The DOI matches its Crossref record; 47 of the 48 references it cites were found in a registry or an index.
Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle
Open accessAbstract
The broad nature of insulin resistant glucose metabolism in skeletal muscle of patients with type 2 diabetes suggests a defect in the proximal part of the insulin signaling network. We sought to identify the pathways compromised in insulin resistance and to test the effect of moderate exercise on whole-body and cellular insulin action. We conducted euglycemic clamps and muscle biopsies on type 2 diabetic patients, obese nondiabetics and lean controls, with and without a single bout of exercise. Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS-1 upon insulin stimulation. Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-1-association with PI 3-kinase defines a key step in insulin resistance.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Using the euglycemic insulin clamp with skeletal muscle biopsy, a number of investigators have examined the insulin signal transduction system in human skeletal muscle of type 2 diabetic subjects and consistently demonstrated defects in IRS-1 tyrosine phosphorylation and PI-3 kinase and Akt activation ( 26 , 54 , 55 ).”
From Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes (2009) · cites this paper as [54]
Experimental — accuracy not yet measuredIn the citing paper
“In contrast, as the MAPK pathway has normal sensitivity to insulin, hyperinsulinemia activates the MAPK pathway, promoting vascular smooth muscle cell growth and activating inflammatory pathways, such as IkB/NF-kB and JNK [107,108].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [107]
In the citing paper
“Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis.”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [7]
In the citing paper
“Association of the p85 subunit of PI3K with IRS-1 and activation of PI3K also are greatly attenuated in obese nondiabetic and type 2 diabetic subjects compared with lean healthy controls [7, 165, 166].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [7]
In the citing paper
“The ability of insulin to activate insulin receptor and IRS-1 tyrosine phosphorylation in muscle in obese nondiabetic subjects is modestly reduced; whereas in type 2 diabetics insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation are severely impaired [7].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [7]
In the citing paper
“Most [1, 7, 152, 153, 156, 161] but not all [155] investigators have found a reduction in tyrosine kinase activity that cannot be explained by alterations in insulin receptor number or insulin receptor binding affinity.”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [7]
In the citing paper
“In insulin-resistant obese nondiabetic subjects, in the NGT insulin resistant offspring of two diabetic parents, and in type 2 diabetic subjects, a substantial decrease in insulin receptor tyrosine phosphorylation has been demonstrated.”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [7]
In the citing paper
“The decrease in insulin-stimulated association of the p85 regulatory subunit of PI3K with IRS-1 is closely correlated with the reduction in insulin-stimulated muscle glycogen synthase activity and in vivo insulin-stimulated glucose disposal [7].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [7]
In the citing paper
“Intact stimulation of the MAPK pathway by insulin in the presence of insulin resistance in the PI3K pathway may play an important role in the development of atherosclerosis [7].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [7]
In the citing paper
“Insulin resistance in the PI3K signaling pathway contrasts with an intact stimulation of the MAPK pathway by insulin in insulin-resistant type 2 diabetic and obese nondiabetics individuals [7, 165].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [7]
In the citing paper
“Under basal conditions, total glycogen synthase activity in type 2 diabetic subjects is reduced, and the ability of insulin to activate glycogen synthase is severely impaired [7, 215–217].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [7]
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
PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 316,394
Alternative 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-citationCheatham, B., Vlahos, C. J., Cheatham, L. A., Wang, L., Blenis, J., & Kahn, C. R. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.7.4902-4911.1994 · Cited by 1,062
Self-citationMeasurement of Size and Turnover Rate of Body Glucose Pool by the Isotope Dilution Method
Steele, R., Wall, J. S., de Bodo, R. C., & Altszuler, N. (1956) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1956.187.1.15 · Cited by 816
Perseghin, G., Price, T. B., Petersen, K. F., Roden, M., Cline, G. W., Gerow, K., Rothman, D. L., & Shulman, G. I. (1996) · New England Journal of Medicine · doi:10.1056/nejm199610313351804 · Cited by 699
Jiang, Z. Y., Lin, Y.-W., Clemont, A., Feener, E. P., Hein, K. D., Igarashi, M., Yamauchi, T., White, M. F., & King, G. L. (1999) · Journal of Clinical Investigation · doi:10.1172/jci5971 · Cited by 604
Dunaif, A., Xia, J., Book, C. B., Schenker, E., & Tang, Z. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118126 · Cited by 561
Effect of physical exercise on sensitivity and responsiveness to insulin in humans
Mikines, K. J., Sonne, B., Farrell, P. A., Tronier, B., & Galbo, H. (1988) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1988.254.3.e248 · Cited by 538
Goodyear, L. J., Giorgino, F., Sherman, L., Carey, J., Smith, R. J., & Dohm, G. L. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117909 · Cited by 527
Ren, J., Semenkovich, C. F., Gulve, E. A., Gao, J. H., & Holloszy, J. O. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36636-x · Cited by 416
Lazar, D. F., Wiese, R. J., Brady, M. J., Mastick, C. C., Waters, S. B., Yamauchi, K., Pessin, J. E., Cuatrecasas, P., & Saltiel, A. R. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.35.20801 · Cited by 396
Exercise regulation of glucose transport in skeletal muscle.
