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 IRS-2 knockout mice using beraprost rescues capillary recruitment and promotes adequate insulin and glucose delivery to skeletal muscle.
“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]
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, suggesting impaired microvascular insulin delivery.
“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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“This is mediated by the involvement of endothelial cells, which regulate the capillary recruitment and glucose uptake((30)).”
Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system
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“Insulin actions in vascular cells are mediated through the phosphoinositide 3-kinase (PI3K)/insulin receptor substrate (IRS)-1/Akt pathway on the one hand, which stimulates the production of vascular dilator NO, and the mitogenic Shc/Ras/MEK pathway on the other hand, leading to the generation of the vasoconstrictor e…”
BackgroundPostprandial hyperglycemia and postprandial hypertriglyceridemia in type 2 diabetes
Hiyoshi, T., Fujiwara, M., & Zemin, Y. (2018) · Journal of Biomedical Research · doi:10.7555/jbr.31.20160164 · Cited by 110 · see citing works
“[43] Kubota T, Kubota N, Kumagai H, et al.”
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“Insulin receptor substrate 2 (IRS-2) also plays an important role in transducing IR activation to eNOS [30].”
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“In the periphery, insulin signaling in endothelial cells plays a pivotal role in glucose uptake and vasodilation within muscle, which can be negatively impacted by insulin resistance (Kubota et al., 2011; Steinberg et al., 1996).”
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“Moreover, in genetic- and diet-induced models of muscle insulin resistance, the physiological actions of insulin to increase muscle microvascular recruitment and nutrient blood flow are impaired, resulting in an abatement in insulin and glucose delivery to the myocyte (4,6,16,43,44).”
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“Mice with IRS2 deletion in their endothelial cells (ETIRS2KO mice) are also insulin resistant, with reductions in insulin-induced eNOS phosphorylation and capillary recruitment and impaired glucose uptake by skeletal muscle [50].”
BackgroundGraded Maximal Exercise Testing to Assess Mouse Cardio-Metabolic Phenotypes
Petrosino, J. M., Silfee, V., Maurya, S. K., Kalyanasundaram, A., Periasamy, M., LaFountain, R. A., Wilson, J. M., Simonetti, O. P., & Ziouzenkova, O. (2016) · PLoS ONE · doi:10.1371/journal.pone.0148010 · Cited by 103 · see citing works
“Additionally, the WT-obese mouse model phenocopies the insulin resistant state, and subsequent impaired delivery of nutrients to skeletal muscles [21], that is seen in obese individuals during exercise testing [22].”
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“insulin resistance, which has been suggested to impair skeletal muscle interstitial insulin levels and promote insulin resistance (111).”
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Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism
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The Role of PPARγ in Cardiovascular Diseases
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GIANT 2.0: genome-scale integrated analysis of gene networks in tissues
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“From impaired insulin signaling in diabetes (1,2) to neuronal loss in Parkinson’s disease (3–5), understanding tissue- and cell-lineage specific processes is necessary in elucidating disease pathophysiology and diseasegene relationships.”
BackgroundEndothelial Cell Glucose Metabolism and Angiogenesis
Du, W., Ren, L., Hamblin, M. H., & Fan, Y. (2021) · Biomedicines · doi:10.3390/biomedicines9020147 · Cited by 91 · see citing works
The endothelial cell: An “early responder” in the development of insulin resistance
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“This includes tyrosine phosphorylation of insulin receptor substrate (IRS) proteins [10, 35, 36] with subsequent signaling through PI3-kinase and activation of Akt and eNOS.”
Muris, D. M. J., Houben, A. J. H. M., Schram, M. T., & Stehouwer, C. D. A. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-012-9231-7 · Cited by 86 · see citing works
“cluding the insulin receptor, insulin receptor substrate 1 (IRS-1), insulin receptor substrate 2 (IRS-2) [56],”
InfluentialSialic acid metabolism as a potential therapeutic target of atherosclerosis
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Endothelial Cells: New Players in Obesity and Related Metabolic Disorders
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Endothelial cell–cardiomyocyte crosstalk in diabetic cardiomyopathy
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Cellular interplay in skeletal muscle regeneration and wasting: insights from animal models
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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 83 · see citing works
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Endothelial Fatty Acid Transport: Role of Vascular Endothelial Growth Factor B
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“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 · see citing works
“(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 · see citing works
Role of oxidative stress in endothelial insulin resistance
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Muscle microvascular blood flow responses in insulin resistance and ageing
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“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 73 · see citing works
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Recent Advances of m6A Demethylases Inhibitors and Their Biological Functions in Human Diseases
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“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 · see citing works
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 · see citing works
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 69 · see citing works
“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.”
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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 · see citing works
“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.”
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 68 · see citing works
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 · see citing works
“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 · see citing works
“[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 68 · see citing works
“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 · see citing works
“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 66 · see citing works
Sathanoori, R., Swärd, K., Olde, B., & Erlinge, D. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125111 · Cited by 66 · see citing works
“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 · see citing works
“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 · see citing works
“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 64 · see citing works
- 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 › Epidemiology › 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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