Cited by 435Metabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic DiseasesDiabetes, Cardiovascular Risks, and Lipoproteins

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Impaired Insulin Signaling in Endothelial Cells Reduces Insulin-Induced Glucose Uptake by Skeletal Muscle

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Kubota, Tetsuya, Kubota, Naoto, Kumagai, Hiroki, Yamaguchi, Shinichi, Kozono, Hideki, Takahashi, Takehiro, Inoue, Mariko, Itoh, Shinsuke, Takamoto, Iseki, Sasako, Takayoshi, Kumagai, Katsuyoshi, Kawai, Tomoko, Hashimoto, Shinji, Kobayashi, Tsuneo, Sato, Maki, Tokuyama, Kumpei, Nishimura, Satoshi, Tsunoda, Masaki, Ide, Tomohiro, Murakami, Koji, Yamazaki, Tomomi, Ezaki, Osamu, Kawamura, Koichi, Masuda, Hirotake, Moroi, Masao, Sugi, Kaoru, Oike, Yuichi, Shimokawa, Hiroaki, Yanagihara, Nobuyuki, Tsutsui, Masato, Terauchi, Yasuo, Tobe, Kazuyuki, Nagai, Ryozo, Kamata, Katsuo, Inoue, Kenji, Kodama, Tatsuhiko, Ueki, Kohjiro, Kadowaki, Takashi·2011·Cell Metabolism

DOI 10.1016/j.cmet.2011.01.018

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Abstract

In obese patients with type 2 diabetes, insulin delivery to and insulin-dependent glucose uptake by skeletal muscle are delayed and impaired. The mechanisms underlying the delay and impairment are unclear. We demonstrate that impaired insulin signaling in endothelial cells, due to reduced Irs2 expression and insulin-induced eNOS phosphorylation, causes attenuation of insulin-induced capillary recruitment and insulin delivery, which in turn reduces glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells completely reverses the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking Irs2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle is restored in these mice. Taken together, our results show that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle. Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance.

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Sato, H., Kubota, N., Kubota, T., Takamoto, I., Iwayama, K., Tokuyama, K., Moroi, M., Sugi, K., Nakaya, K., Goto, M., et al. (2016) · Diabetologia · doi:10.1007/s00125-016-4071-8 · Cited by 19
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BackgroundInfluential
Insulin Receptor Substrate 2 Controls Insulin-Mediated Vasoreactivity and Perivascular Adipose Tissue Function in Muscle
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“, 1989), and therefore insulin access to the muscle interstitium contributes to whole-body insulin sensitivity (Kubota et al., 2011).”
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Perivascular Adipose Tissue Controls Insulin-Stimulated Perfusion, Mitochondrial Protein Expression, and Glucose Uptake in Muscle Through Adipomuscular Arterioles
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Vincenzi, M., Kremić, A., Jouve, A., Lattanzi, R., Miele, R., Benharouga, M., Alfaidy, N., Migrenne, S., Kanthasamy, A. G., Porcionatto, M. A., et al. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000801 · Cited by 21
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BackgroundInfluential
Lipid-induced insulin resistance does not impair insulin access to skeletal muscle
Kolka, C. M., Richey, J. M., Castro, A. V., Broussard, J. L., Ionut, V., & Bergman, R. N. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00015.2015 · Cited by 20
“Impairments in insulin signaling in knockout models have demonstrated impaired insulin access and lowered insulin-mediated glucose uptake, an effect that is reversed by restoring vasodilation (30).”
