The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
Impaired Insulin Signaling in Endothelial Cells Reduces Insulin-Induced Glucose Uptake by Skeletal Muscle
Open accessAbstract
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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“Restoration of NOS3 phosphorylation in endothelial-specific insulin receptor substrate 2 (IRS-2) knockout mice using beraprost (a stable prostaglandin analog) was sufficient to rescue capillary recruitment and to promote adequate insulin and glucose delivery to skeletal muscle [179].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [179]
In the citing paper
“the gradient in insulin concentration from plasma to interstitial fluid is increased in humans with prediabetes and in mouse models of prediabetes during an insulin clamp,152-154 suggesting impaired microvascular insulin delivery.”
From The Vasculature in Prediabetes (2018) · cites this paper as [153]
Citations
Cites
Glucose clamp technique: a method for quantifying insulin secretion and resistance.
DeFronzo, R. A., Tobin, J. D., & Andres, R. (1979) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1979.237.3.e214 · Cited by 7,425
Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes
Petersen, K. F., Dufour, S., Befroy, D., Garcia, R., & Shulman, G. I. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa031314 · Cited by 2,193
Phenotypic Heterogeneity of the Endothelium
Aird, W. C. (2007) · Circulation Research · doi:10.1161/01.res.0000255691.76142.4a · Cited by 1,824
White, M. F., & Kahn, C. R. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42297-6 · Cited by 1,707
Tie2-Cre Transgenic Mice: A New Model for Endothelial Cell-Lineage Analysis in Vivo
Kisanuki, Y. Y., Hammer, R. E., Miyazaki, J.-I., Williams, S. C., Richardson, J. A., & Yanagisawa, M. (2001) · Developmental Biology · doi:10.1006/dbio.2000.0106 · Cited by 1,241
Brüning, J. C., Michael, M. D., Winnay, J. N., Hayashi, T., Hörsch, D., Accili, D., Goodyear, L. J., & Kahn, C. R. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80155-0 · Cited by 1,183
Toward Physiological Understanding of Glucose Tolerance: Minimal-Model Approach
Bergman, R. N. (1989) · Diabetes · doi:10.2337/diab.38.12.1512 · Cited by 1,001
Jiang, Z. Y., Lin, Y.-W., Clemont, A., Feener, E. P., Hein, K. D., Igarashi, M., Yamauchi, T., White, M. F., & King, G. L. (1999) · Journal of Clinical Investigation · doi:10.1172/jci5971 · Cited by 604
A model of the kinetics of insulin in man
Sherwin, R. S., Kramer, K. J., Tobin, J. D., Insel, P. A., Liljenquist, J. E., Berman, M., & Andres, R. (1974) · Journal of Clinical Investigation · doi:10.1172/jci107697 · Cited by 460 · cited 5×
“Recent evidence indicates that insulin delivery to the skeletal muscle interstitium is the ratelimiting step in insulin-stimulated glucose uptake by the skeletal muscle, and is much slower in obese insulin-resistant subjects than in normal subjects (Sherwin et al., 1974; DeFronzo et al., 1979; Yang et al., 1989; Janss…”
BackgroundInfluentialKarnieli, E., Zarnowski, M. J., Hissin, P. J., Simpson, I. A., Salans, L. B., & Cushman, S. W. (1981) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)69319-1 · Cited by 456
Keske, M. A., Clerk, L. H., Lindner, J. R., Klibanov, A. L., Clark, M. G., Rattigan, S., & Barrett, E. J. (2004) · Diabetes · doi:10.2337/diabetes.53.6.1418 · Cited by 439
The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance
Vicent, D., Ilany, J., Kondo, T., Naruse, K., Fisher, S. J., Kisanuki, Y. Y., Bursell, S. E., Yanagisawa, M., King, G. L., & Kahn, C. R. (2003) · Journal of Clinical Investigation · doi:10.1172/jci15211 · Cited by 354
Barrett, E. J., Eggleston, E. M., Inyard, A. C., Wang, H., Li, G., Chai, W., & Liu, Z. (2009) · Diabetologia · doi:10.1007/s00125-009-1313-z · Cited by 323
Insulin transport across capillaries is rate limiting for insulin action in dogs.
