Contrasting Effects of IRS-1 Versus IRS-2 Gene Disruption on Carbohydrate and Lipid Metabolism in Vivo
Open accessAbstract
To examine the impact of homozygous genetic disruption of insulin receptor substrate (IRS)-1 (IRS-1(-/-)) or IRS-2 (IRS-2(-/-)) on basal and insulin-stimulated carbohydrate and lipid metabolism in vivo, we infused 18-h fasted mice (wild-type (WT), IRS-1(-/-), and IRS-2(-/-)) with [3-(3)H]glucose and [(2)H(5)]glycerol and assessed rates of glucose and glycerol turnover under basal (0-90 min) and hyperinsulinemic-euglycemic clamp (90-210 min; 5 mm glucose, and 5 milliunits of insulin.kg(-)(1).min(-)(1)) conditions. Both IRS-1(-)(/-) and IRS-2(-)(/-) mice were insulin-resistant as reflected by markedly impaired insulin-stimulated whole-body glucose utilization compared with WT mice. Insulin resistance in the IRS-1(-)(/-) mice could be ascribed mainly to decreased insulin-stimulated peripheral glucose metabolism. In contrast, IRS-2(-)(/-) mice displayed multiple defects in insulin-mediated carbohydrate metabolism as reflected by (i) decreased peripheral glucose utilization, (ii) decreased suppression of endogenous glucose production, and (iii) decreased hepatic glycogen synthesis. Additionally, IRS-2(-)(/-) mice also showed marked insulin resistance in adipose tissue as reflected by reduced suppression of plasma free fatty acid concentrations and glycerol turnover during the hyperinsulinemic-euglycemic clamp. These data suggest important tissue-specific roles for IRS-1 and IRS-2 in mediating the effect of insulin on carbohydrate and lipid metabolism in vivo in mice. IRS-1 appears to have its major role in muscle, whereas IRS-2 appears to impact on liver, muscle, and adipose tissue.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the liver, insulin activates the insulin receptor kinase, which phosphorylates IRS1 and IRS2, leading to activation of PI3K and ultimately Akt2; Akt2 activation promotes glycogen synthesis and inhibits gluconeogenesis.
“In the liver, insulin activates the insulin receptor kinase, which phosphorylates IRS1 and IRS2, leading to activation of PI3K and ultimately Akt2 (figure 2).83 At this point, Akt2 activation promotes glycogen synthesis and inhibits gluconeogenesis.”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [83]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Disruption of IRS-2 causes type 2 diabetes in mice
Withers, D., Gutiérrez, J., Towery, H., Burks, D., Ren, J.-M., Previs, S., Zhang, Y., Bernal, D., Pons, S., Shulman, G., et al. (1998) · Nature · doi:10.1038/36116 · Cited by 1,850 · see citing works
Self-citationWhite, M. F., & Kahn, C. R. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42297-6 · Cited by 1,723 · see citing works
Self-citationStructure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein
Sun, X. J., Rothenberg, P., Kahn, C. R., Backer, J. M., Araki, E., Wilden, P. A., Cahill, D. A., Goldstein, B. J., & White, M. F. (1991) · Nature · doi:10.1038/352073a0 · Cited by 1,574 · see citing works
Self-citationGriffin, M. E., Marcucci, M. J., Cline, G. W., Bell, K., Barucci, N., Lee, D., Goodyear, L. J., Kraegen, E. W., White, M. F., & Shulman, G. I. (1999) · Diabetes · doi:10.2337/diabetes.48.6.1270 · Cited by 1,267 · see citing works
Self-citationAlternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene
Araki, E., Lipes, M. A., Patti, M.-E., Brüning, J. C., Haag III, B., Johnson, R. S., & Kahn, C. R. (1994) · Nature · doi:10.1038/372186a0 · Cited by 1,252 · see citing works
Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1
Tamemoto, H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., Hayakawa, T., Terauchi, Y., Ueki, K., Kaburagi, Y., Satoh, S., et al. (1994) · Nature · doi:10.1038/372182a0 · Cited by 1,082 · see citing works
Role of IRS-2 in insulin and cytokine signalling
Sun, X. J., Wang, L.-M., Zhang, Y., Yenush, L., Myers, M. G., Glasheen, E. M., Lane, W. S., Pierce, J. H., & White, M. F. (1995) · Nature · doi:10.1038/377173a0 · Cited by 847 · see citing works
Self-citation(1997) · Diabetes reviews · Cited by 671 · see citing works
What if Minkowski Had Been Ageusic? An Alternative Angle on Diabetes
McGarry, J. D. (1992) · Science · doi:10.1126/science.1439783 · Cited by 657 · see citing works
Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling
Withers, D. J., Burks, D. J., Towery, H. H., Altamuro, S. L., Flint, C. L., & White, M. F. (1999) · Nature Genetics · doi:10.1038/12631 · Cited by 530 · see citing works
Self-citationTissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2
Kido, Y., Burks, D. J., Withers, D. J., Brüning, J. C., Kahn, C. R., White, M. F., & Accili, D. (2000) · Journal of Clinical Investigation · doi:10.1172/jci7917 · Cited by 491 · see citing works
Self-citationMechanism of Insulin Resistance in A-ZIP/F-1 Fatless Mice
Kim, J. K., Gavrilova, O., Chen, Y., Reitman, M. L., & Shulman, G. I. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8456 · Cited by 443 · see citing works
Self-citationType 2 Diabetes: When Insulin Secretion Fails to Compensate for Insulin Resistance
Kahn, B. B. (1998) · Cell · doi:10.1016/s0092-8674(00)81125-3 · Cited by 426 · see citing works
EFFECT OF EPINEPHRINE ON RAT DIAPHRAGM
Walaas, O., & Walaas, E. (1950) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)56223-2 · Cited by 410 · see citing works
Lavan, B. E., Fantin, V. R., Chang, E. T., Lane, W. S., Keller, S. R., & Lienhard, G. E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.34.21403 · Cited by 381 · see citing works
The IRS-Signaling System: A Network of Docking Proteins That Mediate Insulin and Cytokine Action
White, M. F., & Yenush, L. (1998) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-80481-6_8 · Cited by 360 · see citing works
Self-citationLavan, B. E., Lane, W. S., & Lienhard, G. E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.17.11439 · Cited by 353 · see citing works
Yamauchi, T., Tobe, K., Tamemoto, H., Ueki, K., Kaburagi, Y., Yamamoto‐Honda, R., Takahashi, Y., Yoshizawa, F., Aizawa, S., Yasuo, A., et al. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.6.3074 · Cited by 288 · see citing works
Insulin Receptor Substrate 3 Is Not Essential for Growth or Glucose Homeostasis
Liu, S. C. H., Wang, Q., Lienhard, G. E., & Keller, S. R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.25.18093 · Cited by 189 · see citing works
Evidence That IRS-2 Phosphorylation Is Required for Insulin Action in Hepatocytes
Rother, K. I., Imai, Y., Caruso, M., Bèguinot, F., Formisano, P., & Accili, D. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.28.17491 · Cited by 167 · see citing works
Higaki, Y., Wojtaszewski, J. F. P., Hirshman, M. F., Withers, D. J., Towery, H. H., White, M. F., & Goodyear, L. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.30.20791 · Cited by 104 · see citing works
Self-citationNew concepts in extracellular signaling for insulin action: the single gateway hypothesis.