Background
Aging differentially impacts vasodilation and angiogenesis in arteries from the white and brown adipose tissues
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Background
Sarco/Endoplasmic Reticulum Ca2+ ATPase 2 Activator Ameliorates Endothelial Dysfunction; Insulin Resistance in Diabetic Mice
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Background
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Koutný, T. (2013) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2013.08.008 · Cited by 18
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Interplay of hypoxia, immune dysregulation, and metabolic stress in pathophysiology of type 1 diabetes
Mittal, R., Lemos, J. R. N., Chapagain, P. P., & Hirani, K. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1599321 · Cited by 17
The Key Role of Akt Protein Kinase in Metabolic-Inflammatory Pathways Cross-Talk: TNF-α Down-Regulation and Improving of Insulin Resistance in HepG2 Cell Line
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Background
Impaired postprandial skeletal muscle vascular responses to a mixed meal challenge in normoglycaemic people with a parent with type 2 diabetes
Russell, R., Roberts‐Thomson, K. M., Hu, D., Greenaway, T. M., Betik, A. C., Parker, L., Sharman, J. E., Richards, S. M., Rattigan, S., Premilovac, D., et al. (2021) · Diabetologia · doi:10.1007/s00125-021-05572-7 · Cited by 18
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Impaired microvascular insulin-dependent dilation in women with a history of gestational diabetes
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“Under normal circumstances, EC can increase NO bioavailability by phosphorylating NO synthase, while insulin resistance can reduce NO bioavailability, leading to oxidative stress, inflammation, glycotoxicity, and EC dysfunction.(155) Vitamin D is essential for the EC function as its deficiency can lead to impaired end…”
Background
Restoration of Impaired Metabolic Energy Balance (ATP Pool) and Tube Formation Potential of Endothelial Cells under “high glucose”, Diabetic Conditions by the Bioinorganic Polymer Polyphosphate
Wang, X., Ackermann, M., Neufurth, M., Wang, S., Li, Q., Feng, Q., Schröder, H. C., & Müller, W. E. G. (2017) · Polymers · doi:10.3390/polym9110575 · Cited by 16
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Metformin improves vascular and metabolic insulin action in insulin-resistant muscle
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Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes
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Effects of Tofogliflozin on Cardiac Function in Elderly Patients With Diabetes Mellitus
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Leite‐Almeida, L., Morato, M., Cosme, D., Afonso, J., Areias, J. C., Guerra, A., Afonso, A. C., Albino‐Teixeira, A., Sousa, T., & Correia‐Costa, L. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.12.005 · Cited by 14
Endothelial HSP72 is not reduced in type 2 diabetes nor is it a key determinant of endothelial insulin sensitivity
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Andrographolide Promotes Uptake of Glucose and GLUT4 Transport through the PKC Pathway in L6 Cells
Liao, J., Yang, Z., Yao, Y., Yang, X., Shen, J., & Zhao, P. (2022) · Pharmaceuticals · doi:10.3390/ph15111346 · Cited by 14
“GLUT4 is responsible for extracellular glucose transport and plays a central role in whole-body glucose metabolism, which is closely related to T2DM [10,11].”
BackgroundInfluential
Tie-2Cre mediated deletion of the vitamin D receptor gene leads to improved skeletal muscle insulin sensitivity and glucose tolerance
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Ablation of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) in Vascular Endothelial Cells Enhances Insulin Sensitivity by Reducing Visceral Fat and Suppressing Angiogenesis
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“Total body weight and adipose tissue weight were not altered in eIrs2KO (21).”
Background
Vagal Hyperactivity Due to Ventromedial Hypothalamic Lesions Increases Adiponectin Production and Release
Suzuki, Y., Shimizu, H., Ishizuka, N., Kubota, N., Kubota, T., Senoo, A., Kageyama, H., Osaka, T., Hirako, S., Kim, H.-J., et al. (2014) · Diabetes · doi:10.2337/db13-0636 · Cited by 14
“Real-time PCR was performed with a Real-Time PCR System (Applied Biosystems Japan, Tokyo, Japan) (31).”
Method
Endothelial Insulin Receptor Restoration Rescues Vascular Function in Male Insulin Receptor Haploinsufficient Mice
Sengupta, A., Patel, P. A., Yuldasheva, N. Y., Mughal, R. S., Galloway, S. L., Viswambharan, H., Walker, A. M., Aziz, A., Smith, J., Ali, N., et al. (2018) · Endocrinology · doi:10.1210/en.2018-00215 · Cited by 14
“reflecting the importance of tissue perfusion to insulin action (30).”
