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X Tian, M Ye, Y Cao, C Wang
Angiotensin II type 1 receptor blocker losartan has shown strongly anti-insulin resistance properties in vivo and in vitro; however, the underlying mechanisms are poorly understood. In this study, we demonstrate that losartan administration increased phosphorylation of Akt and its downstream Akt substrate of 160 kDa (AS160), enhanced plasma membrane translocation of glucose transporter type 4 (GLUT4), and increased glucose uptake, along with increased Src phosphorylation as well as reduced expression of docking protein 1(DOK1) in palmitate-treated 3T3-L1 adipocytes...
December 22, 2016: Experimental and Clinical Endocrinology & Diabetes
Xiaohua Zheng, Gregory D Cartee
AKT1 and AKT2, the AKT isoforms that are highly expressed in skeletal muscle, have distinct and overlapping functions, with AKT2 more important for insulin-stimulated glucose metabolism. In adipocytes, AKT2 versus AKT1 has greater susceptibility for insulin-mediated redistribution from cytosolic to membrane localization, and insulin also causes subcellular redistribution of AKT Substrate of 160 kDa (AS160), an AKT2 substrate and crucial mediator of insulin-stimulated glucose transport. Although skeletal muscle is the major tissue for insulin-mediated glucose disposal, little is known about AKT1, AKT2 or AS160 subcellular localization in skeletal muscle...
December 14, 2016: Scientific Reports
Le-Le Yang, Na Xiao, Jinfeng Liu, Kang Liu, Baolin Liu, Ping Li, Lian-Wen Qi
Baicalin and scutellarin, two flavonoid glucuronic acids isolated from Scutellaria baicalensis, exhibit beneficial effects on glucose homeostasis. Baicalin and scutellarin are similar in structure except scutellarin has an additional hydroxyl at composition C-4'. In this work, we observed that baicalin and scutellarin promoted glucose disposal in mice and in adipocytes. Baicalin selectively increased phosphorylation of AMP-activated kinase (AMPK), while scutellarin selectively enhanced Akt phosphorylation. Both of them increased AS160 phosphorylation and glucose uptake in basal condition...
February 2017: Biochimica et Biophysica Acta
Yupaporn Rattanavichit, Natsasi Chukijrungroat, Vitoon Saengsirisuwan
The role of high fructose ingestion (HFI) in the development of conditions mimicking human metabolic syndrome has mostly been demonstrated in male animals; however, the extent of HFI-induced metabolic alterations in females remains unclear. The present study investigated whether HFI-induced metabolic perturbations differ between sexes and whether HFI aggravates the metabolic disturbances under ovarian hormone deprivation. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were given either water or liquid fructose (10% wt/vol) for 6 wk...
December 1, 2016: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Agnieszka Mikłosz, Bartłomiej Łukaszuk, Małgorzata Żendzian-Piotrowska, Justyna Brańska-Januszewska, Halina Ostrowska, Adrian Chabowski
The Akt substrate of 160 kDa (AS160) is a key regulator of GLUT4 translocation from intracellular depots to the plasma membrane in myocytes. Likely, AS160 also controls LCFAs transport, which requires relocation of fatty acid transporters. The aim of the present study was to determine the impact of AS160 knockdown on lipid milieu in L6 myotubes incubated with palmitate (PA). Therefore, we compared two different settings, namely: 1) AS160 knockdown prior to palmitate incubation (pre-PA-silencing, AS160(-) /PA); 2) palmitate incubation with subsequent AS160 knockdown (post-PA-silencing, PA/AS160(-) )...
October 7, 2016: Journal of Cellular Physiology
Lewan Parker, Nigel K Stepto, Christopher S Shaw, Fabio R Serpiello, Mitchell Anderson, David L Hare, Itamar Levinger
Background: Obesity and aging are associated with increased oxidative stress, activation of stress and mitogen activated protein kinases (SAPK), and the development of insulin resistance and metabolic disease. In contrast, acute exercise also increases oxidative stress and SAPK signaling, yet is reported to enhance insulin sensitivity and reduce the risk of metabolic disease. This study explored this paradox by investigating the effect of a single session of high-intensity interval-exercise (HIIE) on redox status, muscle SAPK and insulin protein signaling in eleven middle-aged obese men...
2016: Frontiers in Physiology
Bingxian Xie, Qiaoli Chen, Liang Chen, Yang Sheng, Hong Yu Wang, Shuai Chen
The AS160 (Akt substrate of 160 kDa) is a Rab-GTPase activating protein (RabGAP) with several other functional domains, and its deficiency in mice or human patients lowers GLUT4 protein levels and causes severe insulin resistance. How its deficiency causes diminished GLUT4 proteins remains unknown. We found that the deletion of AS160 decreased GLUT4 levels in a cell/tissue-autonomous manner. Consequently, skeletal muscle-specific deletion of AS160 caused postprandial hyperglycemia and hyperinsulinemia. The pathogenic effects of AS160 deletion are mainly, if not exclusively, due to the loss of its RabGAP function since the RabGAP-inactive AS160(R917K) mutant mice phenocopied the AS160 knockout mice...