Yang, Y. J., Hope, I. D., Ader, M., & Bergman, R. N. (1989) · Journal of Clinical Investigation · doi:10.1172/jci114339 · Cited by 303
Kubota, N., Kubota, T., Itoh, S., Kumagai, H., Kozono, H., Takamoto, I., Mineyama, T., Ogata, H., Tokuyama, K., Ohsugi, M., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.05.007 · Cited by 244
Self-citationHemodynamic Actions of Insulin in Rat Skeletal Muscle: Evidence for Capillary Recruitment
Rattigan, S., Clark, M. G., & Barrett, E. J. (1997) · Diabetes · doi:10.2337/diab.46.9.1381 · Cited by 242
Clark, M. G. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90477.2008 · Cited by 195
Insulin action and insulin resistance in vascular endothelium
Muniyappa, R., & Quon, M. J. (2007) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e32819f8ecd · Cited by 174
Insulin-Mediated Hemodynamic Changes Are Impaired in Muscle of Zucker Obese Rats
Wallis, M. G., Wheatley, C. M., Rattigan, S., Barrett, E. J., Clark, A. D. H., & Clark, M. G. (2002) · Diabetes · doi:10.2337/diabetes.51.12.3492 · Cited by 164
Obesity Blunts Microvascular Recruitment in Human Forearm Muscle After a Mixed Meal
Keske, M. A., Clerk, L. H., Price, W. J., Jahn, L. A., & Barrett, E. J. (2009) · Diabetes Care · doi:10.2337/dc09-0206 · Cited by 133
Jansson, P., Fowelin, J., von Schenck, H., Smith, U., & Lönnroth, P. (1993) · Diabetes · doi:10.2337/diab.42.10.1469 · Cited by 129
Kubota, T., Kubota, N., Moroi, M., Terauchi, Y., Kobayashi, T., Kamata, K., Suzuki, R., Tobe, K., Namiki, A., Aizawa, S., et al. (2003) · Circulation · doi:10.1161/01.cir.0000070937.52035.25 · Cited by 116
Delayed Transcapillary Transport of Insulin to Muscle Interstitial Fluid in Obese Subjects
Sjöstrand, M., Gudbjörnsdottir, S., Holmäng, A., Lönn, L., Strindberg, L., & Lönnroth, P. (2002) · Diabetes · doi:10.2337/diabetes.51.9.2742 · Cited by 114
Insulin Signaling Stimulates Insulin Transport by Bovine Aortic Endothelial Cells
Wang, H., Wang, A. X., Liu, Z., & Barrett, E. J. (2007) · Diabetes · doi:10.2337/db07-0967 · Cited by 103
Kinetics of Insulin Action In Vivo: Identification of Rate-Limiting Steps
Miles, P. D. G., Levisetti, M. G., Reichart, D. R., Khoursheed, M., Moossa, A. R., & Olefsky, J. M. (1995) · Diabetes · doi:10.2337/diab.44.8.947 · Cited by 101
Chiu, J. D., Richey, J. M., Harrison, L. N., Zuniga, E. A., Kolka, C. M., Kirkman, E. L., Ellmerer, M., & Bergman, R. N. (2008) · Diabetes · doi:10.2337/db07-1444 · Cited by 96
Niwano, K., Arai, M., Tomaru, K., Uchiyama, T., Ohyama, Y., & Kurabayashi, M. (2003) · Circulation Research · doi:10.1161/01.res.0000091336.55487.f7 · Cited by 84
ACTIVE ROLE FOR THE VASCULATURE IN THE DELIVERY OF INSULIN TO SKELETAL MUSCLE
Keske, M. A., Clerk, L. H., Rattigan, S., Clark, M. G., & Barrett, E. J. (2005) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2005.04188.x · Cited by 71
Mechanisms of the Kinetic Defect in Insulin Action in Obesity and NIDDM
Nolan, J. J., Ludvik, B. H., Baloga, J., Reichart, D. R., & Olefsky, J. M. (1997) · Diabetes · doi:10.2337/diab.46.6.994 · Cited by 60
Reduced Access to Insulin-Sensitive Tissues in Dogs With Obesity Secondary to Increased Fat Intake
Ellmerer, M., Hamilton-Wessler, M., Kim, S. P., Hücking, K., Kirkman, E. L., Chiu, J. D., Richey, J. M., & Bergman, R. N. (2006) · Diabetes · doi:10.2337/db05-1509 · Cited by 48
Mode of Transcapillary Transport of Insulin and Insulin Analog NN304 in Dog Hindlimb
Hamilton-Wessler, M., Ader, M., Dea, M. K., Moore, D., Loftager, M., Markussen, J., & Bergman, R. N. (2002) · Diabetes · doi:10.2337/diabetes.51.3.574 · Cited by 48
Influence of AMP-activated protein kinase and calcineurin on metabolic networks in skeletal muscle
Long, Y. C., & Zierath, J. R. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90259.2008 · Cited by 41
Kainoh, M., Maruyama, I., Nishio, S., & Nakadate, T. (1991) · Biochemical Pharmacology · doi:10.1016/0006-2952(91)90651-k · Cited by 40
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Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I
Paneni, F., Beckman, J. A., Creager, M. A., & Cosentino, F. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht149 · Cited by 1,455
Biochemical and cellular properties of insulin receptor signalling
Haeusler, R. A., McGraw, T. E., & Accili, D. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.89 · Cited by 739
Guo, S. (2013) · Journal of Endocrinology · doi:10.1530/joe-13-0327 · Cited by 648
“…levels Alb-cre Guo et al. (1999, 2006, 2009) Liver Irs1K/KTIrs2K/K Hyperglycemia; insulin resistance Alb-cre Guo et al. (1999, 2006, 2009) and Kubota et al. (2008, 2011) Liver Foxo1K/K Reduced blood glucose levels Alb-cre Zhang et al. (2012) Liver Foxo3K/K Normal glucose levels Alb-cre Zhang…”
BackgroundInfluentialEelen, G., de Zeeuw, P., Treps, L., Harjes, U., Wong, B. W., & Carmeliet, P. (2017) · Physiological Reviews · doi:10.1152/physrev.00001.2017 · Cited by 614
What causes the insulin resistance underlying obesity?
Hardy, O. T., Czech, M. P., & Corvera, S. (2012) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e3283514e13 · Cited by 563
Metadata
- 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)
- 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
- 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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