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Gsk3 AND Diabetes

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https://www.readbyqxmd.com/read/29579399/gsk3-activated-stat5-regulates-expression-of-sfrps-to-modulate-adipogenesis
#1
Li Wang, Yuan Wang, Yuan Meng, Chao Zhang, Lijun Di
Adipogenesis is a tightly regulated cellular process and is closely associated with obesity and its associated metabolic disorders, such as diabetes. Multiple transcription factors and signaling pathways are involved in the regulation of adipogenesis. Here, we report that glycogen synthase kinase (GSK3), which was reported to play an important role in many cellular processes, is essential to adipocyte differentiation at early and terminal differentiation phases. Mechanistically, GSK3 modulates adipogenesis through regulation of both canonical Wnt pathways, which involve Wnt/β-catenin signaling, and noncanonical Wnt pathways, which include JNK and Ras-related C3 botulinum toxin substrate signaling...
March 26, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29410317/secreted-amyloid-precursor-protein-alpha-activates-neuronal-insulin-receptors-and-prevents-diabetes-induced-encephalopathy
#2
Brent D Aulston, Jason Shapansky, YaWen Huang, Gary L Odero, Gordon W Glazner
Secreted amyloid precursor protein alpha (sAPPα) is a potent neurotrophin in the CNS but a dedicated receptor has not been found. However, protein interactions involving amyloid beta (Aβ), a peptide cleaved from the same parent peptide as sAPPα, indicate that insulin receptors (IRs) could be a target of amyloid peptides. In this study, in vitro analysis of cortical neuronal cultures revealed that exogenous sAPPα increased IR phosphorylation in the absence of insulin. Furthermore, in an APP overexpressing mouse model, sAPPα bound IRs in the cortex with significantly greater binding in hypoinsulinemic animals...
February 2, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29244860/lithium-reduces-blood-glucose-levels-but-aggravates-albuminuria-in-btbr-ob-ob-mice
#3
Theun de Groot, Lars Damen, Leanne Kosse, Mohammad Alsady, Rosalinda Doty, Ruben Baumgarten, Susan Sheehan, Johan van der Vlag, Ron Korstanje, Peter M T Deen
Glycogen synthase kinase 3 (GSK3) plays an important role in the development of diabetes mellitus and renal injury. GSK3 inhibition increases glucose uptake in insulin-insensitive muscle and adipose tissue, while it reduces albuminuria and glomerulosclerosis in acute kidney injury. The effect of chronic GSK3 inhibition in diabetic nephropathy is not known. We tested the effect of lithium, the only clinical GSK3 inhibitor, on the development of diabetes mellitus and kidney injury in a mouse model of diabetic nephropathy...
2017: PloS One
https://www.readbyqxmd.com/read/29132997/thyroid-hormone-improves-insulin-signaling-and-reduces-the-activation-of-neurodegenerative-pathway-in-the-hippocampus-of-diabetic-adult-male-rats
#4
Fernanda Prieto-Almeida, Ana Carolina Panveloski-Costa, Fernanda Crunfli, Silvania da Silva Teixeira, Maria Tereza Nunes, Andréada Silva Torrão
AIMS: Diabetes mellitus (DM) and impairments of glucose metabolism and insulin resistance in the brain have been suggested as a likely etiology of Alzheimer's disease (AD). Studies have shown that thyroid hormones (THs) improve insulin sensitivity in DM rats and act as mediators of the plasticity of the nervous system altering behavior and cognitive function. Based on these findings, this study aimed to evaluate the effects of diabetes and triiodothyronine (T3) treatment upon proteins associated with DM and AD in the central nervous system...
January 1, 2018: Life Sciences
https://www.readbyqxmd.com/read/29053582/zinc-supplementation-improves-glucose-homeostasis-in-high-fat-fed-mice-by-enhancing-pancreatic-%C3%AE-cell-function
#5
Vinícius Cooper-Capetini, Diogo Antonio Alves de Vasconcelos, Amanda Roque Martins, Sandro Massao Hirabara, José Donato, Angelo Rafael Carpinelli, Fernando Abdulkader
Zinc is an essential component of the insulin granule and it possibly modulates insulin secretion and signaling. Since insulin resistance is a hallmark in the development of type 2 diabetes mellitus, this study aimed at investigating if zinc supplementation is able to improve glucose tolerance and β-cell function in a model of insulin resistance. Male C57BL/6 mice were distributed in four groups according to the diet: normal fat (NF); normal fat supplemented with ZnCl₂ (NFZ); high-fat (HF); and, high-fat chow supplemented with ZnCl₂ (HFZ)...
