Increased collagen content in insulin-resistant skeletal muscle
Abstract
Oversupply and underutilization of lipid fuels are widely recognized to be strongly associated with insulin resistance in skeletal muscle. Recent attention has focused on the mechanisms underlying this effect, and defects in mitochondrial function have emerged as a potential player in this scheme. Because evidence indicates that lipid oversupply can produce abnormalities in extracellular matrix composition and matrix changes can affect the function of mitochondria, the present study was undertaken to determine whether muscle from insulin-resistant, nondiabetic obese subjects and patients with type 2 diabetes mellitus had increased collagen content. Compared with lean control subjects, obese and type 2 diabetic subjects had reduced muscle glucose uptake ( P < 0.01) and decreased insulin stimulation of tyrosine phosphorylation of insulin receptor substrate-1 and its ability to associate with phosphatidylinositol 3-kinase ( P < 0.01 and P < 0.05). Because it was assayed by total hydroxyproline content, collagen abundance was increased in muscle from not only type 2 diabetic patients but also nondiabetic obese subjects (0.26 ± 0.05, 0.57 ± 0.18, and 0.67 ± 0.20 μg/mg muscle wet wt, lean controls, obese nondiabetics, and type 2 diabetics, respectively), indicating that hyperglycemia itself could not be responsible for this effect. Immunofluorescence staining of muscle biopsies indicated that there was increased abundance of types I and III collagen. We conclude that changes in the composition of the extracellular matrix are a general characteristic of insulin-resistant muscle.
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Elevated collagen VI levels correlate with hyperglycemia and insulin resistance.
“Others have further reported correlations between elevated collagen VI levels, hyperglycemia, and insulin resistance (104, 105)”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [104]
ECM remodeling causes changes in signaling via cell surface receptors that sense the extracellular microenvironment.
“ECM remodeling170, 172, 173, 178 causes changes in signaling via cell surface receptors that sense the extracellular microenvironment.162, 179-181”
From The Vasculature in Prediabetes (2018) · cites this paper as [172]
Cites
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197 · see citing works
Glucose clamp technique: a method for quantifying insulin secretion and resistance.
DeFronzo, R. A., Tobin, J. D., & Andres, R. (1979) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1979.237.3.e214 · Cited by 7,425 · see citing works
Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., Sole, J., Nichols, A., Ross, J. S., Tartaglia, L. A., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319451 · Cited by 6,760 · see citing works
Woessner, J. F. (1961) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(61)90291-0 · Cited by 3,851 · see citing works
Weyer, C., Funahashi, T., Tanaka, S., Hotta, K., Matsuzawa, Y., Pratley, R. E., & Tataranni, P. A. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.5.7463 · Cited by 3,541 · see citing works
Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes
Kelley, D. E., He, J., Menshikova, E. V., & Ritov, V. B. (2002) · Diabetes · doi:10.2337/diabetes.51.10.2944 · Cited by 2,321 · see citing works
AdipoQ Is a Novel Adipose-specific Gene Dysregulated in Obesity
Hu, E., Liang, P., & Spiegelman, B. M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.18.10697 · Cited by 2,239 · see citing works
Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes
Petersen, K. F., Dufour, S., Befroy, D., Garcia, R., & Shulman, G. I. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa031314 · Cited by 2,193 · see citing works
Mitochondrial dysfunction in the elderly: possible role in insulin resistance
Petersen, K. F., Befroy, D., Dufour, S., Dziura, J., Ariyan, C., Rothman, D. L., DiPietro, L., Cline, G. W., & Shulman, G. I. (2003) · Science · doi:10.1126/science.1082889 · Cited by 2,107 · 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-citationObesity-induced inflammatory changes in adipose tissue
Wellen, K. E., & Hotamisligil, G. S. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200320514 · Cited by 1,823 · see citing works
Determination of hydroxyproline
Stegemann, H., & Stalder, K. (1967) · Clinica Chimica Acta · doi:10.1016/0009-8981(67)90167-2 · Cited by 1,588 · see citing works
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
Cusi, K., Maezono, K., Osman, A., Pendergrass, M., Patti, M. E., Pratipanawatr, T., DeFronzo, R. A., Kahn, C. R., & Mandarino, L. J. (2000) · Journal of Clinical Investigation · doi:10.1172/jci7535 · Cited by 1,139 · see citing works
Self-citationFuel selection in human skeletal muscle in insulin resistance: a reexamination.
