Lipid-mediated muscle insulin resistance: different fat, different pathways?

Ritter, Olesja; Jelenik, Tomas; Roden, Michael

doi:10.1007/s00109-015-1310-2

Cited by 74Metabolism, Diabetes, and CancerSphingolipid Metabolism and SignalingAdipose Tissue and Metabolism

Lipid-mediated muscle insulin resistance: different fat, different pathways?

Ritter, Olesja, Jelenik, Tomas, Roden, Michael·2015·Journal of Molecular Medicine

DOI 10.1007/s00109-015-1310-2

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Abstract

Increased dietary fat intake and lipolysis result in excessive lipid availability, which relates to impaired insulin sensitivity. Over the last years, several mechanisms possibly underlying lipid-mediated insulin resistance evolved. Lipid intermediates such as diacylglycerols (DAG) associate with changes in insulin sensitivity in many models. DAG activate novel protein kinase C (PKC) isoforms followed by inhibitory serine phosphorylation of insulin receptor substrate 1 (IRS1). Activation of Toll-like receptor 4 (TLR4) raises another lipid class, ceramides (CER), which induce pro-inflammatory pathways and lead to inhibition of Akt phosphorylation. Inhibition of glucosylceramide and ganglioside synthesis results in improved insulin sensitivity and increased activatory tyrosine phosphorylation of IRS1 in the muscle. Incomplete fat oxidation can increase acylcarnitines (ACC), which in turn stimulate pro-inflammatory pathways. This review analyzed the effects of lipid metabolites on insulin action in skeletal muscle of humans and rodents. Despite the evidence for the association of both DAG and CER with insulin resistance, its causal relevance may differ depending on the subcellular localization and the tested cohorts, e.g., athletes. Nevertheless, recent data indicate that individual lipid species and their degree of fatty acid saturation, particularly membrane and cytosolic C18:2 DAG, specifically activate PKCθ and induce both acute lipid-induced and chronic insulin resistance in humans.

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Excess lipids are thought to 'spill over' to other tissues, especially the skeletal muscles, which accumulate the lipids as intermuscular adipose tissue (IMAT), intramuscular adipose tissue and intramyocellular lipid droplets (IMCLs) containing triacylglycerol or fatty acid derivatives such as diacylglycerols (DAG), long chain acyl CoAs, and ceramides.
“Excess lipids are thought to ‘spill over’ to other tissues, especially the skeletal muscles,[ 35 ] which accumulate the lipids as intermuscular adipose tissue (IMAT), intramuscular adipose tissue and intramyocellular lipid droplets (IMCLs) containing triacylglycerol or fatty acid derivatives such as diacylglycerols (DAG), long chain acyl CoAs, and ceramides.[ 36 ]”
From Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review (2022) · cites this paper as [36]

The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus
Randle, P. J., Garland, P. B., Hales, C. N., & Newsholme, E. A. (1963) · The Lancet · doi:10.1016/s0140-6736(63)91500-9 · Cited by 5,093 · see citing works
Inflammatory Mechanisms in Obesity
Gregor, M. F., & Hotamisligil, G. S. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101322 · Cited by 3,754 · see citing works
GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects
Oh, D. Y., Talukdar, S., Bae, E. J., Imamura, T., Morinaga, H., Fan, W., Li, P., Lu, W. J., Watkins, S. M., & Olefsky, J. M. (2010) · Cell · doi:10.1016/j.cell.2010.07.041 · Cited by 2,428 · see citing works
Mechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294 · see citing works
Skeletal 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 · cited 1× · see citing works
“Skeletal muscle accounts for approximately 80–90 % of insulin-stimulated glucose disposal in the postprandial state [10].”
Background
Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin Resistance
Koves, T. R., Ussher, J. R., Noland, R. C., Slentz, D., Mosedale, M., Ilkayeva, O., Bain, J., Stevens, R., Dyck, J. R. B., Newgard, C. B., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.013 · Cited by 1,990 · see citing works
Lipid Droplets and Cellular Lipid Metabolism
Walther, T. C., & Farese, R. V. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061009-102430 · Cited by 1,668 · see citing works
Turnover of Inositol Phospholipids and Signal Transduction
Nishizuka, Y. (1984) · Science · doi:10.1126/science.6147898 · Cited by 1,614 · see citing works
Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle
Yu, C., Chen, Y., Cline, G. W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J. K., Cushman, S. W., Cooney, G. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200958200 · Cited by 1,561 · see citing works
Mechanism of free fatty acid-induced insulin resistance in humans.