November 2016: Diabetes
Kohei Kido, Satoru Ato, Takumi Yokokawa, Yuhei Makanae, Koji Sato, Satoshi Fujita
Acute aerobic exercise (AE) is a major physiological stimulus for skeletal muscle glucose uptake through activation of 5' AMP-activated protein kinase (AMPK). However, the regulation of glucose uptake by acute resistance exercise (RE) remains unclear. To investigate the intracellular regulation of glucose uptake after acute RE versus acute AE, male Sprague-Dawley rats were divided into three groups: RE, AE, or nonexercise control. After fasting for 12 h overnight, the right gastrocnemius muscle in the RE group was exercised at maximum isometric contraction via percutaneous electrical stimulation (3 × 10 sec, 5 sets)...
August 2016: Physiological Reports
Chandni S Thakkar, Rajendra R Kshirsagar, Vinayak R Naik, Asit Ranjan Ghosh, V Vijayakumar, Arvind Saklani, Asha A Kulkarni-Almeida
In an attempt to discover new scaffolds for anti-diabetic activity from plants, we screened extracts from Ixora brachiata Roxb. for their effect on glucose uptake in L6 myotubes. The petroleum (PE) extract of the plant showed a significant increase in insulin stimulated glucose uptake by L6 myotubes. The bioactivity guided fractionation of the crude extract yielded a compound (E)-9-oxooctadec-10-en-12-ynoic acid (OEA). The compound induced a dose dependent increase in insulin stimulated glucose uptake in L6 myotubes with an EC50 of 22...
October 2016: Fitoterapia
Lorena Oróstica, Carlos Rosas, Francisca Plaza-Parrochia, Isis Astorga, Fernando Gabler, Víctor García, Carmen Romero, Margarita Vega
BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine/ metabolic disorder characterized by hyperandrogenemia and in most cases, by hyperinsulinemia in addition to obesity. Besides ovarian dysfunction, endometrial physiology is also disrupted since this tissue is highly dependent on the action of steroids; in case of conception cycles, high percentage of abortion is observed. Because of the endocrine/metabolic alterations, PCOS-women present high probability to develop hyperplasia and endometrial cancer, where an imbalance of cell proliferation/apoptosis processes is detected...
2016: Current Pharmaceutical Design
Kyung Ha Choi, Hyun Ah Lee, Mi Hwa Park, Ji-Sook Han
The effect of mulberry (Morus alba L.) fruit extract (MFE) on hyperglycemia and insulin sensitivity in an animal model of type 2 diabetes was evaluated. C57BL/Ksj-diabetic db/db mice were divided into three groups: diabetic control, rosiglitazone, and MFE groups. Blood glucose, plasma insulin, and intraperitoneal glucose were measured, and an insulin tolerance test was performed after MFE supplementation in db/db mice. In addition, the protein levels of various targets of insulin signaling were measured by western blotting...
August 2016: Journal of Medicinal Food
Baoping Jiang, Liang Le, Wei Zhai, Wenting Wan, Keping Hu, Peng Yong, Chunnian He, Lijia Xu, Peigen Xiao
BACKGROUND: Our previous study has shown that Coreopsis tinctoria increases insulin sensitivity and regulates hepatic metabolism in high-fat diet (HFD)-induced insulin resistance rats. However, it is unclear whether or not marein, a major compound of C. tinctoria, could improve insulin resistance. Here we investigate the effect and mechanism of action of marein on improving insulin resistance in HepG2 cells. METHODS: We investigated the protective effects of marein in high glucose-induced human liver carcinoma cell HepG2...
August 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Julia L Hill, Nobuhide Kobori, Jing Zhao, Natalia S Rozas, Michael J Hylin, Anthony N Moore, Pramod K Dash
Prolonged metabolic suppression in the brain is a well-characterized secondary pathology of both experimental and clinical traumatic brain injury (TBI). AMP-activated kinase (AMPK) acts as a cellular energy sensor that, when activated, regulates various metabolic and catabolic pathways to decrease ATP consumption and increase ATP synthesis. As energy availability after TBI is suppressed, we questioned if increasing AMPK activity after TBI would improve cognitive outcome. TBI was delivered using the electromagnetic controlled cortical impact model on male Sprague-Dawley rats (275-300 g) and C57BL/6 mice (20-25 g)...