Kelley, D. E., & Mandarino, L. J. (2000) · Diabetes · doi:10.2337/diabetes.49.5.677 · Cited by 1,017 · see citing works
Self-citationInfluence of body fat distribution on free fatty acid metabolism in obesity.
Jensen, M. D., Haymond, M. W., Rizza, R. A., Cryer, P. E., & Miles, J. M. (1989) · Journal of Clinical Investigation · doi:10.1172/jci113997 · Cited by 683 · 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-citationTripathy, D., Mohanty, P., Dhindsa, S., Syed, T., Ghanim, H., Aljada, A., & Dandona, P. (2003) · Diabetes · doi:10.2337/diabetes.52.12.2882 · Cited by 658 · see citing works
Paradis, V., Perlemuter, G., Bonvoust, F., Dargère, D., Parfait, B., Vidaud, M., Conti, M., Huet, S., Bâ, N., Buffet, C., et al. (2001) · Hepatology · doi:10.1053/jhep.2001.28055 · Cited by 540 · see citing works
Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency
Irwin, W., Bergamin, N., Sabatelli, P., Reggiani, C., Megighian, A., Merlini, L., Braghetta, P., Columbaro, M., Volpin, D., Bressan, G. M., et al. (2003) · Nature Genetics · doi:10.1038/ng1270 · Cited by 509 · see citing works
Simoneau, J., Veerkamp, J. H., Turcotte, L. P., & Kelley, D. E. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.14.2051 · Cited by 491 · see citing works
Interaction between glucose and free fatty acid metabolism in human skeletal muscle.
Kelley, D. E., Mokáň, M., Simoneau, J. A., & Mandarino, L. J. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116603 · Cited by 481 · see citing works
Self-citationRiser, B. L., DeNichilo, M. O., Cortés, P., Baker, C. J., Grondin, J. M., Yee, J., & Narins, R. G. (2000) · Journal of the American Society of Nephrology · doi:10.1681/asn.v11125 · Cited by 386 · see citing works
Krook, A., Björnholm, M., Galuska, D., Jiang, X. J., Fahlman, R., Myers, M. G., Wallberg-Henriksson, H., & Zierath, J. R. (2000) · Diabetes · doi:10.2337/diabetes.49.2.284 · Cited by 375 · 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-citationEffect of long chain triglyceride infusion on glucose metabolism in man
Thiébaud, D., DeFronzo, R. A., Jacot, E., Golay, A., Acheson, K. J., Maeder, E., Jéquier, E., & Felber, J. (1982) · Metabolism · doi:10.1016/0026-0495(82)90163-9 · Cited by 296 · 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-citationCivitarese, A. E., Jenkinson, C. P., Richardson, D. K., Bajaj, M., Cusi, K. J., Kashyap, S. R., Berria, R., Belfort, R., DeFronzo, R. A., Mandarino, L. J., et al. (2004) · Diabetologia · doi:10.1007/s00125-004-1359-x · Cited by 258 · see citing works
Self-citationSchober, J. M., Chen, N., Grzeszkiewicz, T. M., Jovanovic, I., Emeson, E. E., Ugarova, T. P., Ye, R. D., Lau, L. F., & Lam, S. C.-T. (2002) · Blood · doi:10.1182/blood.v99.12.4457 · Cited by 242 · see citing works
Festa, A., Hanley, A. J., Tracy, R. P., D’Agostino, R., & Haffner, S. M. (2003) · Circulation · doi:10.1161/01.cir.0000091339.70120.53 · Cited by 231 · see citing works
Højlund, K., Wrzesinski, K., Larsen, P. M., Fey, S. J., Roepstorff, P., Handberg, A., Dela, F., Vinten, J., McCormack, J. G., Reynet, C., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212881200 · Cited by 221 · see citing works
Malonyl-CoA and AMP-activated protein kinase: An expanding partnership