Roden, M., Price, T. B., Perseghin, G., Petersen, K. F., Rothman, D. L., Cline, G. W., & Shulman, G. I. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118742 · Cited by 1,539 · see citing works
Self-citation
Lipid-Induced Insulin Resistance in Human Muscle Is Associated With Changes in Diacylglycerol, Protein Kinase C, and IκB-α
Itani, S. I., Ruderman, N. B., Schmieder, F., & Boden, G. (2002) · Diabetes · doi:10.2337/diabetes.51.7.2005 · Cited by 1,390 · see citing works
Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.
Griffin, 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
Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1 H NMR spectroscopy study
Krssak, M., Falk Petersen, K., Dresner, A., DiPietro, L., Vogel, S. M., Rothman, D. L., Shulman, G. I., & Roden, M. (1999) · Diabetologia · doi:10.1007/s001250051123 · Cited by 1,264 · see citing works
Self-citation
Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans
Anderson, E. J., Lustig, M. E., Boyle, K. E., Woodlief, T. L., Kane, D. A., Lin, C.-T., Price, J. W., Kang, L., Rabinovitch, P. S., Szeto, H. H., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37048 · Cited by 1,253 · see citing works
Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance
Holland, W. L., Brozinick, J. T., Wang, L.-P., Hawkins, E. D., Sargent, K. M., Liu, Y., Narra, K., Hoehn, K. L., Knotts, T. A., Siesky, A., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.01.002 · Cited by 1,232 · see citing works
Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes
Goodpaster, B. H. (2001) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.12.5755 · Cited by 1,194 · see citing works
Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism
Cao, H.-M., Gerhold, K., Mayers, J. R., Wiest, M., Watkins, S., & Hotamışlıgil, G. S. (2008) · Cell · doi:10.1016/j.cell.2008.07.048 · Cited by 1,142 · see citing works
Inflammation and Lipid Signaling in the Etiology of Insulin Resistance
Glass, C. K., & Olefsky, J. M. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.001 · Cited by 942 · see citing works
Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance
Pal, D., Dasgupta, S., Kundu, R., Maitra, S., Das, G., Mukhopadhyay, S., Ray, S., Majumdar, S. S., & Bhattacharya, S. (2012) · Nature Medicine · doi:10.1038/nm.2851 · Cited by 922 · see citing works
Discovery of a Class of Endogenous Mammalian Lipids with Anti-Diabetic and Anti-inflammatory Effects
Yore, M. M., Syed, I., Moraes‐Vieira, P. M., Zhang, T., Herman, M. A., Homan, E. A., Patel, R. T., Lee, J., Chen, S., Peroni, O. D., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.035 · Cited by 845 · see citing works
Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease
Glatz, J. F. C., Luiken, J. J. F. P., & Bonen, A. (2010) · Physiological Reviews · doi:10.1152/physrev.00003.2009 · Cited by 757 · see citing works
THE GLUCOSE-FATTY ACID CYCLE
Stanley, J. C. (1981) · British Journal of Anaesthesia · doi:10.1093/bja/53.2.123 · Cited by 731 · see citing works
Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice
Holland, W. L., Bikman, B. T., Wang, L.-P., Yuguang, G., Sargent, K. M., Bulchand, S., Knotts, T. A., Shui, G., Clegg, D. J., Wenk, M. R., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43378 · Cited by 705 · 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
Acylcarnitines
Schooneman, M. G., Vaz, F. M., Houten, S. M., & Soeters, M. R. (2013) · Diabetes · doi:10.2337/db12-0466 · Cited by 616 · see citing works
Insulin resistance and cancer risk: An overview of the pathogenetic mechanisms
Arcidiacono, B., Iiritano, S., Nocera, A., Possidente, K., Nevolo, M. T., Ventura, V., Foti, D., Chiefari, E., & Brunetti, A. (2012) · Experimental Diabetes Research · doi:10.1155/2012/789174 · Cited by 606 · see citing works
Many Ceramides
Hannun, Y. A., & Obeid, L. M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.r111.254359 · Cited by 544 · see citing works
Enhanced insulin sensitivity in mice lacking ganglioside GM3
Yamashita, T., Hashiramoto, A., Haluzik, M., Mizukami, H., Beck, S., Norton, A., Kono, M., Tsuji, S., Daniotti, J. L., Werth, N., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0635898100 · Cited by 531 · see citing works
Free Fatty Acids Produce Insulin Resistance and Activate the Proinflammatory Nuclear Factor-κB Pathway in Rat Liver
Boden, G., She, P., Mozzoli, M., Cheung, P., Gumireddy, K., Reddy, P., Xiang, X., Luo, Z., & Ruderman, N. (2005) · Diabetes · doi:10.2337/diabetes.54.12.3458 · Cited by 528 · see citing works
Effects of fat on insulin-stimulated carbohydrate metabolism in normal men.
