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.
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 human skeletal muscle of type 2 diabetic subjects, defects in IRS-1 tyrosine phosphorylation and PI-3 kinase and Akt activation are consistently demonstrated.
“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]
The Results (section headed “Glycogen synthase activity”; page unavailable in our copy) report that insulin increased IRS-1 tyrosine phosphorylation in lean controls but not in type 2 diabetic subjects. The Discussion also reports profound resistance in the PI 3-kinase signaling pathway. Our copy does not report a defect in Akt activation, so it does not support that part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAs 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.
“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]
Skeletal muscle insulin resistance involves reduced insulin-stimulated glucose uptake and arises from impaired insulin signalling plus several post-receptor defects, including defective glucose transport and phosphorylation and lower glucose oxidation and glycogen synthesis.
“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]
Association of p85 subunit of PI3K with IRS-1 and PI3K activation are greatly attenuated in obese nondiabetic and type 2 diabetic subjects compared with lean healthy controls.
“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 obese nondiabetic subjects, insulin activation of insulin receptor and IRS-1 tyrosine phosphorylation in muscle is modestly reduced; in type 2 diabetics it is severely impaired.
“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]
Most but not all investigators found reduced insulin receptor tyrosine kinase activity in skeletal muscle from normal-weight and obese diabetic subjects that cannot be explained by receptor number or binding affinity.
“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 insulin-resistant obese nondiabetic subjects, NGT insulin-resistant offspring of two diabetic parents, and type 2 diabetic subjects, a substantial decrease in insulin receptor tyrosine phosphorylation has been demonstrated.
“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]
The decrease in insulin-stimulated p85 association with IRS-1 closely correlates with reduced muscle glycogen synthase activity and in vivo insulin-stimulated glucose disposal.
“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]
Intact MAPK pathway stimulation by insulin in the presence of PI3K pathway insulin resistance may play an important role in atherosclerosis development.
“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]
Insulin resistance in the PI3K pathway contrasts with intact insulin stimulation of the MAPK pathway in insulin-resistant type 2 diabetic and obese nondiabetic individuals.
“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]
Under basal conditions, total glycogen synthase activity in type 2 diabetic subjects is reduced, and insulin's ability to activate glycogen synthase is severely impaired.
“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.
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 315,771 · see citing works
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 · see citing works
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 1,067 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Dunaif, A., Xia, J., Book, C. B., Schenker, E., & Tang, Z. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118126 · Cited by 561 · see citing works
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 · see citing works
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 525 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Björnholm, M., Kawano, Y., Lehtihet, M., & Zierath, J. R. (1997) · Diabetes · doi:10.2337/diab.46.3.524 · Cited by 358 · see citing works
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 · see citing works
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 · see citing works
Rothman, D. L., Shulman, R. G., & Shulman, G. I. (1992) · Journal of Clinical Investigation · doi:10.1172/jci115686 · Cited by 328 · see citing works
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× · see citing works
“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 · see citing works
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 297 · see citing works
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 · see citing works
Endemann, G., Yonezawa, K., & Roth, R. A. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)40243-3 · Cited by 257 · see citing works
Schneider, S. H., Amorosa, L. F., Khachadurian, A. K., & Ruderman, N. B. (1984) · Diabetologia · doi:10.1007/bf00266036 · Cited by 257 · see citing works
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 238 · see citing works
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 209 · see citing works
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 · see citing works
Sasaoka, 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 196 · see citing works
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 · see citing works
Self-citationRoles 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 · see citing works
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 176 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Maegawa, H., Shigeta, Y., Egawa, K., & Kobayashi, M. (1991) · Diabetes · doi:10.2337/diab.40.7.815 · Cited by 107 · see citing works
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 · see citing works
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 · see citing works
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 79 · see citing works
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 · see citing works
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 · see citing works
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 54 · see citing works
[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 · see citing works
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 51 · see citing works
Self-citationWorm, D., Vinten, J., Stæhr, P., Henriksen, J. E., Handberg, A., & Beck‐Nielsen, H. (1996) · Diabetologia · doi:10.1007/bf02658508 · Cited by 39 · see citing works
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 · see citing works
Dorrestijn, J., Ouwens, D., van den Berghe, N., Bos, J. L., & Maassen, J. (1996) · Diabetologia · doi:10.1007/bf00403302 · Cited by 22 · see citing works
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 · see citing works
Flagged first, then by citations
1 of the 48 references couldn’t be matched to a known paper.