October 20, 2017: Nutrients
https://www.readbyqxmd.com/read/29016121/synthesis-binding-mode-and-antihyperglycemic-activity-of-potent-and-selective-5-imidazol-2-yl-4-phenylpyrimidin-2-yl-2-2-pyridylamino-ethyl-amine-inhibitors-of-glycogen-synthase-kinase-3
#6
Allan S Wagman, Rustum S Boyce, Sean P Brown, Eric Fang, Dane Goff, Johanna M Jansen, Vincent P Le, Barry H Levine, Simon C Ng, Zhi-Jie Ni, John M Nuss, Keith B Pfister, Savithri Ramurthy, Paul A Renhowe, David B Ring, Wei Shu, Sharadha Subramanian, Xiaohui A Zhou, Cynthia M Shafer, Stephen D Harrison, Kirk W Johnson, Dirksen E Bussiere
In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogues which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogues. Compound 1 (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, phenyl groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position...
October 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28714403/gsk3-inhibitors-in-the-therapeutic-development-of-diabetes-cancer-and-neurodegeneration-past-present-and-future
#7
Mudasir Maqbool, Nasimul Hoda
GSK3 has gained a considerable attention of researchers in the late 1970s as an inevitable drug target to treat diabetes. Furthermore, it was found to have a key role in the development of diseases like cancer and neurodegeneration (ND). A broad spectrum of GSK3 inhibitors have been discovered from time to time in order to curb these diseases. Inhibition of GSK3 by insulin boosts the dephosphorylation of glycogen synthase, hence its activation to convert UDP glucose into glycogen. Lack of insulin and insulin-resistance is supposed to be the cause of type 2 diabetes (Diabetes mellitus)...
November 16, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28710530/proteomic-characterisation-reveals-active-wnt-signalling-by-human-multipotent-stromal-cells-as-a-key-regulator-of-beta-cell-survival-and-proliferation
#8
Miljan Kuljanin, Gillian I Bell, Stephen E Sherman, Gilles A Lajoie, David A Hess
AIMS/HYPOTHESIS: Novel strategies to stimulate the expansion of beta cell mass in situ are warranted for diabetes therapy. The aim of this study was to elucidate the secretome of human bone marrow (BM)-derived multipotent stromal cells (MSCs) with documented islet regenerative paracrine function. We hypothesised that regenerative MSCs will secrete a unique combination of protein factors that augment islet regeneration. METHODS: Human BM-derived MSCs were examined for glucose-lowering capacity after transplantation into streptozotocin-treated NOD/severe combined immunodeficiency (SCID) mice and segregated into samples with regenerative (MSC(R)) vs nonregenerative (MSC(NR)) capacity...
October 2017: Diabetologia
https://www.readbyqxmd.com/read/28431241/akt-pkb-signaling-navigating-the-network
#9
REVIEW
Brendan D Manning, Alex Toker
The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28049096/anti-diabetic-effect-of-three-new-norditerpenoid-alkaloids-in-vitro-and-potential-mechanism-via-pi3k-akt-signaling-pathway
#10
Dan Tang, Qi-Bin Chen, Xue-Lei Xin, Haji-Akber Aisa
Diabetes is a metabolic disease with the characteristic of high blood glucose (hyperglycemia). In our previous study, we found that nigelladines A-C (compounds A-C), three norditerpenoid alkaloids from the seeds of Nigella glandulifera Freyn (Ranunculaceae) exhibited protein of tyrosine phosphatase 1B (PTP1B) inhibitory activity in vitro. In the present study, we further investigated their anti-diabetes activities in L6 moytubes and illuminated the mechanisms of action of compounds A-C. Several parameters of glucose metabolism such as glucose consumption, glycogen content and hexokinase activity were increased by compounds A-C...