Boden, G., Jadali, F., White, J. V., Liang, Y. T., Mozzoli, M. A., Chen, X., Coleman, E., & Smith, C. R. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115399 · Cited by 500 · see citing works
Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease
Samuel, V. T., Liu, Z.-X., Wang, A., Beddow, S. A., Geisler, J. G., Kahn, M., Zhang, X.-M., Monia, B. P., Bhanot, S., & Shulman, G. I. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30400 · Cited by 497 · see citing works
Chain length-specific properties of ceramides
Grösch, S., Schiffmann, S., & Geißlinger, G. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2011.11.001 · Cited by 484 · see citing works
Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats
Storlien, L. H., James, D. E., Burleigh, K. M., Chisholm, D. J., & Kraegen, E. W. (1986) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1986.251.5.e576 · Cited by 458 · see citing works
Tissue-Specific mRNA Expression Profiles of Human Toll-Like Receptors and Related Genes
Nishimura, M., & Naito, S. (2005) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.28.886 · Cited by 443 · see citing works
Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding
Turner, N., Kowalski, G. M., Leslie, S. J., Risis, S., Yang, C., Lee-Young, R. S., Babb, J. R., Meikle, P. J., Lancaster, G. I., Henstridge, D. C., et al. (2013) · Diabetologia · doi:10.1007/s00125-013-2913-1 · Cited by 430 · see citing works
Ceramides as modulators of cellular and whole-body metabolism
Bikman, B. T., & Summers, S. A. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57144 · Cited by 425 · see citing works
Diacylglycerol, when simplicity becomes complex
Carrasco, S., & Mérida, I. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.11.004 · Cited by 423 · see citing works
Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding
Montgomery, M. K., Hallahan, N., Brown, S. H. J., Liu, M., Mitchell, T. W., Cooney, G. J., & Turner, N. A. (2013) · Diabetologia · doi:10.1007/s00125-013-2846-8 · Cited by 416 · see citing works
Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans
Szendroedi, J., Yoshimura, T., Phielix, E., Koliaki, C., Marcucci, M., Zhang, D., Jelenik, T., Müller, J., Herder, C., Nowotny, P., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1409229111 · Cited by 415 · see citing works
Self-citation
Oxidative Capacity, Lipotoxicity, and Mitochondrial Damage in Type 2 Diabetes
Schrauwen, P., & Hesselink, M. K. C. (2004) · Diabetes · doi:10.2337/diabetes.53.6.1412 · Cited by 408 · see citing works
Mechanisms of Disease: hepatic steatosis in type 2 diabetes—pathogenesis and clinical relevance
Roden, M. (2006) · Nature Clinical Practice Endocrinology &#38 Metabolism · doi:10.1038/ncpendmet0190 · Cited by 404 · see citing works
Self-citation
Phosphatidic acid, a key intermediate in lipid metabolism
Athenstaedt, K., & Daum, G. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00822.x · Cited by 403 · see citing works
Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance
Amati, F., Dubé, J. J., Alvarez-Carnero, E., Edreira, M. M., Chomentowski, P., Coen, P. M., Switzer, G. E., Bickel, P. E., Stefanovic-Racic, M., Toledo, F. G. S., et al. (2011) · Diabetes · doi:10.2337/db10-1221 · Cited by 395 · see citing works
Ectopic fat and insulin resistance: pathophysiology and effect of diet and lifestyle interventions.