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 · see citing works
Self-citationDeFronzo, R. A. (2009) · Diabetes · doi:10.2337/db09-9028 · Cited by 3,016 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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-citationCornier, M.-A., Dabelea, D., Hernandez, T. L., Lindstrom, R. C., Steig, A. J., Stob, N. R., Van Pelt, R. E., Wang, H., & Eckel, R. H. (2008) · Endocrine Reviews · doi:10.1210/er.2008-0024 · Cited by 2,162 · see citing works
Diamanti-Kandarakis, E., & Dunaif, A. (2012) · Endocrine Reviews · doi:10.1210/er.2011-1034 · Cited by 1,947 · see citing works
Patti, M. E., Butte, A. J., Crunkhorn, S., Cusi, K., Berria, R., Kashyap, S., Miyazaki, Y., Kohane, I., Costello, M., Saccone, R., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1032913100 · Cited by 1,952 · see citing works
Self-citationMechanisms, Pathophysiology, and Therapy of Arterial Stiffness
Zieman, S. J., Melenovsky, V., & Kass, D. A. (2005) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000160548.78317.29 · Cited by 1,854 · see citing works
Kim, J.-A., Montagnani, M., Koh, K. K., & Quon, M. J. (2006) · Circulation · doi:10.1161/circulationaha.105.563213 · Cited by 1,652 · see citing works
Pathogenesis of type 2 diabetes mellitus
DeFronzo, R. A. (2004) · Medical Clinics of North America · doi:10.1016/j.mcna.2004.04.013 · Cited by 1,342 · see citing works
Self-citationGrundy, S. M. (2010) · Springer eBooks · doi:10.1007/978-1-4419-5839-6_1 · Cited by 1,225 · see citing works
Monocyte chemoattractant protein 1 in obesity and insulin resistance
Sartipy, P., & Loskutoff, D. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1133870100 · Cited by 1,201 · see citing works
Clinical Update: Cardiovascular Disease in Diabetes Mellitus
Wang, C. C. L., Hess, C. N., Hiatt, W. R., & Goldfine, A. B. (2016) · Circulation · doi:10.1161/circulationaha.116.022194 · Cited by 1,183 · see citing works
Role of Mitochondrial Dysfunction in Insulin Resistance
Kim, J.-A., Wei, Y., & Sowers, J. R. (2008) · Circulation Research · doi:10.1161/circresaha.107.165472 · Cited by 1,103 · see citing works
Copps, K. D., & White, M. F. (2012) · Diabetologia · doi:10.1007/s00125-012-2644-8 · Cited by 1,017 · see citing works
“In contrast with AKT, basal or insulin-stimulated ERK1/2 activation in diabetic muscle is unchanged or increased in several studies, compatible with its partial independence from IR/IRS [82, 86].”
BackgroundResultInfluentialActivation of Protein Kinase C Isoforms and Its Impact on Diabetic Complications
Geraldes, P., & King, G. L. (2010) · Circulation Research · doi:10.1161/circresaha.110.217117 · Cited by 993 · see citing works
Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength?
