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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]
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Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature
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“Moreover, muscle glucose uptake has also been strongly related to the endothelial insulin sensitivity.(48) ECs are thus critical in muscle adaptation to exercise training, with a pivotal role in muscle angiogenesis.”
BackgroundHorton, W. B., Love, K. M., Gregory, J. M., Liu, Z., & Barrett, E. J. (2025) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00826.2024 · Cited by 95
Pillon, N. J., Azizi, P., Li, Y. E., Liu, J., Wang, C., Chan, K. L., Hopperton, K. E., Bazinet, R. P., Heit, B., Bilan, P. J., et al. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00611.2014 · Cited by 81
Bedinger, D., & Adams, S. H. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.08.013 · Cited by 85
Kubota, T., Inoue, M., Kubota, N., Takamoto, I., Mineyama, T., Iwayama, K., Tokuyama, K., Moroi, M., Ueki, K., Yamauchi, T., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07358-9 · Cited by 80
Endothelial Fatty Acid Transport: Role of Vascular Endothelial Growth Factor B
Hagberg, C. E., Mehlem, A., Falkevall, A., Muhl, L., & Eriksson, U. (2013) · Physiology · doi:10.1152/physiol.00042.2012 · Cited by 81
Meijer, R. I., de Boer, M. P., Groen, M. R., Eringa, E. C., Rattigan, S., Barrett, E. J., Smulders, Y. M., & Serné, E. H. (2012) · Microcirculation · doi:10.1111/j.1549-8719.2012.00174.x · Cited by 79
“It has been proposed that insulin promotes its own access to muscle interstitium by effects on the microcirculation [2,4,14,19].”
BackgroundHesketh, K. L., Shepherd, S. O., Strauss, J. A., Low, D. A., Cooper, R. J., Wagenmakers, A. J. M., & Cocks, M. S. (2019) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00816.2018 · Cited by 77
“(38) demonstrated the importance of increasing eNOS content through administration of bera-prost sodium, a prostaglandin I2 analogue that increases eNOS mRNA expression and protein synthesis.”
BackgroundLoss of Endothelial FTO Antagonizes Obesity-Induced Metabolic and Vascular Dysfunction
Krüger, N., Biwer, L. A., Good, M. E., Ruddiman, C. A., Wolpe, A. G., DeLalio, L. J., Murphy, S. A., Macal, E. H., Ragolia, L., Serbulea, V., et al. (2019) · Circulation Research · doi:10.1161/circresaha.119.315531 · Cited by 77
Role of oxidative stress in endothelial insulin resistance
Paneni, F. (2015) · World Journal of Diabetes · doi:10.4239/wjd.v6.i2.326 · Cited by 76
Endothelial cell metabolism in cardiovascular physiology and disease
Pasut, A., Lama, E., Van Craenenbroeck, A. H., Kroon, J., & Carmeliet, P. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-025-01162-x · Cited by 74
“In the peripheral circulation, EC-specific ( Tie2 -Cre) deletion of Irs2 leads to reduced capillary recruitment (caused by decreased eNOS phosphorylation), decreased glucose uptake by skeletal muscle and peripheral insulin resistance 36 (Fig.”
Muscle microvascular blood flow responses in insulin resistance and ageing
Keske, M. A., Premilovac, D., Bradley, E. A., Dwyer, R. M., Richards, S. M., & Rattigan, S. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.283549 · Cited by 80
Chai, W., Zhang, X., Barrett, E. J., & Liu, Z. (2014) · Diabetes · doi:10.2337/db13-1597 · Cited by 73
“Recent evidence has confirmed a pivotal role of muscle microvasculature in the determination of muscle insulin action, as it provides the endothelial exchange surface area and changes in muscle microvascular perfusion profoundly affect insulin delivery to and action in muscle (5,6).”
BackgroundKaneto, H., Kimura, T., Obata, A., Shimoda, M., & Kaku, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052596 · Cited by 77
Jokura, H., Watanabe, I., Umeda, M., Hase, T., & Shimotoyodome, A. (2015) · Nutrition Research · doi:10.1016/j.nutres.2015.07.005 · Cited by 73
Recent Advances of m6A Demethylases Inhibitors and Their Biological Functions in Human Diseases
You, Y.-Z., Fu, Y.-D., Huang, M.-J., Shen, D., Zhao, B., Liu, H., Zheng, Y., & Huang, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105815 · Cited by 71
“In parallel to previous reports, obesity decreased AKT phosphorylation in endothelial cells, impairing glucose and insulin tolerance [33].”