Snel, M., Jonker, J. T., Schoones, J., Lamb, H., de Roos, A., Pijl, H., Smit, J. W. A., Meinders, A. E., & Jazet, I. M. (2012) · International Journal of Endocrinology · doi:10.1155/2012/983814 · Cited by 368 · see citing works
Protein Kinase C θ Inhibits Insulin Signaling by Phosphorylating IRS1 at Ser1101
Li, Y., Soos, T. J., Li, X., Wu, J., DeGennaro, M., Sun, X., Littman, D. R., Birnbaum, M. J., & Polakiewicz, R. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.c400186200 · Cited by 358 · see citing works
Ganglioside GM3 Participates in the Pathological Conditions of Insulin Resistance
Tagami, S., Inokuchi, J.-I., Kabayama, K., Yoshimura, H., Kitamura, F., Uemura, S., Ogawa, C., Ishii, A., Saito, M., Ohtsuka, Y., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m103705200 · Cited by 355 · see citing works
Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.
Boden, G., & Chen, X. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118160 · Cited by 344 · see citing works
Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle
Muoio, D. M., & Neufer, P. D. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.010 · Cited by 343 · see citing works
Acylcarnitines activate proinflammatory signaling pathways
Rutkowsky, J. M., Knotts, T. A., Ono‐Moore, K. D., McCoin, C. S., Huang, S., Schneider, D. A., Singh, S., Adams, S. H., & Hwang, D. H. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00656.2013 · Cited by 327 · see citing works
Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites
Lee, J. S., Pinnamaneni, S. K., Eo, S. J., Cho, I. H., Pyo, J. H., Kim, C. K., Sinclair, A. J., Febbraio, M. A., & Watt, M. J. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01438.2005 · Cited by 325 · see citing works
Diacylglycerol Activation of Protein Kinase Cε and Hepatic Insulin Resistance
Jornayvaz, F. R., & Shulman, G. I. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.03.005 · Cited by 315 · see citing works
Pharmacological Inhibition of Glucosylceramide Synthase Enhances Insulin Sensitivity
Aerts, J. M. F. G., Ottenhoff, R., Powlson, A., Grefhorst, A., van Eijk, M., Dubbelhuis, P. F., Aten, J., Kuipers, F., Serlie, M. J. M., Wennekes, T., et al. (2007) · Diabetes · doi:10.2337/db06-1619 · Cited by 301 · see citing works
The Lipid Handbook with CD-ROM
Gunstone, F. D., Harwood, J. L., & Harwood, J. L. (2007) · CRC Press eBooks · doi:10.1201/9781420009675 · Cited by 272 · see citing works
Effects of a 48-h Fat Infusion on Insulin Secretion and Glucose Utilization
Boden, G., Chen, X., Rosner, J., & Barton, M. (1995) · Diabetes · doi:10.2337/diab.44.10.1239 · Cited by 271 · see citing works
Intracellular ceramide synthesis and protein kinase Cζ activation play an essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle cells
POWELL, D. J., TURBAN, S., GRAY, A., HAJDUCH, E., & HUNDAL, H. S. (2004) · Biochemical Journal · doi:10.1042/bj20040139 · Cited by 267 · see citing works
Relationship Between Insulin Sensitivity and Sphingomyelin Signaling Pathway in Human Skeletal Muscle
Strączkowski, M., Kowalska, I., Nikołajuk, A., Dzienis-Straczkowska, S., Kinalska, I., Baranowski, M., Żendzian‐Piotrowska, M., Brzezinska, Z., & Górski, J. (2004) · Diabetes · doi:10.2337/diabetes.53.5.1215 · Cited by 258 · see citing works
Structure and functional properties of diacylglycerols in membranes1This work is dedicated to Professor Vittorio Luzzati on occasion of his 75th birthday.1
Goñi, F. M., & Alonso, A. (1999) · Progress in Lipid Research · doi:10.1016/s0163-7827(98)00021-6 · Cited by 257 · see citing works
Mitochondrial and cellular mechanisms for managing lipid excess
Aon, M. A., Bhatt, N., & Cortassa, S. C. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00282 · Cited by 253 · see citing works
Lipid Mediators of Insulin Resistance
