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]
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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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