Hayashi, T., Wojtaszewski, J., & Goodyear, L. (1997) · American Journal of Physiology · doi:10.1152/ajpendo.1997.273.6.e1039 · Cited by 394
Björnholm, M., Kawano, Y., Lehtihet, M., & Zierath, J. R. (1997) · Diabetes · doi:10.2337/diab.46.3.524 · Cited by 361
Enhanced Peripheral and Splanchnic Insulin Sensitivity in NIDDM Men After Single Bout of Exercise
Devlin, J. T., Hirshman, M., Horton, E. D., & Horton, E. S. (1987) · Diabetes · doi:10.2337/diab.36.4.434 · Cited by 342
Correlation between muscle glycogen synthase activity and in vivo insulin action in man
Bogardus, C., Lillioja, S., Stone, K., & Mott, D. (1984) · Journal of Clinical Investigation · doi:10.1172/jci111304 · Cited by 335
Rothman, D. L., Shulman, R. G., & Shulman, G. I. (1992) · Journal of Clinical Investigation · doi:10.1172/jci115686 · Cited by 327
New Insights Into the Role and Mechanism of Glycogen Synthase Activation by Insulin
Lawrence, J. C., & Roach, P. J. (1997) · Diabetes · doi:10.2337/diab.46.4.541 · Cited by 311 · cited 1×
“Therefore, even though it is possible to increase glucose uptake by overexpressing glycogen synthase in transgenic mice (45), it seems that an increase in glycogen synthase activity alone is insufficient to increase glucose disposal in humans.”
BackgroundDe Fea, K., & Roth, R. A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.50.31400 · Cited by 298
Rondinone, C. M., Wang, L.-M., Lönnroth, P., Wesslau, C., Pierce, J. H., & Smith, U. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.8.4171 · Cited by 295
Kanai, F., Ito, K., Todaka, M., Hayashi, H., Kamohara, S., Ishii, K., Okada, T., Hazeki, O., Ui, M., & Ebina, Y. (1993) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1993.2111 · Cited by 281
Endemann, G., Yonezawa, K., & Roth, R. A. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)40243-3 · Cited by 257
Schneider, S. H., Amorosa, L. F., Khachadurian, A. K., & Ruderman, N. B. (1984) · Diabetologia · doi:10.1007/bf00266036 · Cited by 257
Patti, M., Sun, X., Bruening, J., Araki, E., Lipes, M. A., White, M. F., & Kahn, C. R. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.42.24670 · Cited by 231
Self-citationExercise stimulates the mitogen-activated protein kinase pathway in human skeletal muscle.
