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AKT AND pancreatic beta cells

Yeong-Min Yoo, Yung Chul Park
Streptozotocin (STZ), a glucose analog, induces diabetes in experimental animals by inducing preferential cytotoxicity in pancreatic beta cells. We investigated whether STZ reduced the production of intracellular insulin through autophagy in insulinoma INS-1E cells. Typically, 2 mM STZ treatment for 24 h significantly decreased cell survival. STZ treatment led to significant decrease in phospho-AMP-activated protein kinase (p-AMPK) level; reduction in levels of phospho-protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1α (IRE1α); significant reduction in levels of p85α, p110, phospho-serine and threonine kinase/protein kinase B (p-Akt/PKB) (Ser473), phospho-extracellular-regulated kinase (p-ERK), and phospho-mammalian target of rapamycin (p-mTOR); increase in levels of Cu/Zn-superoxide dismutase (SOD), Mn-SOD, and catalase; decrease in B-cell lymphoma 2 (Bcl-2) expression; increase in Bcl-2-associated X protein (Bax) expression; increase in levels of microtubule-associated protein 1 light chain 3 (LC3) and Beclin 1; and reduction in production of intracellular insulin...
February 27, 2018: DNA and Cell Biology
Lingling Chen, Chunyan Liu, Jianfeng Gao, Zhiwen Xie, Lawrence W C Chan, Damien J Keating, Yibin Yang, Jiazhong Sun, Fuling Zhou, Yongchang Wei, Xiuli Men, Sijun Yang
Mitochondrial function is essential to meet metabolic demand of pancreatic beta cells respond to high nutrient stress. Mitophagy is an essential component to normal pancreatic β-cell function and has been associated with β-cell failure in Type 2 diabetes (T2D). Our previous studies have indicated that mitochondrial Rho (Miro) GTPase-mediated mitochondrial dysfunction under high nutrient stress leads to NOD-like receptor 3 (NLRP3)-dependent proinflammatory responses and subsequent insulin resistance. However, the in vivo mechanism by which Miro1 underlies mitophagy has not been identified...
October 31, 2017: Oncotarget
Nadezhda Mironova, Olga Patutina, Evgenyi Brenner, Alexander Kurilshikov, Valentin Vlassov, Marina Zenkova
Recently, pancreatic RNase A was shown to inhibit tumor and metastasis growth that accompanied by global alteration of miRNA profiles in the blood and tumor tissue (Mironova et al., 2013). Here, we performed a whole transcriptome analysis of murine Lewis lung carcinoma (LLC) after treatment of tumor-bearing mice with RNase A. We identified 966 differentially expressed transcripts in LLC tumors, of which 322 were upregulated and 644 were downregulated after RNase A treatment. Many of these genes are involved in signaling pathways that regulate energy metabolism, cell-growth promoting and transforming activity, modulation of the cancer microenvironment and extracellular matrix components, and cellular proliferation and differentiation...
October 3, 2017: Oncotarget
Jason Peart, Jinming Li, Hojun Lee, Matthew Riopel, Zhi-Chao Feng, Rennian Wang
β1 integrin is essential for pancreatic beta-cell development and maintenance in rodents and humans. However, the effects of a temporal beta-cell specific β1 integrin knockout on adult islet function are unknown. We utilized a mouse insulin 1 promoter driven tamoxifen-inducible Cre-recombinase β1 integrin knockout mouse model (MIPβ1KO) to investigate β1 integrin function in adult pancreatic beta-cells. Adult male MIPβ1KO mice were significantly glucose intolerant due to impaired glucose-stimulated insulin secretion in vivo and ex vivo at 8 weeks post-tamoxifen...
September 8, 2017: Oncotarget
R U Ostrovskaya, S S Yagubova, T A Gudasheva, S B Seredenin
Based on the comorbidity of diabetes, depression, and dementia and recognizing that a deficiency of the nerve growth factor (NGF) is involved in all of these kinds of pathologies, we studied the effect of the mimetic of dimeric dipeptide NGF loop 4, GK-2, on a model of streptozotocin-induced type 2 diabetes in C57Bl/6 mice. GK-2 [hexamethylenediamide bis-(N-monosuccinyl-glutamyl-lysine)] was synthesized at the V.V. Zakusov Scientific Research Institute of Pharmacology. The study revealed the ability of GK-2 to ameliorate hyperglycemia induced by streptozotocine (STZ 100 mg/kg i...