October 2016: Journal of Neurochemistry
Thiago R Araujo, Israelle N Freitas, Jean F Vettorazzi, Thiago M Batista, Junia C Santos-Silva, Maria L Bonfleur, Sandra L Balbo, Antonio C Boschero, Everardo M Carneiro, Rosane A Ribeiro
PURPOSE: L-alanine (Ala) and L-arginine (Arg) have been reported to regulate pancreatic β-cell physiology and to prevent body fat accumulation in diet-induced obesity. Here, we assessed growth and adiposity parameters, glucose tolerance, insulin secretion and the expression of insulin and nutrient-regulated proteins in monosodium glutamate (MSG)-obese mice supplemented with either Ala or Arg. METHODS: Male newborn C57Bl/6 mice received a daily subcutaneous injection of MSG or saline solution (CTL group), during the first 6 days of life...
June 17, 2016: European Journal of Nutrition
Pragya Sharma, Edward B Arias, Gregory D Cartee
Akt substrate of 160 kDa (AS160) phosphorylation on Thr(642) and Ser(588) by Akt is essential for insulin's full effect on glucose transport. However, protein phosphorylation is determined by the balance of actions by kinases and phosphatases, and the specific phosphatase(s) controlling AS160 dephosphorylation is (are) unknown. Accordingly, we assessed roles of highly expressed skeletal muscle serine/threonine phosphatases (PP1, PP2A, PP2B, and PP2C) on AS160 dephosphorylation. Preliminary screening of candidate phosphatases used an AS160 dephosphorylation assay...
September 2016: Diabetes
Meenu Rohini Rajan, Elin Nyman, Preben Kjølhede, Gunnar Cedersund, Peter Strålfors
Insulin resistance is a major aspect of type 2 diabetes (T2D), which results from impaired insulin signaling in target cells. Signaling to regulate forkhead box protein O1 (FOXO1) may be the most important mechanism for insulin to control transcription. Despite this, little is known about how insulin regulates FOXO1 and how FOXO1 may contribute to insulin resistance in adipocytes, which are the most critical cell type in the development of insulin resistance. We report a detailed mechanistic analysis of insulin control of FOXO1 in human adipocytes obtained from non-diabetic subjects and from patients with T2D...
July 22, 2016: Journal of Biological Chemistry
Miguel Baena, Gemma Sangüesa, Alberto Dávalos, María-Jesús Latasa, Aleix Sala-Vila, Rosa María Sánchez, Núria Roglans, Juan Carlos Laguna, Marta Alegret
Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months' supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress...
2016: Scientific Reports
Hung-Wen Liu, Chu-Chun Wei, Yen-Ju Chen, Yun-An Chen, Sue-Joan Chang
SCOPE: An elevated intracellular lipid contents resulted from lipid oversupply links obesity to insulin resistance. Flavanol-rich lychee fruit extract, oligonol, exhibited anti-obesity property in vitro and in vivo; however, the effects of oligonol on peripheral lipid metabolism and insulin sensitivity have not been fully investigated. We hypothesized that oligonol alleviated insulin resistance via decreasing intracellular lipid contents in peripheral tissues. METHODS AND RESULTS: Dietary oligonol supplementation (20 or 200 mg/kg bw) reduced glucose and insulin levels, improved oral glucose tolerance, and suppressed inflammatory markers, MCP-1 and IL-6, in High-Fat diet (HFD) induced obese mice...
May 10, 2016: Molecular Nutrition & Food Research
Pianchou Gongpan, Yanting Lu, Fang Wang, Yuhui Xu, Wenyong Xiong
AS160 (TBC1D4) has been implicated in multiple biological processes. However, the role and the mechanism of action of AS160 in the regulation of cell proliferation remain unclear. In this study, we demonstrated that AS160 knockdown led to blunted cell proliferation in multiple cell types, including fibroblasts and cancer cells. The results of cell cycle analysis showed that these cells were arrested in the G1 phase. Intriguingly, this inhibition of cell proliferation and the cell cycle arrest caused by AS160 depletion were glucose independent...
July 2, 2016: Cell Cycle
Zhenwen Zhang, Penghua Fang, Biao He, Lili Guo, Johan Runesson, Ülo Langel, Mingyi Shi, Yan Zhu, Ping Bo
Our previous studies testified the beneficial effect of central galanin on insulin sensitivity of type 2 diabetic rats. The aim of the study was further to investigate whether central M617, a galanin receptor 1 agonist, can benefit insulin sensitivity. The effects of intracerebroventricular administration of M617 on insulin sensitivity and insulin signaling were evaluated in adipose tissues of type 2 diabetic rats. The results showed that central injection of M617 significantly increased plasma adiponectin contents, glucose infusion rates in hyperinsulinemic-euglycemic clamp tests, GLUT4 mRNA expression levels, GLUT4 contents in plasma membranes, and total cell membranes of the adipose cells but reduced the plasma C-reactive protein concentration in nondiabetic and diabetic rats...
2016: Journal of Diabetes Research
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