Holland, W. L., Knotts, T. A., Chavez, J. A., Wang, L., Hoehn, K. L., & Summers, S. A. (2007) · Nutrition Reviews · doi:10.1301/nr.2007.jun.s39-s46 · Cited by 251 · see citing works
Intramyocellular lipid content in type 2 diabetes patients compared with overweight sedentary men and highly trained endurance athletes
van Loon, L. J. C., Koopman, R., Manders, R., van der Weegen, W., van Kranenburg, G. P., & Keizer, H. A. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00464.2003 · Cited by 239 · see citing works
Inhibiting Glycosphingolipid Synthesis Improves Glycemic Control and Insulin Sensitivity in Animal Models of Type 2 Diabetes
Zhao, H., Przybylska, M., Wu, I., Zhang, J., Siegel, C., Komarnitsky, S., Yew, N. S., & Cheng, S. H. (2007) · Diabetes · doi:10.2337/db06-0719 · Cited by 238 · see citing works
Insulin Resistance Is Associated With Higher Intramyocellular Triglycerides in Type I but Not Type II Myocytes Concomitant With Higher Ceramide Content
Coen, P. M., Dubé, J. J., Amati, F., Stefanović-Račić, M., Ferrell, R. E., Toledo, F. G. S., & Goodpaster, B. H. (2009) · Diabetes · doi:10.2337/db09-0988 · Cited by 229 · see citing works
Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes
Strączkowski, M., Kowalska, I., Baranowski, M., Nikołajuk, A., Otziomek, E., Zabielski, P., Adamska, A., Blachnio, A., Górski, J., & Górska, M. (2007) · Diabetologia · doi:10.1007/s00125-007-0781-2 · Cited by 219 · see citing works
Human Muscle Fiber Type–Specific Insulin Signaling: Impact of Obesity and Type 2 Diabetes
Albers, P. H., Pedersen, A. J. T., Birk, J. B., Steenberg, D. E., Vind, B. F., Baba, O., Nøhr, J., Højlund, K., & Wojtaszewski, J. F. P. (2014) · Diabetes · doi:10.2337/db14-0590 · Cited by 204 · see citing works
Ectopic lipids and organ function.
Szendroedi, J., & Roden, M. (2009) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328321b3a8 · Cited by 200 · see citing works
Self-citation
How Free Fatty Acids Inhibit Glucose Utilization in Human Skeletal Muscle
Roden, M. (2004) · Physiology · doi:10.1152/nips.01459.2003 · Cited by 193 · see citing works
Self-citation
Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans.
Roden, M., Krššák, M., Stingl, H., Gruber, S., Hofer, A., Fürnsinn, C., Moser, E., & Waldhäusl, W. K. (1999) · Diabetes · doi:10.2337/diabetes.48.2.358 · Cited by 189 · see citing works
Self-citation
The Effect of n-3 Fatty Acids on Glucose Homeostasis and Insulin Sensitivity
Flachs, P., Rossmeisl, M., & Kopecký, J. (2014) · Physiological Research · doi:10.33549/physiolres.932715 · Cited by 183 · see citing works
Toll-like Receptor 4 Deficiency Promotes the Alternative Activation of Adipose Tissue Macrophages
Orr, J. S., Puglisi, M. J., Ellacott, K. L. J., Lumeng, C. N.-K., Wasserman, D. H., & Hasty, A. H. (2012) · Diabetes · doi:10.2337/db11-1595 · Cited by 173 · see citing works
Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans
Bergman, B. C., Hunerdosse, D. M., Kerege, A. A., Playdon, M. C., & Perreault, L. (2012) · Diabetologia · doi:10.1007/s00125-011-2419-7 · Cited by 159 · see citing works
Muscle triglycerides and mitochondrial function: possible mechanisms for the development of type 2 diabetes
Roden, M. (2005) · International Journal of Obesity · doi:10.1038/sj.ijo.0803102 · Cited by 149 · see citing works
Self-citation
Influence of Gender, Obesity, and Muscle Lipase Activity on Intramyocellular Lipids in Sedentary Individuals
Moro, C., Galgani, J. E., Luu, L. C. T., Pasarica, M., Mairal, A., Bajpeyi, S., Schmitz, G., Langin, D., Liebisch, G., & Smith, S. R. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0053 · Cited by 149 · see citing works
Ceramides and Glucosylceramides Are Independent Antagonists of Insulin Signaling
Chavez, J. A., Siddique, M. M., Wang, S. T., Ching, J., Shayman, J. A., & Summers, S. A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.522847 · Cited by 147 · see citing works
