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Gsk3 AND Diabetes

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)...
July 14, 2017: Current Pharmaceutical Design
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...
July 14, 2017: Diabetologia
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
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
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
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
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
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]
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
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
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
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
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
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
Yan Zhang, Tao Hu, Hongli Zhou, Yang Zhang, Gang Jin, Yu Yang
This study was performed to evaluate the effects of total polysaccharides extracted from Pleurotus ostreatus on type 2 diabetes. Rats were administered with high-fat diet and streptozotocin (STZ) to induce diabetes. The rats were then treated with 100, 200, and 400 mg/kg/d POP or vehicle for 4 weeks. Our experiments indicated that POP reduces hyperglycemia and hyperlipidemia levels, improves insulin resistance, and increases glycogen storage by activating GSK3 phosphorylation and GLUT4 translocation. Moreover, POP reduces the risk of oxidative damage by increasing superoxide dismutase(SOD), catalase(CAT), and glutathione peroxidase(GSH-Px) activities and decreasing malonaldehyde(MDA) level...
February 2016: International Journal of Biological Macromolecules
Tong-Yan Liu, Chang-Xiang Shi, Run Gao, Hai-Jian Sun, Xiao-Qing Xiong, Lei Ding, Qi Chen, Yue-Hua Li, Jue-Jin Wang, Yu-Ming Kang, Guo-Qing Zhu
Increased glucose production and reduced hepatic glycogen storage contribute to metabolic abnormalities in diabetes. Irisin, a newly identified myokine, induces the browning of white adipose tissue, but its effects on gluconeogenesis and glycogenesis are unknown. In the present study, we investigated the effects and underlying mechanisms of irisin on gluconeogenesis and glycogenesis in hepatocytes with insulin resistance, and its therapeutic role in type 2 diabetic mice. Insulin resistance was induced by glucosamine (GlcN) or palmitate in human hepatocellular carcinoma (HepG2) cells and mouse primary hepatocytes...
November 2015: Clinical Science (1979-)
Ricarda Cortés-Vieyra, Octavio Silva-García, Javier Oviedo-Boyso, Alejandro Huante-Mendoza, Alejandro Bravo-Patiño, Juan J Valdez-Alarcón, B Brett Finlay, Víctor M Baizabal-Aguirre
Glycogen synthase kinase 3 (GSK3) is a constitutively active regulatory enzyme that is important in cancer, diabetes, and cardiovascular, neurodegenerative, and psychiatric diseases. While GSK3α is usually important in neurodegenerative and psychiatric diseases GSK3β is fundamental in the inflammatory response caused by bacterial components. Peptidoglycan (PGN), one of the most abundant cell-wall structures of Gram-positive bacteria, is an important inducer of inflammation. To evaluate whether inhibition of GSK3α and GSK3β activity in bovine endothelial cells (BEC) regulates the expression of the pro-inflammatory cytokine IL-12p40, we treated BEC with SDS-purified PGN from Staphylococcus aureus...
2015: PloS One
M R King, N J Anderson, C Liu, E Law, M Cundiff, T M Mixcoatl-Zecuatl, C G Jolivalt
Peripheral neuropathy is a major complication associated with diabetes and central neuropathy characterized by Alzheimer's disease-like features in the brain is associated with increased dementia risk for patients with diabetes. Although glucose uptake into the cells of the nervous system is insulin-independent, contribution of impaired insulin support is clearly recognized to play a role, however not yet fully understood, in the development of neuropathy. In this study, we assessed the direct role of insulin on the peripheral nervous system (PNS) and central nervous system (CNS) of insulin-dependent type 1 diabetic rats...
September 10, 2015: Neuroscience
Nagesha Guthalu Kondegowda, Rafael Fenutria, Ilana R Pollack, Michael Orthofer, Adolfo Garcia-Ocaña, Josef M Penninger, Rupangi C Vasavada
Diabetes results from a reduction of pancreatic β-cells. Stimulating replication could normalize β-cell mass. However, adult human β-cells are recalcitrant to proliferation. We identified osteoprotegerin, a bone-related decoy receptor, as a β-cell mitogen. Osteoprotegerin was induced by and required for lactogen-mediated rodent β-cell replication. Osteoprotegerin enhanced β-cell proliferation in young, aged, and diabetic mice. This resulted in increased β-cell mass in young mice and significantly delayed hyperglycemia in diabetic mice...
July 7, 2015: Cell Metabolism
Gili Nathan, Sharon Kredo-Russo, Tamar Geiger, Ayelet Lenz, Haggai Kaspi, Eran Hornstein, Shimon Efrat
In-vitro expansion of β cells from adult human pancreatic islets could provide abundant cells for cell replacement therapy of diabetes. However, proliferation of β-cell-derived (BCD) cells is associated with dedifferentiation. Here we analyzed changes in microRNAs (miRNAs) during BCD cell dedifferentiation and identified miR-375 as one of the miRNAs greatly downregulated. We hypothesized that restoration of miR-375 expression in expanded BCD cells may contribute to their redifferentiation. Our findings demonstrate that overexpression of miR-375 alone leads to activation of β-cell gene expression, reduced cell proliferation, and a switch from N-cadherin to E-cadherin expression, which characterizes mesenchymal-epithelial transition...
2015: PloS One
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