The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression
Open accessAbstract
To investigate the role of insulin signaling on postnatal cardiac development, physiology, and cardiac metabolism, we generated mice with a cardiomyocyte-selective insulin receptor knockout (CIRKO) using cre/loxP recombination. Hearts of CIRKO mice were reduced in size by 20–30% due to reduced cardiomyocyte size and had persistent expression of the fetal β-myosin heavy chain isoform. In CIRKO hearts, glucose transporter 1 (GLUT1) expression was reduced by about 50%, but there was a twofold increase in GLUT4 expression as well as increased rates of cardiac glucose uptake in vivo and increased glycolysis in isolated working hearts. Fatty acid oxidation rates were diminished as a result of reduced expression of enzymes that catalyze mitochondrial β-oxidation. Although basal rates of glucose oxidation were reduced, insulin unexpectedly stimulated glucose oxidation and glycogenolysis in CIRKO hearts. Cardiac performance in vivo and in isolated hearts was mildly impaired. Thus, insulin signaling plays an important developmental role in regulating postnatal cardiac size, myosin isoform expression, and the switching of cardiac substrate utilization from glucose to fatty acids. Insulin may also modulate cardiac myocyte metabolism through paracrine mechanisms by activating insulin receptors in other cell types within the heart.
Overview
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
Verification
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 citing paper
“Specifically, deletion of insulin receptors in the heart is associated with reduced rates of FA and glucose oxidation and reduced expression of FAO genes, consistent with mitochondrial dysfunction (26).”
From Cardiac remodeling in obesity (2008) · cites this paper as [26]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate–Phenol–Chloroform Extraction
Chomczynski, P., & Sacchi, N. (1987) · Analytical Biochemistry · doi:10.1006/abio.1987.9999 · Cited by 65,515
Role of Brain Insulin Receptor in Control of Body Weight and Reproduction
Brüning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Müller-Wieland, D., & Kahn, C. R. (2000) · Science · doi:10.1126/science.289.5487.2122 · Cited by 2,235
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
Self-citationBrüning, 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 1,173
Self-citationAutonomous Control of Cell and Organ Size by CHICO, a Drosophila Homolog of Vertebrate IRS1–4
Böhni, R., Riesgo‐Escovar, J. R., Oldham, S., Brogiolo, W., Stocker, H., Andruss, B. F., Beckingham, K., & Hafen, E. (1999) · Cell · doi:10.1016/s0092-8674(00)80799-0 · Cited by 840
Zeng, G., Nystrom, F. H., Ravichandran, L. V., Cong, L.-N., Kirby, M., Mostowski, H., & Quon, M. J. (2000) · Circulation · doi:10.1161/01.cir.101.13.1539 · Cited by 745
Cytoplasmic Signaling Pathways That Regulate Cardiac Hypertrophy
Molkentin, J. D., & Dorn, G. W. (2001) · Annual Review of Physiology · doi:10.1146/annurev.physiol.63.1.391 · Cited by 684
Fatty Acid Oxidation Enzyme Gene Expression Is Downregulated in the Failing Heart
Sack, M. N., Rader, T. A., Park, S., Bastin, J., McCune, S. A., & Kelly, D. P. (1996) · Circulation · doi:10.1161/01.cir.94.11.2837 · Cited by 678
Pierce, S. B., Costa, M. A., Wisotzkey, R. G., Devadhar, S., Homburger, S. A., Buchman, A. R., Ferguson, K. C., Heller, J., Platt, D., Pasquinelli, A. E., et al. (2001) · Genes & Development · doi:10.1101/gad.867301 · Cited by 651
The conserved phosphoinositide 3‐kinase pathway determines heart size in mice
Shioi, T., Kang, P., Douglas, P., Hampe, J., Yballe, C., Lawitts, J., Cantley, L., & Izumo, S. (2000) · EMBO Journal · doi:10.1093/emboj/19.11.2537 · Cited by 646