Lipid Mediators of Insulin Resistance
Holland, W. L., Knotts, T. A., Chavez, J. A., Wang, L.-P., Hoehn, K. L., & Summers, S. A. (2008) · Nutrition Reviews · doi:10.1111/j.1753-4887.2007.tb00327.x · Cited by 147 · see citing works
New insights on glucosylated lipids: Metabolism and functions
Ishibashi, Y., Kohyama‐Koganeya, A., & Hirabayashi, Y. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.06.001 · Cited by 144 · see citing works
Overexpression of Sphingosine Kinase 1 Prevents Ceramide Accumulation and Ameliorates Muscle Insulin Resistance in High-Fat Diet–Fed Mice
Bruce, C. R., Risis, S., Babb, J. R., Yang, C., Kowalski, G. M., Selathurai, A., Lee, R. S., Weir, J. M., Yoshioka, K., Takuwa, Y., et al. (2012) · Diabetes · doi:10.2337/db12-0029 · Cited by 141 · see citing works
A Lipidomics Analysis of the Relationship Between Dietary Fatty Acid Composition and Insulin Sensitivity in Young Adults
Kien, C. L., Bunn, J. Y., Poynter, M. E., Stevens, R., Bain, J. R., IIkayeva, O., Fukagawa, N. K., Champagne, C. M., Crain, K. I., Koves, T. R., et al. (2012) · Diabetes · doi:10.2337/db12-0363 · Cited by 138 · see citing works
Lipid-Induced Insulin Resistance Affects Women Less Than Men and Is Not Accompanied by Inflammation or Impaired Proximal Insulin Signaling
Høeg, L. D., Sjøberg, K. A., Jeppesen, J., Jensen, T. E., Frøsig, C., Birk, J. B., Bisiani, B., Hiscock, N., Pilegaard, H., Wojtaszewski, J. F. P., et al. (2011) · Diabetes · doi:10.2337/db10-0698 · Cited by 136 · see citing works
Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity
Skovbro, M., Baranowski, M., Skov-Jensen, C., Flint, A., Dela, F., Górski, J., & Helge, J. W. (2008) · Diabetologia · doi:10.1007/s00125-008-1014-z · Cited by 133 · see citing works
Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-κB inhibitor (IκB)–nuclear factor-κB (NFκB) activation in rat muscle, in the absence of mitochondrial dysfunction
Barazzoni, R., Zanetti, M., Cappellari, G. G., Semolic, A., Boschelle, M., Codarin, E., Pirulli, A., Cattin, L., & Guarnieri, G. (2011) · Diabetologia · doi:10.1007/s00125-011-2396-x · Cited by 109 · see citing works
Implication of acyl chain of diacylglycerols in activation of different isoforms of protein kinase C
Madani, S., Hichami, A., Legrand, A. B., Belleville, J., & Khan, N. A. (2001) · The FASEB Journal · doi:10.1096/fj.01-0753int · Cited by 108 · see citing works
Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans
Nowotny, B., Zahiragic, L., Krog, D., Nowotny, P., Herder, C., Carstensen, M., Yoshimura, T., Szendroedi, J., Phielix, E., Schadewaldt, P., et al. (2013) · Diabetes · doi:10.2337/db12-1179 · Cited by 108 · see citing works
Self-citation
Increased intramuscular lipid synthesis and low saturation relate to insulin sensitivity in endurance-trained athletes
Bergman, B. C., Perreault, L., Hunerdosse, D. M., Koehler, M. C., Samek, A. M., & Eckel, R. H. (2010) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00684.2009 · Cited by 103 · see citing works
Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severe obesity
Coen, P. M., Hames, K. C., Leachman, E. M., DeLany, J. P., Ritov, V. B., Menshikova, E. V., Dubé, J. J., Stefanović-Račić, M., Toledo, F. G. S., & Goodpaster, B. H. (2013) · Obesity · doi:10.1002/oby.20381 · Cited by 97 · see citing works
Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation
Hoy, A. J., Brandon, A. E., Turner, N., Watt, M. J., Bruce, C. R., Cooney, G. J., & Kraegen, E. W. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90945.2008 · Cited by 92 · see citing works
Comparison of 5 intravenous lipid emulsions and their effects on hepatic steatosis in a murine model
Meisel, J. A., Le, H. D., de Meijer, V. E., Nosé, V., Gura, K. M., Mulkern, R. V., Sharif, M. R. A., & Puder, M. (2011) · Journal of Pediatric Surgery · doi:10.1016/j.jpedsurg.2010.08.018 · Cited by 91 · see citing works