April 2017: Acta Naturae
Annalisa Natalicchio, Nicola Marrano, Giuseppina Biondi, Rosaria Spagnuolo, Rossella Labarbuta, Immacolata Porreca, Angelo Cignarelli, Marco Bugliani, Piero Marchetti, Sebastio Perrini, Luigi Laviola, Francesco Giorgino
This study explored the role of irisin as a new pancreatic β-cell secretagogue and survival factor and its potential role in the communication between skeletal muscle and pancreatic β-cells under lipotoxic conditions. Recombinant irisin stimulated insulin biosynthesis and glucose-stimulated insulin secretion (GSIS) in a PKA-dependent manner and prevented saturated fatty acid-induced apoptosis in human and rat pancreatic β-cells, as well as in human and murine pancreatic islets, via AKT/BCL2 signaling. Treatment of myotubes with 0...
November 2017: Diabetes
Mi-Kyung Kim, Hyun Mi Shin, HyeSook Jung, EunJu Lee, Tae Kyoon Kim, Tae Nyun Kim, Min Jeong Kwon, Soon Hee Lee, Byoung Doo Rhee, Jeong Hyun Park
Type 2 diabetes manifests beta cell deficiencies and alpha cell expansion which is consistent with relative insulin deficiency and glucagon oversecretion. The effects of hyperglycemia on alpha cells are not as understood in comparison to beta cells. Hyperglycemia increases oxidative stress, which induces Akt activation or FoxO activation, depending on cell type. Several studies independently reported that FoxO1 translocations in alpha cells and beta cells were opposite. We compared the responses of pancreatic alpha cells and beta cells against hyperglycemia...
May 19, 2017: Diabetes Research and Clinical Practice
Janica C Wong, Van Vo, Priyatham Gorjala, Ronald R Fiscus
Early studies showed nitric oxide as a pro-inflammatory-cytokine-induced toxin involved in pancreatic β-cell destruction during pathogenesis of type-1 diabetes. However, nitric oxide has both cytotoxic and cytoprotective effects on mammalian cells, depending on concentration and micro-environmental surroundings. Our studies have shown that low/physiological-level nitric oxide selectively activates protein kinase G type Iα isoform, promoting cytoprotective/pro-cell-survival effects in many cell types. In bone marrow-derived stromal/mesenchymal stem cells, protein kinase G type Iα mediates autocrine effects of nitric oxide and atrial natriuretic peptide, promoting DNA-synthesis/proliferation and cell survival...
June 1, 2017: Diabetes & Vascular Disease Research
Jason Peart, Jinming Li, Hojun Lee, Matthew Riopel, Zhi-Chao Feng, Rennian Wang
β1 integrin is essential for pancreatic beta-cell development and maintenance in rodents and humans. However, the effects of a temporal beta-cell specific β1 integrin knockout on adult islet function are unknown. We utilized a mouse insulin 1 promoter driven tamoxifen-inducible Cre-recombinase β1 integrin knockout mouse model (MIPβ1KO) to investigate β1 integrin function in adult pancreatic beta-cells. Adult male MIPβ1KO mice were significantly glucose intolerant due to impaired glucose-stimulated insulin secretion in vivo and ex vivo at 8 weeks post-tamoxifen...
May 18, 2017: Oncotarget
Igor E Deyev, Nadezhda V Popova, Oxana V Serova, Svetlana V Zhenilo, Marì Regoli, Eugenio Bertelli, Alexander G Petrenko
Secretion of mildly alkaline (pH 8.0-8.5) juice to intestines is one of the key functions of the pancreas. Recent reports indicate that the pancreatic duct system containing the alkaline juice may adjoin the endocrine cells of pancreatic islets. We have previously identified the insulin receptor-related receptor (IRR) that is expressed in islets as a sensor of mildly alkaline extracellular media. In this study, we show that those islet cells that are in contact with the excretory ducts are also IRR-expressing cells...
