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Yufeng Li, Zheng Li, Dan Wang, Xiang Zhang, Jia Li, Sher Ali, Jingze Lu, Hao Zong, Xiaolan Xu
Insulin-stimulated GLUT4 translocation from GLUT4 storage vesicles (GSVs) to the plasma membrane (PM) constitutes a key process for blood glucose control. Therefore, compounds that could promote GLUT4 translocation into the PM represent potential drugs for the treatment of diabetes. In this research, we screened for agonists that induce GLUT4 translocation by using a novel pH-sensitive fluorescent probe, insulin-regulated aminopeptidase (IRAP)-mOrange2. We identified as well as validated one agonist, staurosporine, from a 64,000 compound library...
October 18, 2016: Biochemical and Biophysical Research Communications
Clark K Ho, Ganesh Sriram, Katrina M Dipple
Mathematical modeling approaches have been commonly used in complex signaling pathway studies such as the insulin signal transduction pathway. Our expanded mathematical model of the insulin signal transduction pathway was previously shown to effectively predict glucose clearance rates using mRNA levels of key components of the pathway in a mouse model. In this study, we re-optimized and applied our expanded model to study insulin sensitivity in other species and tissues (human skeletal muscle) with altered protein activities of insulin signal transduction pathway components...
October 11, 2016: Molecular Genetics and Metabolism
Nagendra Yaluri, Shalem Modi, Tarja Kokkola
Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor widely used for the treatment of hypercholesterolemia. Recent data indicates that simvastatin increases the risk of new-onset diabetes by impairing both insulin secretion and insulin sensitivity. However, systematic evaluation of mechanistic pathways is lacking. We aimed to explore the effects of simvastatin on glucose uptake and underlying mechanisms using L6 skeletal muscle myotubes. We performed our experiments at basal and insulin-stimulated conditions, at normal (5...
October 12, 2016: Biochemical and Biophysical Research Communications
TingYu Liu, BuChin Yu, Mamoru Kakino, Hitoshi Fujimoto, Yasutoshi Ando, Fumihiko Hakuno, Shin-Ichiro Takahashi
Insulin receptor substrates (IRSs) are major targets of insulin receptor tyrosine kinases. Here we identified diacylglycerol kinase zeta (DGKζ) as an IRS-1-associated protein, and examined roles of DGKζ in glucose transporter 4 (GLUT4) translocation to the plasma membrane. When DGKζ was knocked-down in 3T3-L1 adipocytes, insulin-induced GLUT4 translocation was inhibited without affecting other mediators of insulin-dependent signaling. Similarly, knockdown of phosphatidylinositol 4-phosphate 5-kinase 1α (PIP5K1α), which had been reported to interact with DGKζ, also inhibited insulin-induced GLUT4 translocation...
October 14, 2016: Scientific Reports
Xin-Yu Huang, Liang Zhang, Jian Sun, Neng-Gui Xu, Wei Yi
To determine effect of acupuncture on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats and to evaluate expression of insulin signaling components. Rats were divided into three groups: Sprague-Dawley (SD) rats, OLETF rats, and acupuncture+OLETF rats. Acupuncture was subcutaneously applied to Neiguan (PC6), Zusanli (ST36), and Sanyinjiao (SP6); in contrast, acupuncture to Shenshu (BL23) was administered perpendicularly. For Neiguan (PC6) and Zusanli (ST36), needles were connected to an electroacupuncture (EA) apparatus...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
Bernardo Sousa-Pinto, Laura Gonçalves, Adriana R Rodrigues, Inês Tomada, Henrique Almeida, Delminda Neves, Alexandra M Gouveia
Transforming growth factor beta (TGF-β) plays an important role in the pathogenesis of obesity, influencing the release of inflammation mediators and promoting remodeling and collagen deposition in the adipose tissue (AT). In this context, this work aims to elucidate whether TGF-β and Smad-dependent or Smad-independent signaling pathways contribute to regional differentiation of AT in high-fat diet (HFD) and energy-restricted (ER) rat models. For this, TGF-β, TGF-β receptors I and II, PAI-1 and GLUT4 mRNA levels were quantified by real-time PCR, and western blotting assays allowed the semiquantification of TGF-β and proteins from Smad3, ERK1/2 and Akt signaling pathways in subcutaneous and visceral (epididymal, retroperitoneal and mesenteric) fat depots from control, HFD and ER-treated rats...
August 26, 2016: Journal of Nutritional Biochemistry
Sune Dandanell, Camilla Skovborg, Charlotte Boslev Præst, Kasper Bøgh Kristensen, Malene Glerup Nielsen, Sofie Lionett, Sofie Drevsholt Jørgensen, Andreas Vigelsø, Flemming Dela, Jørn Wulff Helge
OBJECTIVE: Intensive lifestyle interventions (ILI) are criticised for ineffective obesity treatment because weight loss over time is modest and thus of limited clinical relevance. However, a subgroup (5-30%) maintains a clinical weight loss >10%, but it is not clear if cardiometabolic health follows this pattern. The aim was to study the effect of different magnitudes of weight loss maintenance after ILI on cardiometabolic health. METHODS: Eighty out of 2420 former participants (age: 36±1, BMI: 38±1, (means ±SE)) in an 11-12-week ILI were recruited into 3 groups; clinical weight loss maintenance (>10% weight loss), moderate maintenance (1-10%), and weight regain based on weight loss at follow-up (5...