Bergman, R. N. (1997) · PubMed · Cited by 101 · see citing works
Dose-response relationship of insulin to glucose fluxes in the awake and unrestrained mouse
Shen, H.-Q., Zhu, J. S., & Baron, A. (1999) · Metabolism · doi:10.1016/s0026-0495(99)90191-9 · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028 · see citing works
Self-citationLipid-induced insulin resistance: unravelling the mechanism
Samuel, V. T., Petersen, K. F., & Shulman, G. I. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60408-4 · Cited by 1,189 · see citing works
Self-citationEtiology of Insulin Resistance
Petersen, K. F., & Shulman, G. I. (2006) · The American Journal of Medicine · doi:10.1016/j.amjmed.2006.01.009 · Cited by 825 · see citing works
Self-citationTissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Kim, J. K., Fillmore, J. J., Chen, Y., Yu, C., Moore, I. K., Pypaert, M., Lutz, E. P., Kako, Y., Velez-Carrasco, W., Goldberg, I. J., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.121164498 · Cited by 753 · see citing works
Self-citationThe GH/IGF-1 axis in ageing and longevity
Junnila, R. K., List, E. O., Berryman, D. E., Murrey, J. W., & Kopchick, J. J. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.67 · Cited by 574 · see citing works
Differential Effects of Interleukin-6 and -10 on Skeletal Muscle and Liver Insulin Action In Vivo
Kim, H.-J., Higashimori, T., Park, S.-Y., Choi, H., Dong, J., Kim, Y.-J., Noh, H.-L., Cho, Y.-R., Cline, G., Kim, Y.-B., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1060 · Cited by 534 · see citing works
Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association
Bays, H. E., Toth, P. P., Kris-Etherton, P. M., Abate, N., Aronne, L. J., Brown, W. V., Gonzalez-Campoy, J. M., Jones, S. R., Kumar, R., La Forge, R., et al. (2013) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2013.04.001 · Cited by 521 · see citing works
Kim, Y.-B., Nikoulina, S. E., Ciaraldi, T. P., Henry, R. R., & Kahn, B. B. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6928 · Cited by 487 · see citing works
Ibáñez, L., Oberfield, S. E., Witchel, S., Auchus, R. J., Chang, R. J., Codner, E., Dabadghao, P., Darendeliler, F., Elbarbary, N. S., Gambineri, A., et al. (2017) · Hormone Research in Paediatrics · doi:10.1159/000479371 · Cited by 463 · see citing works
PKC-θ knockout mice are protected from fat-induced insulin resistance
Kim, J. K., Fillmore, J. J., Sunshine, M. J., Albrecht, B., Higashimori, T., Kim, D.-W., Liu, Z.-X., Soos, T. J., Cline, G. W., O’Brien, W. R., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200422230 · Cited by 500 · see citing works
Self-citationDysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes
Lin, X., Taguchi, A., Park, S., Kushner, J. A., Li, F., Li, Y., & White, M. F. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22217 · Cited by 313 · see citing works
Self-citationKubota, 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 · see citing works
Glucocorticoid Modulation of Insulin Signaling in Human Subcutaneous Adipose Tissue
Gathercole, L. L., Bujalska, I. J., Stewart, P. M., & Tomlinson, J. W. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1399 · Cited by 73 · see citing works
- Authors
- Previs, S. F., Withers, D. J., Ren, J.-M., White, M. F., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Joslin Diabetes Center (US)
- Corresponding author
- Shulman, Gerald I.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-12
- Volume
- 275
- Issue
- 50
- Pages
- 38990-38994
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2006304210
- Cited by
- 291
- References
- 23
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 7 · 2019: 6 · 2018: 9 · 2017: 5 · 2016: 10 · 2015: 9 · 2014: 7 · 2013: 16 · 2012: 15
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (P30 DK45735, R01 DK-40936)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, P30DK045735)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- IRS-1, insulin receptor substrate 2, insulin resistance, glucose metabolism, lipid metabolism, hyperinsulinemic-euglycemic clamp, hepatic glycogen synthesis, endogenous glucose production
- MeSH terms
- Adipose Tissue, Animals, Fatty Acids, Nonesterified, Food Deprivation, Glucose, Glycerol, Insulin, Liver, Male, Gas Chromatography-Mass Spectrometry, Muscles, Mutation, Phenotype, Phosphoproteins, Radioimmunoassay, Time Factors, Intracellular Signaling Peptides and Proteins, Carbohydrate Metabolism, Lipid Metabolism, Mice, Insulin Receptor Substrate Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