From fatty-acid sensing to chylomicron synthesis: Role of intestinal lipid-binding proteins
Buttet, M., Traynard, V., Tran, T. T. T., Besnard, P., Poirier, H., & Niot, I. (2013) · Biochimie · doi:10.1016/j.biochi.2013.08.011 · Cited by 84 · see citing works
Saturated- and n-6 Polyunsaturated-Fat Diets Each Induce Ceramide Accumulation in Mouse Skeletal Muscle: Reversal and Improvement of Glucose Tolerance by Lipid Metabolism Inhibitors
Frangioudakis, G., Garrard, J. M., Raddatz, K., Nadler, J. L., Mitchell, T. W., & Schmitz‐Peiffer, C. (2010) · Endocrinology · doi:10.1210/en.2010-0250 · Cited by 84 · see citing works
Sphingolipids: agents provocateurs in the pathogenesis of insulin resistance
Lipina, C., & Hundal, H. S. (2011) · Diabetologia · doi:10.1007/s00125-011-2127-3 · Cited by 83 · see citing works
A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals
Boyle, K. E., Canham, J. P., Consitt, L. A., Zheng, D., Koves, T. R., Gavin, T. P., Holbert, D., Neufer, P. D., Ilkayeva, O., Muoio, D. M., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-2253 · Cited by 79 · see citing works
High-Fat Diet-Mediated Lipotoxicity and Insulin Resistance Is Related to Impaired Lipase Expression in Mouse Skeletal Muscle
Badin, P.-M., Vila, I. K., Louche, K., Mairal, A., Marqués, M.-A., Bourlier, V., Tavernier, G., Langin, D., & Moro, C. (2013) · Endocrinology · doi:10.1210/en.2012-2029 · Cited by 78 · see citing works
Free Fatty Acids Inhibit the Glucose-Stimulated Increase of Intramuscular Glucose-6-Phosphate Concentration in Humans1
Krebs, M., Krššák, M., Nowotny, P., Weghuber, D., Gruber, S., Mlynárik, V., Bischof, M. G., Stingl, H., Fürnsinn, C., Waldhäusl, W. K., et al. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.5.7488 · Cited by 78 · see citing works
Self-citation
Acyl Chain Dependence of Diacylglycerol Activation of Protein Kinase C Activityin Vitro
Marignani, P. A., Epand, R. M., & Sebaldt, R. J. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.1196 · Cited by 74 · see citing works
Mitochondrial Plasticity in Obesity and Diabetes Mellitus
Jeleník, T., & Roden, M. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4910 · Cited by 72 · see citing works
Self-citation
Skeletal Muscle Fatty Acid Handling in Insulin Resistant Men
van Hees, A. M. J., Jans, A., Hul, G. B. J., Roche, H. M., Saris, W. H. M., & Blaak, E. E. (2011) · Obesity · doi:10.1038/oby.2011.10 · Cited by 71 · see citing works
Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: a randomised clinical trial
Esther Phielix, E., Jeleník, T., Nowotny, P., Szendroedi, J., & Roden, M. (2013) · Diabetologia · doi:10.1007/s00125-013-3127-2 · Cited by 66 · see citing works
Self-citation
Early Mitochondrial Adaptations in Skeletal Muscle to Diet-Induced Obesity Are Strain Dependent and Determine Oxidative Stress and Energy Expenditure But Not Insulin Sensitivity
Boudina, S., Sena, S., Sloan, C., Tebbi, A., Han, Y. H., O'Neill, B. T., Cooksey, R. C., Jones, D., Holland, W. L., McClain, D. A., et al. (2012) · Endocrinology · doi:10.1210/en.2011-2147 · Cited by 66 · see citing works
Tissue-Specific Differences in the Development of Insulin Resistance in a Mouse Model for Type 1 Diabetes
Jeleník, T., Séquaris, G., Kaul, K., Ouwens, D. M., Esther Phielix, E., Kotzka, J., Knebel, B., Weiß, J., Reinbeck, A. L., Janke, L., et al. (2014) · Diabetes · doi:10.2337/db13-1794 · Cited by 56 · see citing works
Self-citation
Protein kinase Cδ binds TIRAP/Mal to participate in TLR signaling
Kubo-Murai, M., Hazeki, K., Sukenobu, N., et al. (2006) · Molecular Immunology · doi:10.1016/j.molimm.2006.11.005 · Cited by 53 · see citing works
Biochemical studies on cell fusion. I. Lipid composition of fusion-resistant cells.