October 5, 2016: Obesity Research & Clinical Practice
Madina Naimi, Filip Vlavcheski, Brennan Murphy, Tomas Hudlicky, Evangelia Tsiani
Compounds that increase the activity of the energy sensor AMP-activated kinase (AMPK) have the potential to regulate blood glucose levels. Although rosemary extract (RE) has been reported to activate AMPK and reduce blood glucose levels in vivo, the chemical components responsible for these effects are not known. In the present study, we measured the levels of the polyphenol carnosic acid (CA) in RE and examined the effects and the mechanism of action of CA on glucose transport system in muscle cells. High performance liquid chromatography (HPLC) was used to measure the levels of CA in RE...
September 22, 2016: Clinical and Experimental Pharmacology & 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
Liza Margareth Medeiros de Carvalho Sousa, Gabriela Pacheco Mendes, Danila Barreiro Campos, Pietro Sampaio Baruselli, Paula de Carvalho Papa
We hypothesized that stimulatory and superovulatory treatments, using equine chorionic gonadotropin (eCG), modulate the expression of genes related to insulin, cellular modelling and angiogenesis signaling pathways in the bovine corpus luteum (CL). Therefore, we investigated: 1-the effect of these treatments on circulating insulin and somatomedin C concentrations and on gene and protein expression of INSR, IGF1 and IGFR1, as well as other insulin signaling molecules; 2-the effects of eCG on gene and protein expression of INSR, IGF1, GLUT4 and NFKB1A in bovine luteal cells; and 3-the effect of stimulatory and superovulatory treatments on gene and protein expression of ANG, ANGPT1, NOS2, ADM, PRSS2, MMP9 and PLAU...
2016: PloS One
Mei Dou, Yan Ma, Ai Guo Ma, Lei Han, Mi Mi Song, Yan Gang Wang, Min Xiu Yao, Xiao Fang Sun, Ying Li, Shan Gao, Yan Zhang
BACKGROUND AND OBJECTIVES: Peroral supplementation with trivalent-chromium (Cr) or magnesium (Mg) has been shown to improve insulin resistance (IR). The objective of this study was to determine whether combined peroral supplementation with Cr and Mg improves IR more effectively than Cr or Mg alone. METHODS AND STUDY DESIGN: Subjects (n=120, age range 45-59 years old) and diagnosed with IR were randomly divided into four groups and monitored for a period of 3 months: group 1 (the placebo control group), group 2 (160 μg/d Cr), group 3 (200 mg/d Mg), and group 4 (160 μg/d Cr plus 200 mg/d Mg)...
December 2016: Asia Pacific Journal of Clinical Nutrition
U Smith, B B Kahn
Obesity, the major cause of the current global epidemic of type 2 diabetes (T2D), induces insulin resistance in peripheral insulin target tissues. Several mechanisms have been identified related to cross-talk between adipose tissue, skeletal muscle and liver. These mechanisms involve both increased free fatty acid release and altered secretion of adipokines from adipose tissue. A major determinant of metabolic health is the ability of subcutaneous adipose tissue (SAT) to store excess fat rather than allowing it to accumulate in ectopic depots including liver (i...
October 3, 2016: Journal of Internal Medicine
Mei Hua Gao, Dimosthenis Giamouridis, N Chin Lai, Evelyn Walenta, Vivian Almeida Paschoal, Young Chul Kim, Atsushi Miyanohara, Tracy Guo, Min Liao, Li Liu, Zhen Tan, Theodore P Ciaraldi, Simon Schenk, Aditi Bhargava, Da Young Oh, H Kirk Hammond
Using mice rendered insulin resistant with high fat diets (HFD), we examined blood glucose levels and insulin resistance after i.v. delivery of an adeno-associated virus type 8 encoding murine urocortin 2 (AAV8.UCn2). A single i.v. injection of AAV8.UCn2-normalized blood glucose and glucose disposal within weeks, an effect that lasted for months. Hyperinsulinemic-euglycemic clamps showed reduced plasma insulin, increased glucose disposal rates, and increased insulin sensitivity following UCn2 gene transfer...
September 22, 2016: JCI Insight
Jinxie Zhang, Xudong Zhang, Gan Liu, Danfeng Chang, Xin Liang, Xianbing Zhu, Wei Tao, Lin Mei
The inner membrane vesicle system is a complex transport system that includes endocytosis, exocytosis and autophagy. However, the details of the intracellular trafficking pathway of nanoparticles in cells have been poorly investigated. Here, we investigate in detail the intracellular trafficking pathway of protein nanocapsules using more than 30 Rab proteins as markers of multiple trafficking vesicles in endocytosis, exocytosis and autophagy. We observed that FITC-labeled protein nanoparticles were internalized by the cells mainly through Arf6-dependent endocytosis and Rab34-mediated micropinocytosis...