Background
Endothelin-1 activates extracellular signal-regulated kinases 1/2 via transactivation of platelet-derived growth factor receptor in rat L6 myoblasts
Harada, T., Horinouchi, T., Higa, T., Hoshi, A., Higashi, T., Terada, K., Mai, Y., Nepal, P., Horiguchi, M., Hatate, C., et al. (2014) · Life Sciences · doi:10.1016/j.lfs.2014.04.002 · Cited by 14
Oxidative Stress-Associated Protein Tyrosine Kinases and Phosphatases in Fanconi Anemia
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“Insulin signaling is critical for the regulation of glucose levels and the avoidance of diabetes mellitus, whereas defective insulin signaling may cause insulin resistance, leading to multiple diseases, including T2D and obesity (62, 128).”
Endothelial Cell Insulin Signaling Regulates CXCR4 (C-X-C Motif Chemokine Receptor 4) and Limits Leukocyte Adhesion to Endothelium
Rathjen, T., Kunkemoeller, B. H., Cederquist, C., Wang, X., Lockhart, S. M., Patti, J. C., Willenbrock, H., Olsen, G. S., Povlsen, G. K., Beck, H. C., et al. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.122.317476 · Cited by 15
Young Women Are Protected Against Vascular Insulin Resistance Induced by Adoption of an Obesogenic Lifestyle
Smith, J. A. H., Soares, R. N., McMillan, N. J., Jurrissen, T. J., Martinez‐Lemus, L. A., Padilla, J., & Manrique‐Acevedo, C. (2022) · Endocrinology · doi:10.1210/endocr/bqac137 · Cited by 13
Elevated heart rate and decreased muscle endothelial nitric oxide synthase in early development of insulin resistance
Blackwood, S. J., Tischer, D., van de Ven, M. P. F., Pontén, M., Edman, S., Horwath, O., Apró, W., Röja, J., Ekblom, M., Moberg, M., et al. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00148.2024 · Cited by 15
The Vascular Endothelium, a Benign Restrictive Barrier? NO! Role of Nitric Oxide in Regulating Insulin Action
Richey, J. M. (2013) · Diabetes · doi:10.2337/db13-1395 · Cited by 14
“The study showed that knockout of IRS2 caused inhibition of eNOS activation and almost completely inhibits insulin’s transendothelial delivery to the interstitium within 60 min after initiating the insulin clamp (20).”
Background
Association of endothelial dysfunction with incident prediabetes, type 2 diabetes and related traits: the KORA F4/FF4 study
Huemer, M., Huth, C., Schederecker, F., Klug, S. J., Meisinger, C., Köenig, W., Rathmann, W., Peters, A., & Thorand, B. (2020) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2020-001321 · Cited by 13
“This leads to decreased insulin delivery to the skeletal muscle, reducing the uptake of glucose into skeletal muscle 35 and in the long run possibly to the manifestation of type 2 diabetes.”
Hemodynamic actions of insulin: beyond the endothelium
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“…recognized a similar vascular and metabolic insulin-signaling via insulin receptor/phosphatidylinositol 3- kinase (PI3K) pathways (Kim et al., 2006; Kubota et al., 2011), which are present in both endothelium and vascular smooth muscle (VSM), leading to nitric oxide synthase (NOS) activation,…”
Influential
Taurochenodeoxycholic acid alleviates obesity-induced endothelial dysfunction
Lu, H., Wu, Z., Meng, W., Xiong, S., Huang, X., Liu, T., Jiang, X., He, L., Ma, C., Cui, H., et al. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf766 · Cited by 12
“40 While most studies assess obesity-induced ED using animal models or non-invasive human methods, wire myograph on ex vivo human arterioles remains the gold standard for evaluating vascular function, offering a unique bridge from laboratory research to clinical insights.”
Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, With Decreased Expression of Growth Hormone–Releasing Hormone in the Hypothalamus
Hayashi, T., Kubota, T., Inoue, M., Takamoto, I., Aihara, M., Sakurai, Y., Wada, N., Miki, T., Yamauchi, T., Kubota, N., et al. (2021) · Diabetes · doi:10.2337/db20-0482 · Cited by 12
Characterizing skeletal muscle dysfunction in women with polycystic ovary syndrome
McDonnell, T., Cussen, L., McIlroy, M., & O’Reilly, M. (2022) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188221113140 · Cited by 15
Understanding Insulin Actions Beyond Glycemic Control: A Narrative Review
Riachi, R., Khalife, E., Kędzia, A. W., & Niechciał, E. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14145039 · Cited by 16
Sodium–glucose cotransporter 2 inhibitor, tofogliflozin, shows better improvements of blood glucose and insulin secretion in patients with high insulin levels at baseline
Tobe, K., Suganami, H., & Kaku, K. (2017) · Journal of Diabetes Investigation · doi:10.1111/jdi.12761 · Cited by 12
Treating Diabetes by Blocking a Vascular Growth Factor
Carmeliet, P., Wong, B. W., & Bock, K. D. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.10.015 · Cited by 12
Role of reduced insulin-stimulated bone blood flow in the pathogenesis of metabolic insulin resistance and diabetic bone fragility
Hinton, P. S. (2016) · Medical Hypotheses · doi:10.1016/j.mehy.2016.05.008 · Cited by 12
The relationship between insulin resistance and endothelial dysfunction in obese adolescents
Brar, P. C., Patel, P., & Katz, S. D. (2017) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2016-0404 · Cited by 12
“Insulin signaling in vascular endothelial cells is impaired in IR and this leads to ED [3].”
Background
Going Up Inflame: Reviewing the Underexplored Role of Inflammatory Programming in Stress-Induced Intrauterine Growth Restricted Livestock
Hicks, Z. M., & Yates, D. T. (2021) · Frontiers in Animal Science · doi:10.3389/fanim.2021.761421 · Cited by 17
“EPA infusion also improved whole hindlimb mass as well as loin and flexor digitorum superficialis muscle mass in the IUGR fetuses, which is indicative of improvedmuscle growth during late gestation (Lacey et al., 2021).”
Influential
Peroxisome Proliferator-Activated Receptor-Gamma Reduces ER Stress and Inflammation via Targeting NGBR Expression
Ma, J., Zeng, P., Liu, L., Zhu, M., Zheng, J., Wang, C., Zhao, X.-K., Hu, W., Yang, X., Duan, Y., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.817784 · Cited by 12
“A study has showed that skeletal muscle insulin resistance may be caused by impaired insulin signaling pathways in endothelial cells (Kubota et al., 2011).”
Background
Novel Link Between Inflammation, Endothelial Dysfunction, and Muscle Insulin Resistance
Mauvais‐Jarvis, F. (2013) · Diabetes · doi:10.2337/db12-1434 · Cited by 14
“In addition, mice with insulin resistance in the endothelium resulting from double IR substrates IRS1 and IRS-2 deficiencies had decreased insulin-stimulated glucose uptake in skeletal muscle (18).”
Background
Insulin Resistance: An Update on Biochemical and Pathophysiological Mechanisms and Impact on Various Diseases
Little, P. J., Offermanns, S., Cho, H., Liu, Z., Yang, P., Su, Q., Wade, H., Yang, W., Kamato, D., Cohen, N. D., et al. (2026) · iNew Medicine · doi:10.1002/inm3.70028 · Cited by 21
Identification of Potential Mechanisms of Rk1 Combination with Rg5 in the Treatment of Type II Diabetes Mellitus by Integrating Network Pharmacology and Experimental Validation
Liu, Y., Zhang, J., An, C., Liu, C., Zhang, Q., Ding, H., Ma, S., & Xue, W.-J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914828 · Cited by 11
“Among the main target tissues of insulin resistance, skeletal muscles are responsible for ingesting and metabolizing over 80% of glucose, making it an important tissue for regulating glucose homeostasis [31].”
