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Kim A Sjøberg, Christian Frøsig, Rasmus Kjøbsted, Lykke Sylow, Maximilian Kleinert, Andrew C Betik, Christopher S Shaw, Bente Kiens, Jørgen F P Wojtaszewski, Stephen Rattigan, Erik A Richter, Glenn K McConell
Insulin resistance is a major health risk, and although exercise clearly improves skeletal muscle insulin sensitivity, the mechanisms are unclear. Here we show that initiation of a euglycemic-hyperinsulinemic clamp 4 h after single-legged exercise in humans increased microvascular perfusion (determined by contrast-enhanced ultrasound) by 65% in the exercised leg and 25% in the rested leg (P < 0.05) and that leg glucose uptake increased 50% more (P < 0.05) in the exercised leg than in the rested leg. Importantly, infusion of the nitric oxide synthase inhibitor l-N(G)-monomethyl-l-arginine acetate (l-NMMA) into both femoral arteries reversed the insulin-stimulated increase in microvascular perfusion in both legs and abrogated the greater glucose uptake in the exercised compared with the rested leg...
June 2017: Diabetes
Rasmus Kjøbsted, Jørgen F P Wojtaszewski, Jonas T Treebak
Skeletal muscle insulin resistance precedes development of type 2 diabetes (T2D). As skeletal muscle is a major sink for glucose disposal, understanding the molecular mechanisms involved in maintaining insulin sensitivity of this tissue could potentially benefit millions of people that are diagnosed with insulin resistance. Regular physical activity in both healthy and insulin-resistant individuals is recognized as the single most effective intervention to increase whole-body insulin sensitivity and thereby positively affect glucose homeostasis...
2016: EXS
Rasmus Kjøbsted, Nanna Munk-Hansen, Jesper B Birk, Marc Foretz, Benoit Viollet, Marie Björnholm, Juleen R Zierath, Jonas T Treebak, Jørgen F P Wojtaszewski
Earlier studies have demonstrated that muscle insulin sensitivity to stimulate glucose uptake is enhanced several hours after an acute bout of exercise. Using 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR), we recently demonstrated that prior activation of AMPK is sufficient to increase insulin sensitivity in mouse skeletal muscle. Here we aimed to determine whether activation of AMPK is also a prerequisite for the ability of muscle contraction to increase insulin sensitivity. We found that prior in situ contraction of m...
October 26, 2016: Diabetes
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
Despoina Manousaki, Jack W Kent, Karin Haack, Sirui Zhou, Pingxing Xie, Celia M Greenwood, Paul Brassard, Deborah E Newman, Shelley Cole, Jason G Umans, Guy Rouleau, Anthony G Comuzzie, J Brent Richards
OBJECTIVE: A common nonsense mutation in TBC1D4 was recently found to substantially increase the odds of type 2 diabetes in Greenlandic Inuit, leading to exclusively increased postprandial glucose. We investigated the frequency and effect of the TBC1D4 mutation on glucose metabolism and type 2 diabetes diagnosis among Canadian and Alaskan Inuit. RESEARCH DESIGN AND METHODS: Exome sequencing of the TBC1D4 variant was performed in 114 Inuit from Nunavik, Canada, and Sanger sequencing was undertaken in 1,027 Alaskan Inuit from the Genetics of Coronary Artery Disease in Alaskan Natives (GOCADAN) Study...
November 2016: Diabetes Care
Cathrine Laustrup Møller, Rasmus Kjøbsted, Pablo J Enriori, Thomas Elbenhardt Jensen, Cecilia Garcia-Rudaz, Sara A Litwak, Kirsten Raun, Jørgen Wojtaszewski, Birgitte Schjellerup Wulff, Michael A Cowley
The melanocortin system includes five G-protein coupled receptors (family A) defined as MC1R-MC5R, which are stimulated by endogenous agonists derived from proopiomelanocortin (POMC). The melanocortin system has been intensely studied for its central actions in body weight and energy expenditure regulation, which are mainly mediated by MC4R. The pituitary gland is the source of various POMC-derived hormones released to the circulation, which raises the possibility that there may be actions of the melanocortins on peripheral energy homeostasis...