July 2017: Biochimie
Ting Yuan, Sahar Rafizadeh, Kanaka Durga Devi Gorrepati, Blaz Lupse, Jose Oberholzer, Kathrin Maedler, Amin Ardestani
AIMS/HYPOTHESIS: Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of nutritional status at the cellular and organismic level. While mTORC1 mediates beta cell growth and expansion, its hyperactivation has been observed in pancreatic islets from animal models of type 2 diabetes and leads to beta cell loss. We sought to determine whether such mTORC1 activation occurs in humans with type 2 diabetes or in metabolically stressed human islets and whether mTORC1 blockade can restore beta cell function of diabetic islets...
April 2017: Diabetologia
Betty C Villafuerte, Michelle T Barati, Madhavi J Rane, Susan Isaacs, Ming Li, Daniel W Wilkey, Michael L Merchant
BACKGROUND: A targeted analysis of the 50kDa C-terminal fragment of insulin-response element binding protein-1 (IRE-BP1) activation of target genes through the insulin receptor substrate receptor/PI-3 kinase/Akt pathway has been demonstrated for the insulin growth factor-1 receptor. The broader effects of 50kDa C-terminal IRE-BP1 fragment over-expression on protein abundance in pancreatic islet beta cells have not been determined. RESULTS: Liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses of replicate lysates of pancreatic islets isolated from background strain animals and transgenic animals, overexpressing IRE-BP1 in pancreatic islet beta cells, demonstrated statistically significant increases in the expression of proteins involved in protein synthesis, endoplasmic reticulum (ER) stress and scaffolding proteins important for protein kinase C signaling; some of which were confirmed by immunoblot analyses...
February 2017: Biochimica et Biophysica Acta
Diego Soares Carvalho, Marilia Melo Diniz, André Abour Haidar, Maria de Fátima Cavanal, Eduardo da Silva Alves, Angelo Rafael Carpinelli, Frida Zaladek Gil, Aparecida Emiko Hirata
Maternal hyperglycemia can result in defects in glucose metabolism and pancreatic β-cell function in offspring. The purpose of this study was to evaluate the impact of maternal diabetes mellitus on pancreatic islets, muscle and adipose tissue of the offspring, with or without oral l-Arginine supplementation. The induction of diabetes was performed using streptozotocin (60mg/kg). Animals were studied at 3 months of age and treatment (sucrose or l-Arginine) was administered from weaning. We observed that l-Arg improved insulin sensitivity in the offspring of diabetic mothers (DA), reflected by higher insulin-induced phosphorylation of Akt in muscle and adipose tissue...
November 15, 2016: European Journal of Pharmacology
Jiayue Yang, Richard T Waldron, Hsin-Yuan Su, Aune Moro, Hui-Hua Chang, Guido Eibl, Kevin Ferreri, Fouad R Kandeel, Aurelia Lugea, Ling Li, Stephen J Pandol
Epidemiological studies support strong links between obesity, diabetes, and pancreatic disorders including pancreatitis and pancreatic adenocarcinoma (PDAC). Type 2 diabetes (T2DM) is associated with insulin resistance, hyperglycemia, and hyperinsulinemia, the latter due to increased insulin secretion by pancreatic beta-cells. We reported that high-fat diet-induced PDAC progression in mice is associated with hyperglycemia, hyperinsulinemia, and activation of pancreatic stellate cells (PaSC). We investigated here the effects of high concentrations of insulin and glucose on mouse and human PaSC growth and fibrosing responses...
October 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Yaxi Chen, Li Tian, Shan Wan, Ying Xie, Xiang Chen, Xiao Ji, Qian Zhao, Chunyu Wang, Kun Zhang, Janet M Hock, Haoming Tian, Xijie Yu
MiR-17-92 cluster contributes to the regulation of mammalian development, aging and tumorigenesis. The functional roles of miR-17-92 in pancreatic beta-cells are largely unknown. In this study, we found that conditional deletion of miR-17-92 in mouse pancreatic beta-cells (miR-17-92βKO) significantly reduces glucose tolerance and the first phase of insulin secretion, despite normal ad libitum fed and fasting glucose levels. Proliferation is down-regulated in pancreatic beta-cells after deleting miR-17-92. MiR-17-92βKO mice show higher phosphatase and tensin homologue (PTEN) and lower phosphorylated AKT in islets...