Aronson, D., Violán, M., Dufresne, S. D., Zangen, D., Fielding, R. A., & Goodyear, L. J. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119282 · Cited by 213
Insulin Signaling in Human Skeletal Muscle: Time Course and Effect of Exercise
Wojtaszewski, J. F. P., Hansen, B. F., Kiens, B., & Richter, E. A. (1997) · Diabetes · doi:10.2337/diab.46.11.1775 · Cited by 206
Mandarino, L. J., Wright, K. S., Verity, L. S., Nichols, J., Bell, J. M., Kolterman, O. G., & Beck-Nielsen, H. (1987) · Journal of Clinical Investigation · doi:10.1172/jci113118 · Cited by 194
Self-citationSasaoka, T., Draznin, B., Leitner, J. W., Langlois, W. J., & Olefsky, J. M. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)34120-0 · Cited by 193
Roles of Glucose Transport and Glucose Phosphorylation in Muscle Insulin Resistance of NIDDM
Bonadonna, R. C., Bonora, E., Prato, S. D., Saccomani, M. P., Cobelli, C., Natali, A., Frascerra, S., Pecori, N., Ferrannini, E., Bier, D., et al. (1996) · Diabetes · doi:10.2337/diab.45.7.915 · Cited by 191
Self-citationGoodyear, L. J., Giorgino, F., Balon, T. W., Condorelli, G., & Smith, R. J. (1995) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1995.268.5.e987 · Cited by 177
The Effect of Physical Training on Glucose Tolerance and Plasma Lipids in Maturity-onset Diabetes
Ruderman, N. B., Ganda, O. P., & Johansen, K. (1979) · Diabetes · doi:10.2337/diab.28.1.s89 · Cited by 155
Insulin, but Not Contraction, Activates Akt/PKB in Isolated Rat Skeletal Muscle
Brozinick, J. T., & Birnbaum, M. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.24.14679 · Cited by 149
Intracellular Defects in Glucose Metabolism in Obese Patients With NIDDM
Kelley, D. E., Mokan, M., & Mandarino, L. J. (1992) · Diabetes · doi:10.2337/diab.41.6.698 · Cited by 121
Self-citationInsulin-induced hexokinase II expression is reduced in obesity and NIDDM.
Pendergrass, M., Koval, J., Vogt, C., Yki-Jarvinen, H., Iozzo, P., Pipek, R., Ardehali, H., Printz, R., Granner, D., DeFronzo, R. A., et al. (1998) · Diabetes · doi:10.2337/diabetes.47.3.387 · Cited by 119
Self-citationMcGuire, M. C., Fields, R. M., Nyomba, B. L. G., Raz, I., Bogardus, C., Tonks, N. K., & Sommercorn, J. (1991) · Diabetes · doi:10.2337/diab.40.7.939 · Cited by 113
Maegawa, H., Shigeta, Y., Egawa, K., & Kobayashi, M. (1991) · Diabetes · doi:10.2337/diab.40.7.815 · Cited by 107
Rat skeletal muscle hexokinase II mRNA and activity are increased by a single bout of acute exercise
O'Doherty, R. M., Bracy, D. P., Osawa, H., Wasserman, D. H., & Granner, D. K. (1994) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1994.266.2.e171 · Cited by 98
Glycogen synthase activation in human skeletal muscle: effects of diet and exercise.
Kochan, R. G., Lamb, D. R., Lutz, S. A., Perrill, C. V., Reimann, E. M., & Schlender, K. K. (1979) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1979.236.6.e660 · Cited by 82
Regulation of hexokinase II activity and expression in human muscle by moderate exercise
Koval, J., DeFronzo, R. A., O'Doherty, R. M., Printz, R. L., Ardehali, H., Granner, D. K., & Mandarino, L. J. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.274.2.e304 · Cited by 80
Self-citationLund, S. A., Pryor, P. R., Østergaard, S. D., Schmitz, O., Pedersen, O. B., & Holman, G. D. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)00293-2 · Cited by 67
Bak, J. F., JACOBSEN, U. K., Jørgensen, F. S., & Pedersen, O. B. (1989) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-69-1-158 · Cited by 61
Insulin-sensitive tyrosine kinase: relationship with in vivo insulin action in humans
Nyomba, B. L. G., Ossowski, V., Bogardus, C., & Mott, D. M. (1990) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1990.258.6.e964 · Cited by 55
[25] Immune complex kinase assays for mitogen-activated protein kinase and MEK
Reuter, C. W., Catling, A. D., & Weber, M. J. (1995) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(95)55027-5 · Cited by 52
Effects of exercise and insulin on insulin signaling proteins in human skeletal muscle
Koval, J., Maezono, K., Patti, M., Pendergrass, M., DeFronzo, R. A., & Mandarino, L. J. (1999) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-199907000-00012 · Cited by 52
Self-citationDorrestijn, J., Ouwens, D. M., van den Berghe, N., Bos, J. L., & Maassen, J. A. (1996) · Diabetologia · doi:10.1007/bf00403302 · Cited by 40
Worm, D., Vinten, J., Stæhr, P., Henriksen, J. E., Handberg, A., & Beck‐Nielsen, H. (1996) · Diabetologia · doi:10.1007/bf02658508 · Cited by 39
Glycogen depletion and increased insulin sensitivity and responsiveness in muscle after exercise
Zorzano, A., Balon, T. W., Goodman, M. N., & Ruderman, N. B. (1986) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1986.251.6.e664 · Cited by 38
Insulin activation of phosphatidylinositol 3-kinase in human skeletal muscle in vivo
Hickey, M. S., Tanner, C. J., O’Neill, D. S., Morgan, L. J., Dohm, G. L., & Houmard, J. A. (1997) · Journal of Applied Physiology · doi:10.1152/jappl.1997.83.3.718 · Cited by 17
Flagged first, then by citations
1 of the 48 references couldn’t be matched to a known paper.