Stem Cells and Their Progeny Respond to Nutritional Changes during Drosophila Oogenesis
Drummond‐Barbosa, D., & Spradling, A. C. (2001) · Developmental Biology · doi:10.1006/dbio.2000.0135 · Cited by 631
PPAR Signaling in the Control of Cardiac Energy Metabolism
Barger, P. M., & Kelly, D. P. (2000) · Trends in Cardiovascular Medicine · doi:10.1016/s1050-1738(00)00077-3 · Cited by 502
Utilization of energy-providing substrates in the isolated working rat heart
Taegtmeyer, H., Hems, R., & Krebs, H. A. (1980) · Biochemical Journal · doi:10.1042/bj1860701 · Cited by 468
Self-citationIRS-2 pathways integrate female reproduction and energy homeostasis
Burks, D. J., de Mora, J. F., Schubert, M., Withers, D. J., Myers, M. G., Towery, H. H., Altamuro, S. L., Flint, C. L., & White, M. F. (2000) · Nature · doi:10.1038/35030105 · Cited by 462
Izumo, S., Lompré, A., Matsuoka, R., Koren, G., Schwartz, K., Nadal‐Ginard, B., & Mahdavi, V. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112908 · Cited by 448
Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy
Depré, C., Shipley, G. L., Chen, W., Han, Q., Doenst, T., Moore, M. L. G., Stepkowski, S. M., Davies, P. J., & Taegtmeyer, H. (1998) · Nature Medicine · doi:10.1038/3253 · Cited by 423
Self-citationChan, T. M., & Exton, J. H. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90014-2 · Cited by 416
Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice
Belke, D. D., Larsen, T. S., Gibbs, E. M., & Severson, D. L. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.5.e1104 · Cited by 401
Self-citationThe effect of insulin on renal sodium metabolism: A review with clinical implications
DeFronzo, R. A. (1981) · Diabetologia · doi:10.1007/bf00252649 · Cited by 391
Abel, E. D., Kaulbach, H. C., Tian, R., Hopkins, J. C. A., Duffy, J., Doetschman, T., Minnemann, T., Boers, M.-E., Hadro, E., Grasemann, C., et al. (1999) · Journal of Clinical Investigation · doi:10.1172/jci7605 · Cited by 358
Self-citationWu, P., Sato, J., Zhao, Y., Jaskiewicz, J. A., POPOV, M. K., & HARRIS, A. R. (1998) · Biochemical Journal · doi:10.1042/bj3290197 · Cited by 310
Genetic Dissection of Cardiac Growth Control Pathways
MacLellan, W. R., & Schneider, M. D. (2000) · Annual Review of Physiology · doi:10.1146/annurev.physiol.62.1.289 · Cited by 286
Glucose Regulation of Gene Transcription
Vaulont, S., Vasseur-Cognet, M., & Kahn, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.r000016200 · Cited by 270
Responses of GLUT4-Deficient Hearts to Ischemia Underscore the Importance of Glycolysis
Tian, R., & Abel, E. D. (2001) · Circulation · doi:10.1161/01.cir.103.24.2961 · Cited by 233
Self-citationStorlien, L. H., Jenkins, A. B., Chisholm, D. J., Pascoe, W. S., Khouri, S., & Kraegen, E. W. (1991) · Diabetes · doi:10.2337/diabetes.40.2.280 · Cited by 229
Aikawa, R., Nawano, M., Gu, Y., Katagiri, H., Asano, T., Zhu, W., Nagai, R., & Komuro, I. (2000) · Circulation · doi:10.1161/01.cir.102.23.2873 · Cited by 228
Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter
Race, J. E., Makhlouf, F. N., Logue, P. J., Wilson, F. H., Dunham, P. B., & Holtzman, E. J. (1999) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1999.277.6.c1210 · Cited by 223
Nitric oxide stimulates glucose transport and metabolism in rat skeletal muscle in vitro
Young, M. E., Radda, G. K., & Leighton, B. (1997) · Biochemical Journal · doi:10.1042/bj3220223 · Cited by 214
Self-citationA role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program
Sack, M. N., Disch, D. L., Rockman, H. A., & Kelly, D. P. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.12.6438 · Cited by 206
Developmental and hormonal regulation of sarcomeric myosin heavy chain gene family.