March 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27849005/insulin-igf-signaling-affects-cell-transformation-in-the-balb-c-3t3-cell-model
#11
Doerte Poburski, Christiane Leovsky, Josefine Barbara Boerner, Luisa Szimmtenings, Michael Ristow, Michael Glei, René Thierbach
The increased cancer mortality of diabetes type 2 patients is most likely an evidence of the tight connection between tumor development and energy metabolism. A major focus of today's research is still the identification of key proteins of both diseases and the development of corresponding inhibitors. In this study we combined the two-stage BALB/c-3T3 cell transformation assay (BALB-CTA) with the IR/IGF-1R inhibitor OSI-906 (linsitinib) and analyzed alterations in protein activity and energy parameters in non-transformed as well as transformed cells...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27649495/renoprotective-effects-of-atorvastatin-in-diabetic-mice-downregulation-of-rhoa-and-upregulation-of-akt-gsk3
#12
Thiago Bruder-Nascimento, Glaucia Callera, Augusto Cesar Montezano, Tayze T Antunes, Ying He, Aurelie Nguyen Dinh Cat, Nathanne S Ferreira, Pedro A Barreto, Vânia C Olivon, Rita C Tostes, Rhian M Touyz
Potential benefits of statins in the treatment of chronic kidney disease beyond lipid-lowering effects have been described. However, molecular mechanisms involved in renoprotective actions of statins have not been fully elucidated. We questioned whether statins influence development of diabetic nephropathy through reactive oxygen species, RhoA and Akt/GSK3 pathway, known to be important in renal pathology. Diabetic mice (db/db) and their control counterparts (db/+) were treated with atorvastatin (10 mg/Kg/day, p...
2016: PloS One
https://www.readbyqxmd.com/read/27580020/mulberry-anthocyanin-extract-ameliorates-insulin-resistance-by-regulating-pi3k-akt-pathway-in-hepg2-cells-and-db-db-mice
#13
COMPARATIVE STUDY
Fujie Yan, Guanhai Dai, Xiaodong Zheng
This study evaluated the capacity of mulberry anthocyanin extract (MAE) on insulin resistance amelioration in HepG2 cells induced by high glucose and palmitic acid and diabetes-related metabolic changes in type 2 diabetic mice. In vitro, MAE alleviated insulin resistance in HepG2 cells and increased glucose consumption, glucose uptake and glycogen content. Enzyme activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were decreased due to PPARγ coactivator 1α (PGC-1α) and forkhead box protein O1 (FOXO1) inhibition...
October 2016: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/27546510/mg53-is-a-double-edged-sword-for-human-diseases
#14
REVIEW
Yan Zhang, Hong-Kun Wu, Feng-Xiang Lv, Rui-Ping Xiao
Mitsugumin 53 (MG53), also named Trim72, is a multi-functional TRIM-family protein, which is abundantly expressed in cardiac and skeletal muscle. It has been shown that MG53 not only plays important physiological roles but also acts as a crucial pathogenic factor of various diseases. First, MG53 preserves cardiac and skeletal muscle integrity via facilitating plasma membrane repair. Second, MG53 is essentially involved in cardiac ischemic preconditioning and postconditioning by activating PI3K-Akt-GSK3β and ERK1/2 cell survival signaling pathways...
August 25, 2016: Sheng Li Xue Bao: [Acta Physiologica Sinica]
https://www.readbyqxmd.com/read/27534430/knockdown-of-gsk3%C3%AE-increases-basal-autophagy-and-ampk-signalling-in-nutrient-laden-human-aortic-endothelial-cells
#15
Karen A Weikel, José M Cacicedo, Neil B Ruderman, Yasuo Ido
High concentrations of glucose and palmitate increase endothelial cell inflammation and apoptosis, events that often precede atherogenesis. They may do so by decreasing basal autophagy and AMP-activated protein kinase (AMPK) activity, although the mechanisms by which this occurs are not clear. Decreased function of the lysosome, an organelle required for autophagy and AMPK, have been associated with hyperactivity of glycogen synthase kinase 3β (GSK3β). To determine whether GSK3β affects nutrient-induced changes in autophagy and AMPK activity, we used a primary human aortic endothelial cell (HAEC) model of type 2 diabetes that we had previously characterized with impaired AMPK activity and autophagy [Weikel et al...