Saha, A. K., & Ruderman, N. B. (2003) · Molecular and Cellular Biochemistry · doi:10.1023/a:1026053302036 · Cited by 177 · see citing works
Macdonald, G. A., Bridle, K. R., Ward, P. J., Walker, N. I., Houglum, K., George, D. K., Smith, J. L., Powell, L. W., Crawford, D. H., & Ramm, G. A. (2001) · Journal of Gastroenterology and Hepatology · doi:10.1046/j.1440-1746.2001.02445.x · Cited by 156 · see citing works
Licastro, F., Masliah, E., Pedrini, S., & Thal, L. J. (2000) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000017209 · Cited by 137 · see citing works
Connective Tissue Growth Factor Is a Regulator for Fibrosis in Human Chronic Pancreatitis
di Mola, F. F., Friess, H., Martignoni, M. E., et al. (1999) · Annals of Surgery · doi:10.1097/00000658-199907000-00010 · Cited by 133 · see citing works
Effects of Lipid on Basal Carbohydrate Metabolism in Normal Men
Boden, G. H., & Jadali, F. (1991) · Diabetes · doi:10.2337/diab.40.6.686 · Cited by 126 · see citing works
Inhibition by insulin of hepatic glucose production in the normal dog
Steele, R., Bishop, J. S., Dunn, A., ALTSZULER, N., Rathgeb, I., & de Bodo, R. C. (1965) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1965.208.2.301 · Cited by 111 · see citing works
Skeletal muscle lipid concentration quantified by magnetic resonance imaging
Goodpaster, B. H., Stenger, V. A., Boada, F. E., McKolanis, T. M., Davis, D., Ross, R., & Kelley, D. E. (2004) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/79.5.748 · Cited by 90 · see citing works
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Khan, T., Muise, E. S., Iyengar, P., Wang, Z. V., Chandalia, M., Abate, N., Zhang, B. B., Bonaldo, P., Chua, S., & Scherer, P. E. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01300-08 · Cited by 1,053 · see citing works
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Self-citation
- Authors
- Berria, R., Wang, L., Richardson, D. K., Finlayson, J., Belfort, R., Pratipanawatr, T., De Filippis, E. A., Kashyap, S., & Mandarino, L. J.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2006-03
- Volume
- 290
- Issue
- 3
- Pages
- E560-E565
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2108084986
- Cited by
- 171
- References
- 38
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 7 · 2023: 8 · 2022: 9 · 2021: 18 · 2020: 14 · 2019: 6 · 2018: 8 · 2017: 13 · 2016: 7 · 2015: 10 · 2014: 5 · 2013: 8 · 2012: 4
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK047936, R01-DK-66938, F32DK061189, R01-DK-47936)
- National Center for Research Resources (M01RR01346, M01RR001346)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- 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
- Keywords
- insulin resistance, skeletal muscle, collagen, extracellular matrix, type 2 diabetes, obesity, hyperglycemia, mitochondrial dysfunction, IRS-1, phosphatidylinositol 3-kinase, glucose uptake, type I collagen, type III collagen
- MeSH terms
- Adult, Biopsy, Diabetes Mellitus, Type 2, Extracellular Matrix, Female, Glucose, Humans, Hydroxyproline, Insulin, Insulin Resistance, Male, Microscopy, Fluorescence, Middle Aged, Obesity, Phosphoproteins, Phosphorylation, Tyrosine, Muscle, Skeletal, Collagen Type I, Collagen Type III, Insulin Receptor Substrate Proteins
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