December 5, 2016: Molecular and Cellular Endocrinology
Mary Topalovski, Michelle Hagopian, Miao Wang, Rolf A Brekken
The deposition of extracellular matrix (ECM) is a defining feature of pancreatic ductal adenocarcinoma (PDA), where ECM signaling can promote cancer cell survival and epithelial plasticity programs. However, ECM signaling can also limit PDA tumor growth by producing cytotoxic levels of reactive oxygen species. For example, excess fibronectin stimulation of α5β1 integrin on stromal cells in PDA results in reduced angiogenesis and increased tumor cell apoptosis because of oxidative stress. Fibulin-5 (Fbln5) is a matricellular protein that blocks fibronectin-integrin interaction and thus directly limits ECM-driven reactive oxygen species production and supports PDA progression...
October 14, 2016: Journal of Biological Chemistry
Jelena Kolic, Jocelyn E Manning Fox, Oleg G Chepurny, Aliya F Spigelman, Mourad Ferdaoussi, Frank Schwede, George G Holz, Patrick E MacDonald
OBJECTIVES: Phosphatidylinositol-3-OH kinase (PI3K) signalling in the endocrine pancreas contributes to glycaemic control. However, the mechanism by which PI3K modulates insulin secretion from the pancreatic beta cell is poorly understood. Thus, our objective was two-fold; to determine the signalling pathway by which acute PI3K inhibition enhances glucose-stimulated insulin secretion (GSIS) and to examine the role of this pathway in islets from type-2 diabetic (T2D) donors. METHODS: Isolated islets from mice and non-diabetic or T2D human donors, or INS 832/13 cells, were treated with inhibitors of PI3K and/or phosphodiesterases (PDEs)...
July 2016: Molecular Metabolism
Isabele Bringhenti, Fernanda Ornellas, Carlos Alberto Mandarim-de-Lacerda, Marcia Barbosa Aguila
OBJECTIVE: Mothers fed a high-fat (HF) diet can cause different adverse alterations in their offspring. The study aimed to verify the pancreatic islet structure and insulin-signaling pathway in adulthood of offspring of mothers fed a HF diet during the pregnancy. METHODS: Female mice (mothers) were randomly assigned to receive either standard chow (Mo-SC) or a HF diet (Mo-HF) ad libitum. After 2 mo on the experimental diets, 3-mo-old female mice were mated with male C57 BL/6 mice that were fed a SC diet...
October 2016: Nutrition
Tobias Boothe, Gareth E Lim, Haoning Cen, Søs Skovsø, Micah Piske, Shu Nan Li, Ivan R Nabi, Patrick Gilon, James D Johnson
OBJECTIVE: The role and mechanisms of insulin receptor internalization remain incompletely understood. Previous trafficking studies of insulin receptors involved fluorescent protein tagging at their termini, manipulations that may be expected to result in dysfunctional receptors. Our objective was to determine the trafficking route and molecular mechanisms of functional tagged insulin receptors and endogenous insulin receptors in pancreatic beta-cells. METHODS: We generated functional insulin receptors tagged with pH-resistant fluorescent proteins between domains...
May 2016: Molecular Metabolism
Seo-Yun Yang, Jae-Jin Lee, Jin-Hee Lee, Kyungeun Lee, Seung Hoon Oh, Yu-Mi Lim, Myung-Shik Lee, Kong-Joo Lee
Secretagogin (SCGN), a Ca(2+)-binding protein having six EF-hands, is selectively expressed in pancreatic β-cells and neuroendocrine cells. Previous studies suggested that SCGN enhances insulin secretion by functioning as a Ca(2+)-sensor protein, but the underlying mechanism has not been elucidated. The present study explored the mechanism by which SCGN enhances glucose-induced insulin secretion in NIT-1 insulinoma cells. To determine whether SCGN influences the first or second phase of insulin secretion, we examined how SCGN affects the kinetics of insulin secretion in NIT-1 cells...
June 15, 2016: Biochemical Journal
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