Timon, I. M. (2014) · World Journal of Diabetes · doi:10.4239/wjd.v5.i4.444 · Cited by 982 · see citing works
Signaling pathways in insulin action: molecular targets of insulin resistance
Pessin, J. E., & Saltiel, A. R. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10582 · Cited by 939 · see citing works
Cusi, K. J. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.02.003 · Cited by 912 · see citing works
Self-citationDeFronzo, R. A. (2010) · Diabetologia · doi:10.1007/s00125-010-1684-1 · Cited by 889 · see citing works
Self-citationCardiovascular Actions of Insulin
Muniyappa, R., Montagnani, M., Koh, K. K., & Quon, M. J. (2007) · Endocrine Reviews · doi:10.1210/er.2007-0006 · Cited by 873 · see citing works
FROM MICE TO MEN: Insights into the Insulin Resistance Syndromes
Biddinger, S. B., & Kahn, C. R. (2005) · Annual Review of Physiology · doi:10.1146/annurev.physiol.68.040104.124723 · Cited by 700 · see citing works
Self-citationNew Perspectives into the Molecular Pathogenesis and Treatment of Type 2 Diabetes
Saltiel, A. R. (2001) · Cell · doi:10.1016/s0092-8674(01)00239-2 · Cited by 684 · see citing works
Pathogenesis of insulin resistance in skeletal muscle
Abdul-Ghani, M. A., & DeFronzo, R. A. (2010) · Journal of Biomedicine and Biotechnology · doi:10.1155/2010/476279 · Cited by 670 · see citing works
Self-citationPara-Inflammation in the Aging Retina
Xu, H., Chen, M., & Forrester, J. V. (2009) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2009.06.001 · Cited by 659 · see citing works
Ceramide Content Is Increased in Skeletal Muscle From Obese Insulin-Resistant Humans
Adams, J. M., Pratipanawatr, T., Berria, R., Wang, E. L., DeFronzo, R. A., Sullards, M. C., & Mandarino, L. J. (2004) · Diabetes · doi:10.2337/diabetes.53.1.25 · Cited by 670 · see citing works
Self-citationObesity and polycystic ovary syndrome
Barber, T., McCarthy, M. I., Wass, J. A. H., & Franks, S. (2006) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2006.02587.x · Cited by 655 · see citing works
Insulin resistance and sarcopenia: mechanistic links between common co-morbidities
Cleasby, M. E., Jamieson, P. M., & Atherton, P. J. (2016) · Journal of Endocrinology · doi:10.1530/joe-15-0533 · Cited by 596 · see citing works
Insulin Resistance and Atherosclerosis: Implications for Insulin-Sensitizing Agents
Di Pino, A., & DeFronzo, R. A. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00141 · Cited by 535 · see citing works
Self-citationStefan, N., Vozarova, B., Funahashi, T., Matsuzawa, Y., Weyer, C., Lindsay, R. S., YOUNGREN, J. F., Havel, P. J., Pratley, R. E., Bogardus, C., et al. (2002) · Diabetes · doi:10.2337/diabetes.51.6.1884 · Cited by 557 · see citing works
How does blood glucose control with insulin save lives in intensive care?
den Berghe, G. V. (2004) · Journal of Clinical Investigation · doi:10.1172/jci23506 · Cited by 547 · see citing works
Invited Review: Effects of acute exercise and exercise training on insulin resistance
Henriksen, E. J. (2002) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01219.2001 · Cited by 535 · see citing works
Insulin Resistance, Obesity and Lipotoxicity
Yazıcı, D., & Sezer, H. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-48382-5_12 · Cited by 507 · see citing works
Taylor, R. (2013) · Diabetes Care · doi:10.2337/dc12-1805 · Cited by 485 · see citing works
Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes
Rask‐Madsen, C., & King, G. L. (2006) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0366 · Cited by 483 · see citing works
Metabolic syndrome: Definition, pathophysiology, and mechanisms
Miranda, P. J., DeFronzo, R. A., Califf, R. M., & Guyton, J. R. (2005) · American Heart Journal · doi:10.1016/j.ahj.2004.07.013 · Cited by 480 · see citing works
Self-citationBiddinger, S. B., Hernandez-Ono, A., Rask-Madsen, C., Haas, J. T., Alemán, J. O., Suzuki, R., Scapa, E. F., Agarwal, C., Carey, M. C., Stephanopoulos, G., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.11.013 · Cited by 469 · see citing works
Self-citationIntensive insulin therapy protects the endothelium of critically ill patients
Langouche, L. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25385 · Cited by 465 · see citing works
Volpi, E., Mittendorfer, B., Rasmussen, B. B., & Wolfe, R. R. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.12.7021 · Cited by 464 · see citing works
Lomonaco, R., Ortiz‐Lopez, C., Orsak, B., Webb, A., Hardies, J., Darland, C., Finch, J., Gastaldelli, A., Harrison, S. A., Tio, F. O., et al. (2011) · Hepatology · doi:10.1002/hep.25539 · Cited by 461 · see citing works