October 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27526674/hgf-alleviates-high-glucose-induced-injury-in-podocytes-by-gsk3%C3%AE-inhibition-and-autophagy-restoration
#16
Congying Zhang, Bo Hou, Siying Yu, Qi Chen, Nong Zhang, Hui Li
Podocyte injury or loss plays a major role in the pathogenesis of proteinuric kidney disease including diabetic nephropathy (DN). High basal level of autophagy is critical for podocyte health. Recent studies have revealed that hepatocyte growth factor (HGF) can ameliorate podocyte injury and proteinuria. However, little is known about the impact of HGF on podocyte autophagy. In this study, we investigated whether and how HGF affects autophagy in podocytes treated with high glucose (HG) conditions. HGF significantly diminishes apoptosis, oxidative stress and autophagy impairment inflicted by HG in podocytes...
November 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27497670/sulforaphane-prevents-neuronal-apoptosis-and-memory-impairment-in-diabetic-rats
#17
Gengyin Wang, Hui Fang, Yanfeng Zhen, Gang Xu, Jinli Tian, Yazhong Zhang, Dandan Zhang, Guyue Zhang, Jing Xu, Zhiyue Zhang, Mingyue Qiu, Yijia Ma, Hongrui Zhang, Xinxin Zhang
BACKGROUND/AIMS: To explore the effects of sulforaphane (SFN) on neuronal apoptosis in hippocampus and memory impairment in diabetic rats. METHODS: Thirty male rats were randomly divided into normal control, diabetic model and SFN treatment groups (N = 10 in each group). Streptozotocin (STZ) was applied to establish diabetic model. Water Morris maze task was applied to test learning and memory. Tunel assaying was used to detect apoptosis in hippocampus. The expressions of Caspase-3 and myeloid cell leukemia 1(MCL-1) were detected by western blotting...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27294151/nanoparticle-delivered-human-biliverdin-reductase-based-peptide-increases-glucose-uptake-by-activating-irk-akt-gsk3-axis-the-peptide-is-effective-in-the-cell-and-wild-type-and-diabetic-ob-ob-mice
#18
Peter E M Gibbs, Tihomir Miralem, Nicole Lerner-Marmarosh, Mahin D Maines
Insulin's stimulation of glucose uptake by binding to the IRK extracellular domain is compromised in diabetes. We have recently described an unprecedented approach to stimulating glucose uptake. KYCCSRK (P2) peptide, corresponding to the C-terminal segment of hBVR, was effective in binding to and inducing conformational change in the IRK intracellular kinase domain. Although myristoylated P2, made of L-amino acids, was effective in cell culture, its use for animal studies was unsuitable. We developed a peptidase-resistant formulation of the peptide that was efficient in both mice and cell culture systems...
2016: Journal of Diabetes Research
https://www.readbyqxmd.com/read/27163678/microrna-194-modulates-glucose-metabolism-and-its-skeletal-muscle-expression-is-reduced-in-diabetes
#19
Celine Latouche, Alaina Natoli, Medini Reddy-Luthmoodoo, Sarah E Heywood, James A Armitage, Bronwyn A Kingwell
BACKGROUND: The regulation of microRNAs (miRNAs) at different stages of the progression of type 2 diabetes mellitus (T2DM) and their role in glucose homeostasis was investigated. METHODS: Microarrays were used to assess miRNA expression in skeletal muscle biopsies taken from healthy individuals and patients with pre-diabetes or T2DM, and insulin resistant offspring of rat dams fed a high fat diet during pregnancy. RESULTS: Twenty-three miRNAs were differentially expressed in patients with T2DM, and 7 in the insulin resistant rat offspring compared to their controls...
2016: PloS One
https://www.readbyqxmd.com/read/26824655/electron-transport-chain-remodeling-by-gsk3-during-oogenesis-connects-nutrient-state-to-reproduction
#20
Matthew H Sieber, Michael B Thomsen, Allan C Spradling
Reproduction is heavily influenced by nutrition and metabolic state. Many common reproductive disorders in humans are associated with diabetes and metabolic syndrome. We characterized the metabolic mechanisms that support oogenesis and found that mitochondria in mature Drosophila oocytes enter a low-activity state of respiratory quiescence by remodeling the electron transport chain (ETC). This shift in mitochondrial function leads to extensive glycogen accumulation late in oogenesis and is required for the developmental competence of the oocyte...
January 28, 2016: Cell
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