Research works printed but not linked: 9
- Cheatham, 1994, Mol Cell Biol, 14, 4902, 10.1128/MCB.14.7.4902 · DOI
- Nyomba, 1990, Am J Physiol, 258, E964
- Hayashi, 1997, Am J Physiol, 273, E1039
- Koval, 1998, Am J Physiol, 274, E304
- O’Doherty, 1994, Am J Physiol, 266, E171
- Mikines, 1988, Am J Physiol, 254, E248
- Goodyear, 1995, Am J Physiol, 268, E987
- Zorzano, 1986, Am J Physiol, 251, E664
- Kochan, 1979, Am J Physiol, 236, E660
Cited by
Sorted by citations
Insulin signalling and the regulation of glucose and lipid metabolism
Saltiel, A. R., & Kahn, C. R. (2001) · Nature · doi:10.1038/414799a · Cited by 5,326
Self-citationDeFronzo, R. A. (2009) · Diabetes · doi:10.2337/db09-9028 · Cited by 3,016
Self-citationMechanisms 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
DeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611
Self-citationSkeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes
DeFronzo, R. A., & Tripathy, D. (2009) · Diabetes Care · doi:10.2337/dc09-s302 · Cited by 2,102
“Molecular etiology of the skeletal muscle insulin resistance in genetically predisposed individuals Using the euglycemic insulin clamp with skeletal muscle biopsy, a number of investigators have examined the insulin signal transduction system in human skeletal muscle of type 2 diabetic subjects and consistently demons…”
BackgroundSelf-citation
Metadata
- Authors
- Cusi, K., Maezono, K., Osman, A., Pendergrass, M., Patti, M. E., Pratipanawatr, T., DeFronzo, R. A., Kahn, C. R., & Mandarino, L. J.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Harvard University (US)
- Tulane University (US)
- Joslin Diabetes Center (US)
- Corresponding author
- Mandarino, Lawrence J.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2000-02-01
- Volume
- 105
- Issue
- 3
- Pages
- 311-320
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC377440
- OpenAlex
- W2120852510
- Cited by
- 1,139
- References
- 48
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 19 · 2023: 27 · 2022: 35 · 2021: 45 · 2020: 33 · 2019: 35 · 2018: 24 · 2017: 37 · 2016: 52 · 2015: 54 · 2014: 53 · 2013: 57 · 2012: 65
- FWCI
- 13.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health (5k08dk002526-03)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-24092, DK02526, R01DK047936, R01DK033201, R01DK024092, R01-DK-47936)
- National Center for Research Resources (M01RR001346)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin resistance, skeletal muscle, type 2 diabetes, PI3K signaling, MAPK signaling, insulin receptor, IRS-1, p85 regulatory subunit, physical activity, glucose uptake, obesity, euglycemic clamp, insulin signaling
- MeSH terms
- Adult, Diabetes Mellitus, Type 2, Female, Humans, Insulin Resistance, Male, Phosphoproteins, Receptor, Insulin, Signal Transduction, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, 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