2016: PloS One
E Molinari, H Bar, A M Pyle, P Patrizio
STUDY QUESTION: Can RNA sequencing of human cumulus cells (CC) reveal molecular pathways involved in the physiology of reproductive aging? STUDY FINDING: Senescent but not young CC activate gene pathways associated with hypoxia and oxidative stress. WHAT IS KNOWN ALREADY: Shifts in socioeconomic norms are resulting in larger numbers of women postponing childbearing. The reproductive potential is sharply decreased with aging, and the reasons are poorly understood...
August 2016: Molecular Human Reproduction
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
Niels Grarup, Ida Moltke, Anders Albrechtsen, Torben Hansen
Type 2 diabetes (T2D) is an increasing health problem worldwide with particularly high occurrence in specific subpopulations and ancestry groups. The high prevalence of T2D is caused both by changes in lifestyle and genetic predisposition. A large number of studies have sought to identify the genetic determinants of T2D in large, open populations such as Europeans and Asians. However, studies of T2D in population isolates are gaining attention as they provide several advantages over open populations in genetic disease studies, including increased linkage disequilibrium, homogeneous environmental exposure, and increased allele frequency...
October 2015: Review of Diabetic Studies: RDS
Anup K Nair, Leslie J Baier
Genetic studies in large outbred populations have documented a complex, highly polygenic basis for type 2 diabetes (T2D). Most of the variants currently known to be associated with T2D risk have been identified in large studies that included tens of thousands of individuals who are representative of a single major ethnic group such as European, Asian, or African. However, most of these variants have only modest effects on the risk for T2D; identification of definitive 'causal variant' or 'causative loci' is typically lacking...
October 2015: Review of Diabetic Studies: RDS
Rasmus Kjøbsted, Andreas J T Pedersen, Janne R Hingst, Rugivan Sabaratnam, Jesper B Birk, Jonas M Kristensen, Kurt Højlund, Jørgen F P Wojtaszewski
Current evidence on exercise-mediated AMPK regulation in skeletal muscle of patients with type 2 diabetes (T2D) is inconclusive. This may relate to inadequate segregation of trimeric complexes in the investigation of AMPK activity. We examined the regulation of AMPK and downstream targets ACC-β, TBC1D1, and TBC1D4 in muscle biopsy specimens obtained from 13 overweight/obese patients with T2D and 14 weight-matched male control subjects before, immediately after, and 3 h after exercise. Exercise increased AMPK α2β2γ3 activity and phosphorylation of ACCβ Ser(221), TBC1D1 Ser(237)/Thr(596), and TBC1D4 Ser(704) Conversely, exercise decreased AMPK α1β2γ1 activity and TBC1D4 Ser(318)/Thr(642) phosphorylation...
May 2016: Diabetes
Paul Duffield Brewer, Estifanos N Habtemichael, Irina Romenskaia, Cynthia Corley Mastick, Adelle C F Coster
The RabGAP AS160/TBC1D4 controls exocytosis of the insulin-sensitive glucose transporter Glut4 in adipocytes. Glut4 is internalized and recycled through a highly regulated secretory pathway in these cells. Glut4 also cycles through a slow constitutive endosomal pathway distinct from the fast transferrin (Tf) receptor recycling pathway. This slow constitutive pathway is the only Glut4 cycling pathway in undifferentiated fibroblasts. The α2-macroglobulin receptor LRP1 cycles with Glut4 and the Tf receptor through all three exocytic pathways...
January 8, 2016: Journal of Biological Chemistry
Ling Shen, Michael Haas, David Q-H Wang, Aaron May, Chunmin C Lo, Silvana Obici, Patrick Tso, Stephen C Woods, Min Liu
Although ginseng has been reported to ameliorate hyperglycemia in animal models and clinical studies, the molecular mechanisms are largely unknown. We previously reported that chronic treatment with ginsenoside Rb1 (Rb1), a major component of ginseng, significantly reduced fasting glucose and improved glucose tolerance in high-fat diet (HFD)-induced obese rats. These effects were greater than those observed in pair-fed rats, suggesting a direct effect of Rb1 on glucose homeostasis, and this possibility was confirmed in the present study...
