting in the 3...
November 3, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29099264/co-targeting-pi3k-mtor-and-igf1r-with-small-molecule-inhibitors-for-treating-undifferentiated-pleomorphic-sarcoma
#10
Caitlin D May, Sharon M Landers, Svetlana Bolshakov, XiaoYan Ma, Davis R Ingram, Christine M Kivlin, Kelsey L Watson, Ghadah A Al Sannaa, Angela D Bhalla, Wei-Lien Wang, Alexander J Lazar, Keila E Torres
Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Previous studies demonstrated that high expression of activated protein kinase B (AKT) in patients with UPS corresponds to poor disease-specific survival. Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation...
October 3, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29074727/liver-reptin-ruvbl2-controls-glucose-and-lipid-metabolism-with-opposite-actions-on-mtorc1-and-mtorc2-signalling
#11
Joaquim Javary, Nathalie Allain-Courtois, Nicolas Saucisse, Pierre Costet, Capucine Heraud, Fadila Benhamed, Rémi Pierre, Corinne Bure, Nestor Pallares-Lupon, Marcio Do Cruzeiro, Catherine Postic, Daniela Cota, Pierre Dubus, Jean Rosenbaum, Samira Benhamouche-Trouillet
OBJECTIVE: The AAA+ ATPase Reptin is overexpressed in hepatocellular carcinoma and preclinical studies indicate that it could be a relevant therapeutic target. However, its physiological and pathophysiological roles in vivo remain unknown. This study aimed to determine the role of Reptin in mammalian adult liver. DESIGN AND RESULTS: We generated an inducible liver-specific Reptin knockout (RepinLKO ) mouse model. Following Reptin invalidation, mice displayed decreased body and fat mass, hypoglycaemia and hypolipidaemia...
October 26, 2017: Gut
https://www.readbyqxmd.com/read/29058763/s14g-humanin-alleviates-insulin-resistance-and-increases-autophagy-in-neurons-of-app-ps1-transgenic-mouse
#12
Kun Han, Ning Jia, Yi Zhong, Xiuli Shang
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by Aβ plaque deposition in the brain, which is related to the disorder of autophagosome maturation, transport and formation of autolysosome. Notably, abnormal insulin signaling is connected with cognitive dysfunction in AD. In this study, using APP/PS1 transgenic mice as AD model, we investigated the mechanism by which S14G-humanin (HNG) improved autophagy and insulin signaling in AD brain. Immunohistochemistry was used to determine the levels of mTOR and Aβ deposition, and Western blot analysis was used to determine IRS-1, IRS-1 pSEr636, ULK1, p62, LC3 I/LC3 II protein levels...
October 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29030784/anti-tnf-%C3%AE-antibody-alleviates-insulin-resistance-in-rats-with-sepsis-induced-stress-hyperglycemia
#13
W Qu, C Han, M Li, J Zhang, Z Jiang
PURPOSE: To explore the effects and mechanisms of anti-tumor necrosis factor-α (TNF-α) antibody on insulin resistance (IR) in rats with sepsis-induced stress hyperglycemia. METHODS: The sepsis-induced stress hyperglycemic rat model was constructed by cecal ligation and puncture combined with the intraperitoneal injection of lipopolysaccharide. The rats were randomly divided into six groups: normal control (NC) group, surgical rats (Cntl) group, high-dose anti-TNF-α antibody therapy (TNF, 6 mg/kg) group, low-dose anti-TNF-α antibody therapy (Tnf, 3 mg/kg) group, insulin therapy (INS) group, and INS + Tnf group...