Mahdavi, V., Izumo, S., & Nadal-Ginard, B. (1987) · Circulation Research · doi:10.1161/01.res.60.6.804 · Cited by 202
Depré, C., Young, M. E., Ying, J., Ahuja, H. S., Han, Q., Garza, N. L., Davies, P. J., & Taegtmeyer, H. (2000) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2000.1139 · Cited by 194
Self-citationMihaylova, V. T., Borland, C. Z., Manjarrez, L., Stern, M., & Sun, H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.13.7427 · Cited by 192
Malonyl-CoA metabolism in cardiac myocytes and its relevance to the control of fatty acid oxidation
Awan, M. M., & SAGGERSON, E. D. (1993) · Biochemical Journal · doi:10.1042/bj2950061 · Cited by 188
Mechanisms of control of heart glycolysis
Depré, C., Rider, M. H., & Hue, L. (1998) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1998.2580277.x · Cited by 164
Kraegen, E. W., Sowden, J. A., Halstead, M. B., Clark, P. W., Rodnick, K. J., Chisholm, D. J., & James, D. E. (1993) · Biochemical Journal · doi:10.1042/bj2950287 · Cited by 154
The Insulin Receptor - A Critical Link in Glucose Homeostasis and Insulin Action
Patti, M., & Kahn, C. R. (1998) · Journal of Basic and Clinical Physiology and Pharmacology · doi:10.1515/jbcpp.1998.9.2-4.89 · Cited by 138
Self-citationActions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms
Brownsey, R. W. (1997) · Cardiovascular Research · doi:10.1016/s0008-6363(97)00051-5 · Cited by 132
Ren, J. T., Sowers, J. R., Walsh, M. F., & Brown, R. A. (2000) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2000.279.4.h1708 · Cited by 111
Cooksey, R. C., Hebert, L. F., Zhu, J.-H., Wofford, P., Garvey, W. T., & McClain, D. A. (1999) · Endocrinology · doi:10.1210/endo.140.3.6563 · Cited by 111
Self-citationThe Effects of Acute and Chronic Diabetes on Myocardial Metabolism in Rats
Chen, V., Ianuzzo, C. D., Fong, B. C., & Spitzer, J. J. (1984) · Diabetes · doi:10.2337/diab.33.11.1078 · Cited by 95
Jagasia, D. H., Whiting, J. M., Concato, J., Pfau, S. E., & McNulty, P. H. (2001) · Circulation · doi:10.1161/01.cir.103.13.1734 · Cited by 92
Slieker, L. J., Sundell, K. L., Heath, W. F., Osborne, H. E., Bue, J., Manetta, J., & Sportsman, J. R. (1992) · Diabetes · doi:10.2337/diab.41.2.187 · Cited by 90
Montessuit, C., & Thorburn, A. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.13.9006 · Cited by 82
The isolated working mouse heart: methodological considerations
Larsen, T. S., Belke, D. D., Sas, R., Giles, W. R., Severson, D. L., Lopaschuk, G. D., & Tyberg, J. V. (1999) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s004240050870 · Cited by 67
Self-citationKainulainen, H., Breiner, M., Schürmann, A., MARTTINEN, A., Virjo, A., & Joost, H. (1994) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/0925-4439(94)90007-8 · Cited by 66
Insulin effects on protein synthesis are independent of glucose and energy metabolism
Flaim, K. E., Kochel, P. J., Kira, Y., Kobayashi, K., Fossel, E. T., Jefferson, L. S., & Morgan, H. E. (1983) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1983.245.1.c133 · Cited by 63
Transcriptional Regulation of the Human GLUT4 Gene Promoter in Diabetic Transgenic Mice
Olson, A. L., & Pessin, J. E. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.40.23491 · Cited by 62
Nitric oxide inhibits glycogen synthesis in isolated rat hepatocytes
Sprangers, F., SAUERWEIN, P. H., Romijn, A., van WOERKOM, M. G., & MEIJER, J. A. (1998) · Biochemical Journal · doi:10.1042/bj3301045 · Cited by 61
Chatham, J. C. (1999) · Cardiovascular Research · doi:10.1016/s0008-6363(99)00056-5 · Cited by 54