September 2015: Physiological Reports
Thea Kristensen, Merete Fredholm, Susanna Cirera
Obesity is a world-wide exponentially growing health problem that increases the risk of co-morbidities including metabolic syndrome, pre-diabetes, Type 2 Diabetes Mellitus (T2DM), and cancer. These co-morbidities are all complex conditions constituting a big challenge when searching for susceptibility genes. Identification of relevant genes, which could contribute to an earlier identification of individuals prone to develop diabetes, is urgently needed as many long-term complications can be avoided by preventive measures...
December 2015: Mammalian Genome: Official Journal of the International Mammalian Genome Society
Marianna Di Chiara, Bob Glaudemans, Dominique Loffing-Cueni, Alex Odermatt, Hadi Al-Hasani, Olivier Devuyst, Nourdine Faresse, Johannes Loffing
The Rab GTPase-activating protein TBC1D4 (AS160) controls trafficking of the glucose transporter GLUT4 in adipocytes and skeletal muscle cells. TBC1D4 is also highly abundant in the renal distal tubule, although its role in this tubule is so far unknown. In vitro studies suggest that it is involved in the regulation of renal transporters and channels such as the epithelial sodium channel (ENaC), aquaporin-2 (AQP2), and the Na+-K+-ATPase. To assess the physiological role of TBC1D4 in the kidney, wild-type (TBC1D4+/+) and TBC1D4-deficient (TBC1D4-/-) mice were studied...
November 1, 2015: American Journal of Physiology. Renal Physiology
Sally J Deeb, Stefka Tyanova, Michael Hummel, Marc Schmidt-Supprian, Juergen Cox, Matthias Mann
Characterization of tumors at the molecular level has improved our knowledge of cancer causation and progression. Proteomic analysis of their signaling pathways promises to enhance our understanding of cancer aberrations at the functional level, but this requires accurate and robust tools. Here, we develop a state of the art quantitative mass spectrometric pipeline to characterize formalin-fixed paraffin-embedded tissues of patients with closely related subtypes of diffuse large B-cell lymphoma. We combined a super-SILAC approach with label-free quantification (hybrid LFQ) to address situations where the protein is absent in the super-SILAC standard but present in the patient samples...
November 2015: Molecular & Cellular Proteomics: MCP
Peter H Albers, Kirstine N Bojsen-Møller, Carsten Dirksen, Annette K Serup, Dorte E Kristensen, Jan Frystyk, Trine R Clausen, Bente Kiens, Erik A Richter, Sten Madsbad, Jørgen F P Wojtaszewski
Roux-en-Y gastric bypass (RYGB) leads to increased peripheral insulin sensitivity. The aim of this study was to investigate the effect of RYGB on expression and regulation of proteins involved in regulation of peripheral glucose metabolism. Skeletal muscle and adipose tissue biopsies from glucose-tolerant and type 2 diabetic subjects at fasting and during a hyperinsulinemic-euglycemic clamp before as well as 1 wk and 3 and 12 mo after RYGB were analyzed for relevant insulin effector proteins/signaling components...
September 2015: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Gregory D Cartee
No abstract text is available yet for this article.
June 2015: Diabetes
Rasmus Sjørup Biensø, Jesper Olesen, Lasse Gliemann, Jakob Friis Schmidt, Mikkel Sillesen Matzen, Jørgen F P Wojtaszewski, Ylva Hellsten, Henriette Pilegaard
BACKGROUND: The aim was to investigate the molecular mechanisms behind exercise training-induced improvements in glucose regulation in aged subjects. METHODS: Twelve elderly male subjects completed 8 weeks of exercise training. Before and after the training period, the subjects completed an oral glucose tolerance test (OGTT) and a muscle biopsy was obtained from the vastus lateralis before and 45 minutes into the OGTT. Blood samples were collected before and up to 120 minutes after glucose intake...
July 2015: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Chao Quan, Bingxian Xie, Hong Yu Wang, Shuai Chen
The Rab GTPase activating protein (RabGAP), AS160/TBC1D4, is an important substrate of protein kinase B (PKB), and regulates insulin-stimulated trafficking of glucose transporter 4. Besides, AS160/TBC1D4 has also been shown to regulate trafficking of many other membrane proteins including FA translocase/CD36 in cardiomyocytes. However, it is not clear whether it plays any role in regulating heart functions in vivo. Here, we found that PKB-mediated phosphorylation of Thr649 on AS160/TBC1D4 represented one of the major PAS-binding signals in the heart in response to insulin...
2015: PloS One
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