Self-citationFrank, N., Geor, R. J., Bailey, S. R., Durham, A. E., & Johnson, P. J. (2010) · Journal of Veterinary Internal Medicine · doi:10.1111/j.1939-1676.2010.0503.x · Cited by 431 · see citing works
Signaling pathways in obesity: mechanisms and therapeutic interventions
Wen, X., Zhang, B., Wu, B., Xiao, H., Li, Z., Li, R., Xu, X., & Li, T. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01149-x · Cited by 456 · see citing works
Endothelial Dysfunction in Obesity and Insulin Resistance: A Road to Diabetes and Heart Disease
Caballero, A. E. (2003) · Obesity Research · doi:10.1038/oby.2003.174 · Cited by 416 · see citing works
Obesity and Polycystic Ovary Syndrome: Implications for Pathogenesis and Novel Management Strategies
Barber, T. M., Hanson, P., Weickert, M. O., & Franks, S. (2019) · Clinical Medicine Insights: Reproductive Health · doi:10.1177/1179558119874042 · Cited by 411 · see citing works
Energy metabolism in health and diseases
Liu, H., Wang, S., Wang, J., Guo, X., Song, Y., Fu, K., Gao, Z., Liu, D., He, W., & Yang, L. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02141-x · Cited by 438 · see citing works
Dose-Response Effect of Elevated Plasma Free Fatty Acid on Insulin Signaling
Belfort, R., Mandarino, L., Kashyap, S., Wirfel, K., Pratipanawatr, T., Berria, R., DeFronzo, R. A., & Cusi, K. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1640 · Cited by 404 · see citing works
Self-citationObesity and polycystic ovary syndrome
Barber, T. M., & Franks, S. (2021) · Clinical Endocrinology · doi:10.1111/cen.14421 · Cited by 385 · see citing works
Hong, S.-H., & Choi, K. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020494 · Cited by 390 · see citing works
Draznin, B. (2006) · Diabetes · doi:10.2337/db06-0391 · Cited by 390 · see citing works
Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects
Reyna, S. M., Ghosh, S., Tantiwong, P., Meka, C. S. R., Eagan, P. A., Jenkinson, C. P., Cersósimo, E., DeFronzo, R. A., Coletta, D. K., Sriwijitkamol, A., et al. (2008) · Diabetes · doi:10.2337/db08-0038 · Cited by 381 · see citing works
Self-citationTargeting hepatic glucose metabolism in the treatment of type 2 diabetes
Rines, A. K., Sharabi, K., Tavares, C. D. J., & Puigserver, P. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.151 · Cited by 380 · see citing works
Federici, M., Menghini, R., Mauriello, A., Hribal, M. L., Ferrelli, F., Lauro, D., Sbraccia, P., Spagnoli, L. G., Sesti, G., & Lauro, R. (2002) · Circulation · doi:10.1161/01.cir.0000023043.02648.51 · Cited by 372 · see citing works
The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia
Sylow, L., Tokarz, V. L., Richter, E. A., & Klip, A. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.03.020 · Cited by 366 · see citing works
Bajaj, M. S., Suraamornkul, S., Piper, P. K., Hardies, L. J., Glass, L. C., Cersósimo, E., Pratipanawatr, T., Miyazaki, Y., & DeFronzo, R. A. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031315 · Cited by 354 · see citing works
Self-citationKim, B., & Feldman, E. L. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2015.3 · Cited by 357 · see citing works
eNOS, metabolic syndrome and cardiovascular disease
Huang, P. L. (2009) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2009.03.005 · Cited by 357 · see citing works
Exercise as a therapeutic intervention for the prevention and treatment of insulin resistance
Hawley, J. A. (2004) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.505 · Cited by 344 · see citing works
Parpal, S., Karlsson, M., Thorn, H., & Strålfors, P. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007454200 · Cited by 339 · see citing works
Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS)
Dunaif, A., Wu, X., Lee, A., & Diamanti-Kandarakis, E. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.2.e392 · Cited by 337 · see citing works
Insulin: The master regulator of glucose metabolism
Norton, L., Shannon, C. E., Gastaldelli, A., & DeFronzo, R. A. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155142 · Cited by 337 · see citing works
Self-citationTamura, Y., Tanaka, Y., Sato, F., Choi, J. B., Watada, H., Niwa, M., Kinoshita, J., Ooka, A., Kumashiro, N., Igarashi, Y., et al. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1959 · Cited by 334 · see citing works
Montagnani, M., Golovchenko, I., Kim, I., Koh, G. Y., Goalstone, M. L., Mundhekar, A. N., Johansen, M. L., Kucik, D. F., Quon, M. J., & Draznin, B. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m103728200 · Cited by 328 · see citing works
Chemistry and Biochemistry of Type 2 Diabetes
Ross, S. A., Gulve, E. A., & Wang, M. (2004) · Chemical Reviews · doi:10.1021/cr0204653 · Cited by 326 · see citing works
Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?