ResultMitochondrial involvement in skeletal muscle insulin resistance: A case of imbalanced bioenergetics
Affourtit, C. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.07.008 · Cited by 67
State of the science on brain insulin resistance and cognitive decline due to Alzheimer's disease
Rhea, E. M., Leclerc, M., Yassine, H. N., Capuano, A. W., Tong, H., Petyuk, V. A., Macauley, S. L., Fioramonti, X., Carmichael, O., Calon, F., et al. (2023) · Aging and disease · doi:10.14336/ad.2023.0814 · Cited by 70
Dutta, T., Chai, H. S., Ward, L. E., Ghosh, A. K., Persson, X.-M. T., Ford, G. C., Kudva, Y. C., Sun, Z., Asmann, Y. W., Kocher, J., et al. (2012) · Diabetes · doi:10.2337/db11-0874 · Cited by 70
“Since skeletal muscle is a key target organ of insulin action (4,20,21), we sought to determine whether pathways based on the skeletal muscle transcriptome have any concordance with those of plasma metabolites in T1D during insulin deficiency.”
BackgroundLastra, G., & Manrique, C. M. (2015) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2015-0010 · Cited by 70
Endothelial Glycocalyx Hyaluronan
Wang, G., Tiemeier, G. L., van den Berg, B. M., & Rabelink, T. J. (2020) · American Journal Of Pathology · doi:10.1016/j.ajpath.2019.07.022 · Cited by 67
Novel Role of the IGF-1 Receptor in Endothelial Function and Repair
Imrie, H., Viswambharan, H., Sukumar, P., Abbas, A., Cubbon, R. M., Yuldasheva, N. Y., Gage, M., Smith, J., Galloway, S. L., Skromna, A., et al. (2012) · Diabetes · doi:10.2337/db11-1494 · Cited by 68
“In contrast to a recent report (31), the endothelial cell insulin resistance demonstrated in the present report had no effect on whole-body glucose uptake.”
ResultShort-term high glucose exposure impairs insulin signaling in endothelial cells
Nigris, V. D., Pujadas, G., Sala, L. L., Testa, R., Genovese, S., & Ceriello, A. (2015) · Cardiovascular Diabetology · doi:10.1186/s12933-015-0278-0 · Cited by 68
“[12] demonstrated that the expression levels of insulin-stimulated phosphorylations of AKT and eNOS were decreased by 70–80 % in endothelial cells extracted from the abdominal aorta of 8-week high-fat diet-fed mice and ob/ob mice, treated with an insulin concentration of 100 nmol/L for 30 min, indicating that insulin…”
MethodJahn, L. A., Hartline, L. M., Rao, N., Logan, B. R., Kim, J. J., Aylor, K. W., Gan, L., Westergren, H. U., & Barrett, E. J. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3293 · Cited by 73
“Recent rodent studies have demonstrated that introducing oxidative stress specifically in vascular smooth muscle cells (33) or interfering with insulin signaling specifically in vascular endothelial cells (34) induces wholebody metabolic insulin resistance.”
BackgroundNocturnin: at the crossroads of clocks and metabolism
Stubblefield, J. J., Terrien, J., & Green, C. B. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.03.007 · Cited by 67
“Kubota and colleagues found that impairment of insulin signaling in endothelial cells is associated with reduced glucose uptake in skeletal muscle of mice [44].”
BackgroundCardiovascular impact of drugs used in the treatment of diabetes
Triggle, C. R., & Ding, H. (2014) · Therapeutic Advances in Chronic Disease · doi:10.1177/2040622314546125 · Cited by 67
Sathanoori, R., Swärd, K., Olde, B., & Erlinge, D. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125111 · Cited by 66
“It is known that elevated production of free fatty acids can enhance vascular insulin resistance by inhibiting insulin signaling [24 – 26].”
The Barrier Within: Endothelial Transport of Hormones
Kolka, C. M., & Bergman, R. N. (2012) · Physiology · doi:10.1152/physiol.00012.2012 · Cited by 66
“The insulin receptors present on endothelial cells have been shown to be involved in the uptake of insulin (98), and more recent studies have shown that a knockout mouse model of endothelial IRS-2 is insulin resistant, and impaired insulin signaling in endothelial cells reduces insulin-mediated glucose uptake as well…”
Wang, Y., Cheng, K. K. Y., Lam, K. S. L., Wu, D., Wang, Y., Huang, Y., Vanhoutte, P. M., Sweeney, G., Li, Y., & Xu, A. (2011) · Diabetes · doi:10.2337/db11-0666 · Cited by 64
“The existence of the vicious cycle between insulin resistance and endothelial dysfunction in the development of diabetes and cardiovascular disease has been documented in both animal studies (8) and clinical investigations (1,9).”
BackgroundNovel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists
Mabilleau, G., Pereira, M., & Chenu, C. (2017) · Journal of Endocrinology · doi:10.1530/joe-17-0278 · Cited by 66
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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