A xanthene derivative, DS20060511, attenuates glucose intolerance by inducing skeletal muscle-specific GLUT4 translocation in mice
Furuzono, S., Kubota, T., Taura, J., Konishi, M., Naito, A., Tsutsui, M., Karasawa, H., Kubota, N., & Kadowaki, T. (2021) · Communications Biology · doi:10.1038/s42003-021-02491-6 · Cited by 11
Lower Maternal Body Condition During Pregnancy Affects Skeletal Muscle Structure and Glut-4 Protein Levels But Not Glucose Tolerance in Mature Adult Sheep
Costello, P. M., Hollis, L. J., Cripps, R. L., Bearpark, N., Patel, H. P., Sayer, A. A., Cooper, C. C., Hanson, M. A., Ozanne, S. E., & Green, L. (2013) · Reproductive Sciences · doi:10.1177/1933719113477494 · Cited by 14
“In mice, impaired insulin signaling in endothelial cells led to attenuated insulininduced capillary recruitment and insulin delivery, and reduced glucose uptake in skeletal muscle.(38) Our observation of decreased Akt1 (significant) and IGF-IR (trend only) levels in LBCS offspring vastus muscle are consistent with dec…”
Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo
Williams, I. M., McClatchey, P. M., Bracy, D. P., Valenzuela, F. A., & Wasserman, D. H. (2018) · Diabetes · doi:10.2337/db18-0288 · Cited by 12
“Furthermore, the ability of insulin to activate endothelial NOS (eNOS) in endothelial cells (ECs) is impaired in mouse models of obesity and insulin resistance (14).”
Background
Alpha lipoic acid protects against dexamethasone-induced metabolic abnormalities via APPL1 and PGC-1 α up regulation
Mohammed, M. A., Mahmoud, M. O., Awaad, A. S., Gamal, G. M., & Abdelfatah, D. (2019) · Steroids · doi:10.1016/j.steroids.2019.01.004 · Cited by 11
“the insulin and glucose supply to the muscles [41] through a production of endothelial nitric oxide (NO) results from the activation of the AMPK and Akt signaling pathways [42].”
Uncovering the role of prokineticin pathway on Epicardial Adipose Tissue (EAT) development and EAT-associated cardiomyopathy
Vincenzi, M., & Nebigil, C. G. (2025) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2025.02.006 · Cited by 11
Endothelium-Dependent Delivery of Insulin to Muscle Interstitium
Rask‐Madsen, C., & King, G. L. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.02.008 · Cited by 10
“In the study by Kubota et al. (2011), plasma glucose levels measured 30 min after glucose administration were approximately 180 mg/dl higher in high-fat-fed mice but only 40 mg/dl higher in ETIrs2KO mice, compared with controls.”
BackgroundResultInfluential
Ganglioside GM1 contributes to extracellular/intracellular regulation of insulin resistance, impairment of insulin signaling and down-stream eNOS activation, in human aortic endothelial cells after short- or long-term exposure to TNFα
Sasaki, N., Itakura, Y., & Toyoda, M. (2017) · Oncotarget · doi:10.18632/oncotarget.23726 · Cited by 10
“At the moment, beraprost sodium is available as a potential therapeutic for vascular insulin resistance that acts by upregulating eNOS levels, but therapeutic strategies still need further development [9].”
Background
Cyanidin‐3‐O‐Glucoside Supplementation Ameliorates Metabolic Insulin Resistance via Restoration of Nitric Oxide‐Mediated Endothelial Insulin Transport
Geng, X., Ji, J., Liu, Y., Li, X., Chen, Y., Su, L., & Zhao, L. (2021) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202100742 · Cited by 11
Angiogenesis
Warmke, N., Walker, A. M., & Cubbon, R. M. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809657-4.99736-9 · Cited by 10
Iloprost infusion prevents the insulin‐induced reduction in skeletal muscle microvascular blood volume but does not enhance peripheral glucose uptake in type 2 diabetic patients
Emanuel, A. L., de Clercq, N. C., Koopen, A. M., van Poelgeest, E. M., Serlie, M. J. M., van Raalte, D. H., Kramer, M. H. H., Nieuwdorp, M., Eringa, E. C., & Serné, E. H. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13410 · Cited by 10
“In addition, glucose uptake in isolated skeletal muscle from mice treated with beraprost remained unchanged.(6) This study reveals that, in patients with type 2 diabetes, insulin reduces skeletal muscle MBV.”