October 13, 2017: Journal of Endocrinological Investigation
https://www.readbyqxmd.com/read/28990055/defective-insulin-signaling-and-the-protective-effects-of-dimethyldiguanide-during-follicular-development-in-the-ovaries-of-polycystic-ovary-syndrome
#14
Fan Wang, Shaobing Wang, Zhenghong Zhang, Qingqiang Lin, Yiping Liu, Yijun Xiao, Kaizhuan Xiao, Zhengchao Wang
It is established that the physiological effects of insulin are primarily mediated by the insulin signaling pathway. However, a defective insulin signaling is closely associated with the clinical manifestations of polycystic ovary syndrome (PCOS), which include excess androgen levels, insulin resistance and anovulation, and is involved in the pathophysiology of PCOS at the molecular level. Dimethyldiguanide (DMBG) has been widely employed to alleviate reproduction dysfunction in women with PCOS, however, the exact mechanism of this effect remains unclear...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28977849/endoplasmic-reticulum-stress-induces-autophagy-and-apoptosis-while-inhibiting-proliferation-and-drug-resistance-in-multiple-myeloma-through-the-pi3k-akt-mtor-signaling-pathway
#15
Yun-Feng Fu, Xiao Liu, Meng Gao, Ya-Nan Zhang, Jing Liu
We investigated the effects of endoplasmic reticulum stress (ERS) on autophagy, proliferation, apoptosis, and drug resistance in multiple myeloma (MM). MM patients enrolled in our study (n = 268) were classified into sensitive and resistant groups based on chemotherapy efficacy, and their serum levels of β2-MG, albumin (ALB), lactic dehydrogenase (LDH), Ca(2+) and hemoglobin were determined. In addition, human MM U266 and MOLP-2/R cells were divided into blank, tunicamycin (TM), TM + insulin-like growth factor-1 (IGF-1), and TM + rapamycin groups, and measured expression of ERS-related, PI3K/Akt/mTOR pathway-related, and autophagy-related mRNA and proteins...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28971834/differential-localisation-and-anabolic-responsiveness-of-mtor-complexes-in-human-skeletal-muscle-in-response-to-feeding-and-exercise
#16
Nathan Hodson, Chris McGlory, Sara Y Oikawa, Stewart Jeromson, Zhe Song, Markus A Ruegg, D Lee Hamilton, Stuart M Phillips, Andrew Philp
Mechanistic target of rapamycin (mTOR) resides as two complexes within skeletal muscle. mTOR complex 1 (mTORC1-Raptor positive) regulates skeletal muscle growth, whereas mTORC2 (Rictor positive) regulates insulin sensitivity. To examine the regulation of these complexes in human skeletal muscle, we utilised immunohistochemical analysis to study the localisation of mTOR complexes prior to and following protein-carbohydrate feeding (FED) and resistance exercise plus protein-carbohydrate feeding (EXFED) in unilateral exercise model...
September 27, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28944847/geniposide-promotes-autophagy-to-inhibit-insulin-resistance-in-hepg2-cells-via-p62-nf%C3%A2-%C3%AE%C2%BAb-glut%C3%A2-4
#17
Hongwei Jiang, Yujin Ma, Junqiang Yan, Jie Liu, Liping Li
Insulin resistance (IR) is known to be an important factor, which can lead to the onset of type 2 diabetes. Autophagy is a cellular process, which sequesters senescent or damaged proteins in autophagosomes for recycling of their products. Insulin and intracellular molecules, including mammalian target of rapamycin (mTOR), are well‑known inhibitors of autophagy. In patients with type 2 diabetes, the expression levels of glucose transporter 4 (GLUT‑4) in skeletal muscles are significantly decreased, indicating decreased glucose‑processing ability...
November 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28934129/a-comprehensive-survey-of-the-roles-of-highly-disordered-proteins-in-type-2-diabetes
#18
Zhihua Du, Vladimir N Uversky
Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that is strongly associated with hyperglycemia (high blood sugar) related to either insulin resistance or insufficient insulin production. Among the various molecular events and players implicated in the manifestation and development of diabetes mellitus, proteins play several important roles. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database has information on 34 human proteins experimentally shown to be related to the T2DM pathogenesis...
September 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28923179/drugs-and-hyperglycemia-a-practical-guide
#19
REVIEW
Vandana Jain, Ronak Kumar Patel, Zaureen Kapadia, Sneha Galiveeti, Maryann Banerji, Lisel Hope
Drug-induced diabetes is one of the factors contributing to the increasing incidence of diabetes worldwide. This review considers the frequency, pathogenesis and treatment of drug-induced diabetes. Drugs that induce diabetes include hormonal therapy, especially glucocorticoids and androgen blockers, cardiovascular drugs, especially statins, beta-blockers and diuretics, antipsychotics, especially clozapine, olanzapine and quetiapine, antiretrovirals (protease inhibitors and non-reverse transcriptase inhibitors - NRTIs) and other drugs (mechanistic target of rapamycin inhibitors -mTORs, post organ transplantation drugs, tyrosine kinase inhibitors and interferon-alpha)...
October 2017: Maturitas
https://www.readbyqxmd.com/read/28919254/palmitic-acid-stimulates-energy-metabolism-and-inhibits-insulin-pi3k-akt-signaling-in-differentiated-human-neuroblastoma-cells-the-role-of-mtor-activation-and-mitochondrial-ros-production
#20
Erika Calvo-Ochoa, Karina Sánchez-Alegría, Cecilia Gómez-Inclán, Patricia Ferrera, Clorinda Arias
The high consumption of saturated lipids has been largely associated with the increasing prevalence of metabolic diseases. In particular, saturated fatty acids such as palmitic acid (PA) have been implicated in the development of insulin resistance in peripheral tissues. However, how neurons develop insulin resistance in response to lipid overload is not fully understood. Here, we used cultured rat cortical neurons and differentiated human neuroblastoma cells to demonstrate that PA blocks insulin-induced metabolic activation, inhibits the activation of the insulin/PI3K/Akt pathway and activates mTOR kinase downstream of Akt...
September 15, 2017: Neurochemistry International
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