Meza, C. A., La Favor, J. D., Kim, D.-H., & Hickner, R. C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20153775 · Cited by 323 · see citing works
Insulin resistance in the nervous system
Kim, B., & Feldman, E. L. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2011.12.004 · Cited by 321 · see citing works
Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance
Cooper, S. A., Whaley-Connell, A., Habibi, J., Wei, Y., Lastra, G., Manrique, C., Stas, S., & Sowers, J. R. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00522.2007 · Cited by 317 · see citing works
Insulin Resistance and Atherosclerosis
Nigro, J., Osman, N., Dart, A. M., & Little, P. J. (2006) · Endocrine Reviews · doi:10.1210/er.2005-0007 · Cited by 316 · see citing works
Pathophysiologic Approach to Therapy in Patients With Newly Diagnosed Type 2 Diabetes
DeFronzo, R. A., Eldor, R., & Abdul‐Ghani, M. A. (2013) · Diabetes Care · doi:10.2337/dcs13-2011 · Cited by 316 · see citing works
Self-citationBouzakri, K., Roques, M., Gual, P., Espinosa, S., Guebre-Egziabher, F., Riou, J.-P., Laville, M., Le Marchand-Brustel, Y., Tanti, J.-F., & Vidal, H. (2003) · Diabetes · doi:10.2337/diabetes.52.6.1319 · Cited by 305 · see citing works
Pathophysiological implications of insulin resistance on vascular endothelial function
Wheatcroft, S. B., Williams, I. L., Shah, A. M., & Kearney, M. T. (2003) · Diabetic Medicine · doi:10.1046/j.1464-5491.2003.00869.x · Cited by 307 · see citing works
Selective Insulin and Leptin Resistance in Metabolic Disorders
Könner, A. C., & Brüning, J. C. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.07.004 · Cited by 304 · see citing works
Karlsson, H., Zierath, J. R., Kane, S., Krook, A., Lienhard, G. E., & Wallberg‐Henriksson, H. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1692 · Cited by 301 · see citing works
Qin, B., Nagasaki, M., Ren, M., Bajotto, G., Oshida, Y., & Sato, Y. (2003) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(03)00173-6 · Cited by 298 · see citing works
The Role of Adipose Tissue and Lipotoxicity in the Pathogenesis of Type 2 Diabetes
Cusi, K. J. (2010) · Current Diabetes Reports · doi:10.1007/s11892-010-0122-6 · Cited by 294 · see citing works
Self-citationAberrant insulin signaling in Alzheimer's disease: current knowledge
Bedse, G., Domenico, F. D., Serviddio, G., & Cassano, T. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00204 · Cited by 294 · see citing works
Skeletal muscle insulin resistance: role of mitochondria and other ROS sources
Di Meo, S., Iossa, S., & Venditti, P. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0598 · Cited by 282 · see citing works
Adipokines: a link between obesity and dementia?
Kiliaan, A. J., Arnoldussen, I. A. C., & Gustafson, D. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70085-7 · Cited by 285 · see citing works
Pirola, L., Johnston, A., & OBBERGHEN, E. V. (2004) · Diabetologia · doi:10.1007/s00125-003-1313-3 · Cited by 283 · see citing works
Corbould, A., Kim, Y.-B., Youngren, J. F., Pender, C., Kahn, B. B., Lee, A., & Dunaif, A. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00361.2004 · Cited by 283 · see citing works
Role of endothelial dysfunction in insulin resistance
Hsueh, W. A., & Quiñones, M. J. (2003) · The American Journal of Cardiology · doi:10.1016/s0002-9149(03)00611-8 · Cited by 271 · see citing works
Role of immune cells in obesity induced low grade inflammation and insulin resistance
Asghar, A., & Sheikh, N. (2017) · Cellular Immunology · doi:10.1016/j.cellimm.2017.03.001 · Cited by 275 · see citing works
Januś, A., Szahidewicz-Krupska, E., Mazur, G. J., & Doroszko, A. (2016) · Mediators of Inflammation · doi:10.1155/2016/3634948 · Cited by 271 · see citing works