BackgroundInfluential
The transcriptional coregulator CITED2 suppresses expression of IRS-2 and impairs insulin signaling in endothelial cells
Kunkemoeller, B. H., Chen, K., Lockhart, S. M., Wang, X., & Rask‐Madsen, C. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00435.2020 · Cited by 9
Altered Transendothelial Transport of Hormones as a Contributor to Diabetes
Yoon, N., Dang, T. Q., Chasiotis, H., Kelly, S. P., & Sweeney, G. (2014) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2014.38.2.92 · Cited by 9
“Indeed, the efficiency and extent of insulin delivery to the interstitial space can be inhibited physiologically by diet [30].”
Background
Disruption of Insulin Receptor Signaling in Endothelial Cells Shows the Central Role of an Intact Islet Blood Flow for In Vivo β-Cell Function
Carlsson, P., & Jansson, L. E. (2015) · Diabetes · doi:10.2337/db14-1523 · Cited by 9
“Skeletal muscle endothelium deficiency of Irs2 has previously been shown to reduce Akt and endothelial nitric oxide synthase phosphorylation influencing nitric oxide production (12).”
Background
Habitual Hot-Tub Bathing and Cardiovascular Risk Factors in Patients With Type 2 Diabetes Mellitus: A Cross-Sectional Study
Katsuyama, H., Hakoshima, M., Adachi, H., Masui, Y., Sako, A., Inokuma, S., & Yanai, H. (2022) · Cardiology Research · doi:10.14740/cr1371 · Cited by 8
“The upregulation of HSP 70 enhances the phosphorylation of endothelial nitric oxide synthase (eNOS), which, in turn, elevates insulin signaling and glucose uptake by the skeletal muscle [27].”
Background
Microvascular insulin resistance with enhanced muscle glucose disposal in CD36 deficiency
Shibao, C. A., Peche, V. S., Pietka, T., Samovski, D., Williams, I. M., Abumrad, N. N., Gamazon, E. R., Goldberg, I. J., Wasserman, D. H., & Abumrad, N. A. (2024) · Diabetologia · doi:10.1007/s00125-024-06292-4 · Cited by 10
Metformin does not Enhance Insulin‐Stimulated Vasodilation in Skeletal Muscle Resistance Arteries of the OLETF Rat
Crissey, J. M., Padilla, J., Jenkins, N. T., Martin, J. S., Rector, R. S., Thyfault, J. P., & Laughlin, M. H. (2013) · Microcirculation · doi:10.1111/micc.12078 · Cited by 8
“In healthy individuals, insulin-mediated increases in skeletal muscle blood flow account for as much as 40–50% of total insulinstimulated glucose uptake in skeletal muscle [4,29,46].”
Background
Safety of artificial pancreas in hepato-biliary-pancreatic surgery: A prospective study
Hayashi, H., Tajima, H., Hanazaki, K., Takamura, H., Gabata, R., Okazaki, M., Ohbatake, Y., Nakanuma, S., Makino, I., Miyashita, T., et al. (2019) · Asian Journal of Surgery · doi:10.1016/j.asjsur.2019.03.011 · Cited by 8
Notable Underlying Mechanism for Pancreatic β-Cell Dysfunction and Atherosclerosis: Pleiotropic Roles of Incretin and Insulin Signaling
Kaneto, H., Obata, A., Kimura, T., Shimoda, M., Sanada, J., Fushimi, Y., Katakami, N., Matsuoka, T., & Kaku, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249444 · Cited by 8
Transendothelial movement of adiponectin is restricted by glucocorticoids
Dang, T. Q., Yoon, N., Chasiotis, H., Dunford, E. C., Feng, Q., He, P., Riddell, M. C., Kelly, S. P., & Sweeney, G. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0363 · Cited by 8
“Indeed, delivery of insulin to the interstitial space has been shown to be altered by diet (Kubota et al. 2011).”