Roos, D. S., & Choppin, P. W. (1985) · The Journal of Cell Biology · doi:10.1083/jcb.101.4.1578 · Cited by 50 · see citing works
Skeletal Muscle Lipogenic Protein Expression Is Not Different between Lean and Obese Individuals: A Potential Factor in Ceramide Accumulation
Thrush, A. B., Brindley, D. N., Chabowski, A., Heigenhauser, G. J. F., & Dyck, D. J. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2565 · Cited by 47 · see citing works
The Path to Insulin Resistance: Paved with Ceramides?
Zierath, J. R. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.02.005 · Cited by 38 · see citing works
Diabetes mellitus is associated with increased intramyocellular triglyceride, but not diglyceride, content in obese humans
Anastasiou, C. A., Kavouras, S. A., Lentzas, Y., Gova, A., Sidossis, L. S., & Melidonis, A. (2009) · Metabolism · doi:10.1016/j.metabol.2009.05.019 · Cited by 34 · see citing works
A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle
Hussey, S. E., Lum, H., Alvarez, A. V., Cipriani, Y., Garduño‐García, J. D. J., Anaya, L., Dubé, J. J., & Musi, N. (2013) · Diabetologia · doi:10.1007/s00125-013-3111-x · Cited by 31 · see citing works
Training status diverges muscle diacylglycerol accumulation during free fatty acid elevation
Chow, L. S., Mashek, D. G., Austin, E. E., Eberly, L. E., Persson, X.-M. T., Mashek, M. T., Seaquist, E. R., & Jensen, M. D. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00166.2014 · Cited by 26 · see citing works
Fecal excretions of hydroxy fatty acid and bile acid in diabetic diarrheal patients
Nakamura, T., Imamura, K.-I., Kasai, F., et al. (1993) · Journal of Diabetes and its Complications · doi:10.1016/1056-8727(93)90017-s · Cited by 24 · see citing works
Characterization of Fatty Acid Clearance in Premature Neonates during Intralipid Infusion
Morris, S. A., Simmer, K. N., & Gibson, R. A. (1998) · Pediatric Research · doi:10.1203/00006450-199802000-00015 · Cited by 23 · see citing works
The Effects of Long‐ or Medium‐Chain Fat Diets on Glucose Tolerance and Myocellular Content of Lipid Intermediates in Rats
den Bosch, J. D. V., Joris Hoeks, J., Timmers, S., Houten, S. M., van Dijk, P., Boon, W., van Beurden, D., Schaart, G., Kersten, S., Voshol, P. J., et al. (2010) · Obesity · doi:10.1038/oby.2010.152 · Cited by 21 · see citing works
The Evaluation of the Role of Beta‐Hydroxy Fatty Acids on Chronic Inflammation and Insulin Resistance
Soydan, A. S., Dökmetaş, H. S., Cetin, M., Koyuncu, A., Kaptanoglu, E., & Elden, H. (2006) · Mediators of Inflammation · doi:10.1155/mi/2006/64980 · Cited by 9 · see citing works

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Authors: Ritter, O., Jelenik, T., & Roden, M.
Affiliations: Deutsches Diabetes-Zentrum e.V. (DE)
Corresponding author: Roden, Michael
ORCID: Ritter, Olesja
Roden, Michael
Venue: Journal of Molecular Medicine
Publisher: Springer Science and Business Media LLC
Published: 2015-06-25
Volume: 93
Issue: 8
Pages: 831-843
ISSN: 0946-2716 (ISSN-L)
1432-1440
DOI: 10.1007/s00109-015-1310-2
OpenAlex: W851185968
Cited by: 74
References: 109
Citations by year: 2026: 3 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 5 · 2021: 4 · 2020: 2 · 2019: 6 · 2018: 9 · 2017: 11 · 2016: 11 · 2015: 1
FWCI: 1.02
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Journal of Molecular Medicine (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords: skeletal muscle insulin sensitivity, diacylglycerol, ceramide, TLR4, protein kinase C theta, IRS-1, IRS-1 serine phosphorylation, acylcarnitines, ganglioside biosynthesis, dietary fat, lipolysis, fatty acid saturation, inflammation, Akt signaling, athletes
MeSH terms: Animals, Dietary Fats, Humans, Insulin, Insulin Resistance, Muscles, Signal Transduction, Lipid Metabolism

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Lipid-mediated muscle insulin resistance: different fat, different pathways?

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