Modulation of Basal Hepatic Glycogenolysis by Nitric Oxide
Borgs, M., Bollen, M., Keppens, S., Yap, S. H., Stalmans, W., & Vanstapel, F. J. L. A. (1996) · Hepatology · doi:10.1002/hep.510230637 · Cited by 49
Glucose metabolism in perfused mouse hearts overexpressing human GLUT-4 glucose transporter
Belke, D. D., Larsen, T. S., Gibbs, E. M., & Severson, D. L. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.3.e420 · Cited by 48
Self-citationThe effects of acute and chronic diabetes on myocardial metabolism in rats
Chen, V., Ianuzzo, C. D., Bc, F., et al. (1984) · Diabetes · doi:10.2337/diabetes.33.11.1078 · Cited by 30
Slieker, L. J., Sundell, K. L., Heath, W. F., et al. (1992) · Diabetes · doi:10.2337/diabetes.41.2.187 · Cited by 19
The impact of type 2 diabetes on the regulation of cardiac energy metabolism and function
Chatham, J. C. (2001) · Journal of Molecular and Cellular Cardiology · doi:10.1016/s0022-2828(01)90587-5 · Cited by 4
Flagged first, then by citations
Research works printed but not linked: 11
- Laughlin, 1992, Am J Physiol, 262, E875
- Baron, 1994, Am J Physiol, 267, E187
- Kolter, 1997, Am J Physiol, 273, E59
- 10.1210/en.140.3.1151 · DOI
- Chomczynski, 1987, Anal Biochem, 162, 156, 10.1016/0003-2697(87)90021-2 · DOI
- Manning, 1994, Am J Physiol, 266, H1672
- Liu, 1993, Cell, 75, 59
- Young, 2001, J Mol Cell Cardiol, 33, A181
- Laybutt, 1997, Am J Physiol, 273, H1309
- Goodwin, 1998, Am J Physiol, 274, H1239
- Litwin, 2001, Circulation, 104(Suppl. II), II-569
Cited by
Sorted by citations
Diabetic Cardiomyopathy Revisited
Boudina, S., & Abel, E. D. (2007) · Circulation · doi:10.1161/circulationaha.106.679597 · Cited by 1,543
Self-citationPhysiological and pathological cardiac hypertrophy
Shimizu, I., & Minamino, T. (2016) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2016.06.001 · Cited by 919
Cardiovascular Actions of Insulin
Muniyappa, R., Montagnani, M., Koh, K. K., & Quon, M. J. (2007) · Endocrine Reviews · doi:10.1210/er.2007-0006 · Cited by 888
Abel, E. D., Litwin, S. E., & Sweeney, G. (2008) · Physiological Reviews · doi:10.1152/physrev.00017.2007 · Cited by 736
Self-citationDiabetic cardiomyopathy, causes and effects
Boudina, S., & Abel, E. D. (2010) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-010-9131-7 · Cited by 737
Self-citation
Metadata
- Authors
- Belke, D. D., Betuing, S., Tuttle, M. J., Graveleau, C., Young, M. E., Pham, M., Zhang, D., Cooksey, R. C., McClain, D. A., Litwin, S. E., Taegtmeyer, H., Severson, D., Kahn, C. R., & Abel, E. D.
- Affiliations
- University of Calgary (CA)
- University of Utah (US)
- Joslin Diabetes Center (US)
- Corresponding author
- Abel, E. Dale
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2002-03-01
- Volume
- 109
- Issue
- 5
- Pages
- 629-639
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W4236765824
- Cited by
- 330
- References
- 52
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 14 · 2023: 7 · 2022: 9 · 2021: 14 · 2020: 15 · 2019: 8 · 2018: 9 · 2017: 19 · 2016: 12 · 2015: 15 · 2014: 12 · 2013: 18 · 2012: 13
- FWCI
- 5.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health (DK31036)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK033201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- insulin signaling, insulin receptor, heart development, cardiac hypertrophy, myosin heavy chain isoforms, glucose transporter 1, GLUT4, cardiac glucose uptake, glycolysis, fatty acid oxidation, mitochondrial beta-oxidation, glucose oxidation, glycogenolysis, cardiac contractility
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