Angiotensin II–Induced Insulin Resistance Is Associated With Enhanced Insulin Signaling
Ogihara, T., Asano, T., Ando, K., Chiba, Y., Sakoda, H., Anai, M., Shojima, N., Ono, H., Onishi, Y., Fujishiro, M., et al. (2002) · Hypertension · doi:10.1161/01.hyp.0000040262.48405.a8 · Cited by 274 · see citing works
Belfiore, A., & Malaguarnera, R. (2011) · Endocrine Related Cancer · doi:10.1530/erc-11-0074 · Cited by 272 · see citing works
Cusi, K. J., Chang, Z., Harrison, S., Lomonaco, R., Bril, F., Orsak, B., Ortiz‐Lopez, C., Hecht, J., Feldstein, A. E., Webb, A., et al. (2013) · Journal of Hepatology · doi:10.1016/j.jhep.2013.07.042 · Cited by 272 · see citing works
Self-citationComplementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism
Taniguchi, C. M., Ueki, K., & Kahn, C. R. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23187 · Cited by 278 · see citing works
Self-citationRetractedÖst, A., Svensson, K., Ruishalme, I., Brännmark, C., Franck, N., Krook, H., Sandström, P., Kjølhede, P., & Strålfors, P. (2010) · Molecular Medicine · doi:10.2119/molmed.2010.00023 · Cited by 271 · see citing works
Molecular Mechanisms of Insulin Resistance That Impact Cardiovascular Biology
Wang, C. C. L., Goalstone, M. L., & Draznin, B. (2004) · Diabetes · doi:10.2337/diabetes.53.11.2735 · Cited by 269 · see citing works
Signalling aspects of insulin resistance in skeletal muscle
Schmitz‐Peiffer, C. (2000) · Cellular Signalling · doi:10.1016/s0898-6568(00)00110-8 · Cited by 268 · see citing works
The endothelium and vascular inflammation in diabetes
Hartge, M., Unger, T., & Kintscher, U. (2007) · Diabetes and Vascular Disease Research · doi:10.3132/dvdr.2007.025 · Cited by 268 · see citing works
Role of Insulin Resistance and Lipotoxicity in Non-Alcoholic Steatohepatitis
Cusi, K. J. (2009) · Clinics in Liver Disease · doi:10.1016/j.cld.2009.07.009 · Cited by 263 · see citing works
Self-citationRole of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes
Yung, J. H. M., & Giacca, A. (2020) · Cells · doi:10.3390/cells9030706 · Cited by 267 · see citing works
Regulation by Insulin of Gene Expression in Human Skeletal Muscle and Adipose Tissue
Ducluzeau, P., Peretti, N., Laville, M., Andréelli, F., Véga, N., Riou, J. P., & Vidal, H. (2001) · Diabetes · doi:10.2337/diabetes.50.5.1134 · Cited by 263 · see citing works
S-Nitrosylation-dependent Inactivation of Akt/Protein Kinase B in Insulin Resistance
Yasukawa, T., Tokunaga, E., Ota, H., Sugita, H., Martyn, J. A. J., & Kaneki, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411871200 · Cited by 262 · see citing works
Hwang, H., Bowen, B. P., Lefort, N., Flynn, C. R., De Filippis, E. A., Roberts, C., Smoke, C. C., Meyer, C., Højlund, K., Yi, Z., et al. (2010) · Diabetes · doi:10.2337/db09-0214 · Cited by 255 · see citing works
Self-citationScazzocchio, B., Varı́, R., Filesi, C., D’Archivio, M., Santangelo, C., Giovannini, C., Iacovelli, A., Silecchia, G., Volti, G. L., Galvano, F., et al. (2011) · Diabetes · doi:10.2337/db10-1461 · Cited by 263 · see citing works
Richardson, D. K., Kashyap, S., Bajaj, M., Cusi, K., Mandarino, S. J., Finlayson, J., DeFronzo, R. A., Jenkinson, C. P., & Mandarino, L. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m408985200 · Cited by 259 · see citing works
Self-citationGene Expression Profile in Skeletal Muscle of Type 2 Diabetes and the Effect of Insulin Treatment
Sreekumar, R., Halvatsiotis, P., Schimke, J. C., & Nair, K. S. (2002) · Diabetes · doi:10.2337/diabetes.51.6.1913 · Cited by 257 · see citing works
Eckel, R. H., Barouch, W. W., & Ershow, A. G. (2002) · Circulation · doi:10.1161/01.cir.0000017823.53114.4c · Cited by 256 · see citing works
- 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 › Epidemiology › 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