2016: Theranostics
Zhu Li, Julie L Frey, G William Wong, Marie-Claude Faugere, Michael J Wolfgang, Jason K Kim, Ryan C Riddle, Thomas L Clemens
Recent studies have identified the osteoblast as an insulin responsive cell that participates in global energy homeostasis. Here we show that Glut4 is required for insulin-dependent uptake and oxidation of glucose in mature osteoblasts. In primary cultures of mouse osteoblasts, insulin increased uptake and oxidation of (14)C-glucose in a dose-dependent fashion, but did not significantly affect uptake or oxidation of (14)C-oleate. In vitro, undifferentiated osteoblasts expressed three high affinity glucose transporters: Glut1, Glut4, and Glut3...
September 30, 2016: Endocrinology
Ester García-Casarrubios, Carlos de Moura, Ana I Arroba, Nuria Pescador, María Calderon-Dominguez, Laura Garcia, Laura Herrero, Dolors Serra, Susana Cadenas, Flavio Reis, Eugenia Carvalho, Maria Jesus Obregon, Ángela M Valverde
New onset diabetes after transplantation (NODAT) is a metabolic disorder that affects 40% of patients on immunosuppressive agent (IA) treatment, such as rapamycin (also known as sirolimus). IAs negatively modulate insulin action in peripheral tissues including skeletal muscle, liver and white fat. However, the effects of IAs on insulin sensitivity and thermogenesis in brown adipose tissue (BAT) have not been investigated. We have analyzed the impact of rapamycin on insulin signaling, thermogenic gene-expression and mitochondrial respiration in BAT...
September 26, 2016: Biochimica et Biophysica Acta
Thomas Morville, Mads Rosenkilde, Thor Munch-Andersen, Peter Riis Andersen, Katja Kjær, Signe Helbo, Marianne Kristensen, Andreas Vigelsø, Nick Mattsson, Hanne Kruuse Rasmusen, Amelia Guadalupe-Grau, Angela Fago, Christina Neigaard Hansen, Brigitte Twelkmeyer, Jesper Løvind Andersen, Flemming Dela, Jørn Wulff Helge
INTRODUCTION/PURPOSE: Fat metabolism and muscle adaptation was investigated in 6 older trained men (age: 61 ± 4 years; VO2max: 48 ± 2 mL kg min) following repeated prolonged exercise). METHODS: 2706 km (1,681 miles) cycling was performed over 14 days and a blood sample and a muscle biopsy were obtained at rest after an overnight fast before and 30 hours after the completion of the cycling. VO2-max and maximal fat oxidation were measured using incremental exercise tests...
September 28, 2016: Medicine and Science in Sports and Exercise
Jami M Gurley, Olga Ilkayeva, Robert M Jackson, Beth A Griesel, Phillip White, Satochi Matsuzaki, Rizwan Qaisar, Holly Van Remmen, Kenneth M Humphries, Christopher B Newgard, Ann Louise Olson
Impaired GLUT4-dependent glucose uptake is a contributing factor in the development of whole body insulin resistance in obese patients and obese animal models. Previously, we demonstrated that transgenic mice engineered to express the human GLUT4 gene under the control of the human GLUT4 promoter (TG), are resistant to obesity-induced insulin resistance. A likely mechanism underlying increased insulin sensitivity is increased glucose uptake in skeletal muscle. The purpose of this study was to investigate the broader metabolic consequences of enhanced glucose uptake into muscle...
September 27, 2016: Diabetes
Liza Margareth Sousa, Renata Silva, Vanessa Fonseca, Rafael Leandro, Thiago Di Vincenzo, Ana Bárbara Alves-Wagner, Ubiratan Fabres Machado, Paula Papa
This study aimed to determine in the canine corpus luteum throughout the diestrus: 1) the influence of insulin on glucose utilization; 2) the regulation of genes potentially involved; and 3) the influence of hypoxia on glucose transporter expression and steroidogenesis, after treatment with cobalt chloride (CoCl2). Glucose uptake by luteal cells increased 2.7 folds (P<0.05) in response to insulin; a phenomenon related to increased expression of glucose transporter (GLUT) 4 and phosphorylation of protein kinase B (AKT)...
September 27, 2016: Journal of Endocrinology
Yukari Nakao, Hideto Yoshihara, Ko Fujimori
Baicalein has been used as a Chinese medicine, and is an abundant plant flavonoid present in fruits and vegetables. Here, we examined the effects of baicalein in adipogenesis and investigated its molecular mechanism in adipocytes. Baicalein lowered the intracellular lipid accumulation and decreased the transcription levels of the adipocyte-specific genes in mouse 3T3-L1 adipocytes. Glucose uptake mediated by glucose transporter 4 (GLUT4) was reduced, causing down-regulation of the intracellular lipid accumulation...
2016: PloS One
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