Insulin Resistance and Endothelial Dysfunction: Macro and Microangiopathy
Arce‐Esquivel, A. A., Aaron, K. E., Catherine, R., & Laughli, M. H. (2013) · InTech eBooks · doi:10.5772/56475 · Cited by 9
Beraprost Sodium for Chronic Diabetic Foot Ulcer: A Randomized Controlled Trial in Thammasat University Hospital
Awsakulsutthi, S., Punpho, K., Mamom, J., Baikrut, P., & Yingchoorod, P. (2014) · Annals of Vascular Diseases · doi:10.3400/avd.oa.13-00092 · Cited by 7

Authors: Kubota, T., Kubota, N., Kumagai, H., Yamaguchi, S., Kozono, H., Takahashi, T., Inoue, M., Itoh, S., Takamoto, I., Sasako, T., Kumagai, K., Kawai, T., Hashimoto, S., Kobayashi, T., Sato, M., Tokuyama, K., Nishimura, S., Tsunoda, M., Ide, T., Murakami, K., Yamazaki, T., Ezaki, O., Kawamura, K., Masuda, H., Moroi, M., Sugi, K., Oike, Y., Shimokawa, H., Yanagihara, N., Tsutsui, M., Terauchi, Y., Tobe, K., Nagai, R., Kamata, K., Inoue, K., Kodama, T., Ueki, K., & Kadowaki, T.
Affiliations: Toho University Ohashi Medical Center (JP)
National Institute of Health and Nutrition (JP)
The University of Tokyo (JP)
Hosei University (JP)
University of Tsukuba (JP)
Akita University (JP)
Kumamoto University (JP)
Tohoku University (JP)
University of Occupational and Environmental Health Japan (JP)
University of the Ryukyus (JP)
Yokohama City University (JP)
University of Toyama (JP)
Research Center for Advanced Science and Technology, The University of Tokyo (JP)
Corresponding author: Kubota, Naoto
Kadowaki, Takashi
ORCID: Kubota, Tetsuya
Kubota, Naoto
Takahashi, Takehiro
Inoue, Mariko
Itoh, Shinsuke
Sasako, Takayoshi
Kumagai, Katsuyoshi
Kawai, Tomoko
Kobayashi, Tsuneo
Sato, Maki
Tokuyama, Kumpei
Nishimura, Satoshi
Murakami, Koji
Yamazaki, Tomomi
Ezaki, Osamu
Masuda, Hirotake
Moroi, Masao
Oike, Yuichi
Shimokawa, Hiroaki
Tsutsui, Masato
Terauchi, Yasuo
Tobe, Kazuyuki
Nagai, Ryozo
Inoue, Kenji
Kodama, Tatsuhiko
Ueki, Kohjiro
Kadowaki, Takashi
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2011-03
Volume: 13
Issue: 3
Pages: 294-307
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2011.01.018
OpenAlex: W1978030502
Cited by: 435
References: 33
Citations by year: 2026: 16 · 2025: 25 · 2024: 11 · 2023: 19 · 2022: 30 · 2021: 29 · 2020: 23 · 2019: 31 · 2018: 26 · 2017: 34 · 2016: 28 · 2015: 40 · 2014: 33 · 2013: 47 · 2012: 30
FWCI: 15.96
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 905 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
Funders: Japan Science and Technology Corporation
Ministry of Education, Culture, Sports, Science and Technology (16209030, 18209033, 19591037, 20229008, 21390279)
Core Research for Evolutional Science and Technology
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: insulin receptor substrate 2, eNOS phosphorylation, skeletal muscle glucose uptake, insulin delivery, capillary recruitment, endothelial dysfunction, type 2 diabetes, obesity, skeletal muscle insulin resistance, high-fat diet, endothelial-specific knockout mice
MeSH terms: Animals, Dietary Fats, Glucose, Insulin, Mice, Obese, Phosphorylation, Signal Transduction, Mice, Knockout, Muscle, Skeletal, Endothelial Cells, Mice, Nitric Oxide Synthase Type III, Insulin Receptor Substrate Proteins

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Impaired Insulin Signaling in Endothelial Cells Reduces Insulin-Induced Glucose Uptake by Skeletal Muscle

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