Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women.
Abstract
Regional fat distribution is an important determinant of insulin resistance in obesity. In the current study, the relationship between skeletal muscle insulin sensitivity, mid‐thigh muscle composition, and the metabolic profile of muscle was investigated. Muscle composition was assessed by computed tomography of the mid‐thigh, and by activities of marker enzymes of aerobic‐oxidative and glycolytic pathways and muscle fiber typing using biopsies of the vastus lateralis muscle. Muscle with reduced Hounsfield attenuation on computed tomography scans was increased in proportion to obesity, and was strongly related to insulin resistance, reduced muscle oxidative capacity, and increased anaerobic and glycolytic capacities by muscle. These findings suggest that as part of its expression of insulin resistance, skeletal muscle of obese individuals is also poorly equipped for substrate oxidation and manifests increased storage of fat.—Simoneau, J.‐A., Colberg, S. R., Thaete, F. L., Kelley, D. E. Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women. FASEB J. 9, 273–278 (1995)
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Impaired metabolic flexibility correlates with intramyocellular accumulation of lipids, and 24-h RQ can predict subsequent weight gain.
“Impaired flexibility also correlates with intramyocellular accumulation of lipids (107), and 24-h RQ can predict subsequent weight gain (110, 113).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [107]
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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
Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome
Wajchenberg, B. L. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.6.0415 · Cited by 2,961 · see citing works
“(312) found that measurements of muscle fat and visceral obesity were independent predictors of insulin resistance.”
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“A recent observation is that CT-derived muscle attenuation values are strong correlates of insulin resistance in obese subjects (24).”
BackgroundAttenuation of skeletal muscle and strength in the elderly: the Health ABC Study
Goodpaster, B. H., Carlson, C. L., Visser, M., Kelley, D. E., Scherzinger, A., Harris, T. B., Stamm, E., & Newman, A. B. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.90.6.2157 · Cited by 1,226 · see citing works
“Lower skeletal muscle attenuation values on CT have also been associated with diminished muscle function as defined by reduced oxidative enzyme capacity (25), lower maximal aerobic capacity (11), and insulin resistance (11).”
BackgroundSelf-citationGoodpaster, B. H. (2001) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.12.5755 · Cited by 1,194 · see citing works
“with prior studies demonstrating that skeletal muscle from insulin-resistant and obese subjects is characterized by lower oxidative capacity (15, 17) and lower fasting rates of fatty acid oxidation (17, 48, 49).”
Skeletal Muscle Triglyceride Levels Are Inversely Related to Insulin Action
Pan, D. A., Lillioja, S., Kriketos, A. D., Milner, M. R., Baur, L. A., Bogardus, C., Jenkins, A. B., & Storlien, L. H. (1997) · Diabetes · doi:10.2337/diab.46.6.983 · Cited by 1,179 · see citing works
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“The chief impetus for this query derives from the emerging concept that fat deposition within skeletal muscle is increased in obesity and is associated with the severity of insulin resistance (23, 38, 53).”
BackgroundMethodSelf-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
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“tions among reduced muscle attenuation and low aerobic capacity (9), a diminished oxidative enzyme capacity within muscle (28), insulin resistance (9, 28), and a blunted lipolytic response by insulin (14); and that weight loss increases the mean attenuation value of muscle (8).”
BackgroundSelf-citationDecreased Muscle Strength and Quality in Older Adults With Type 2 Diabetes
Park, S. W., Goodpaster, B. H., Strotmeyer, E. S., de Rekeneire, N., Harris, T. B., Schwartz, A. V., Tylavsky, F. A., & Newman, A. B. (2006) · Diabetes · doi:10.2337/db05-1183 · Cited by 751 · see citing works
“Reduced muscle attenuation values have been associated with reduced oxidative enzyme activity (24) and lower maximal aerobic capacity (25).”
BackgroundGoodpaster, B. H., Thaete, F. L., & Kelley, D. E. (2000) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/71.4.885 · Cited by 707 · see citing works
“This finding is consistent with several previous reports from our laboratory (14, 19, 20, 31, 32).”
ResultSelf-citationLipid oxidation is reduced in obese human skeletal muscle
Kim, J.-Y., Hickner, R. C., Cortright, R. L., Dohm, G. L., & Houmard, J. A. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.5.e1039 · Cited by 634 · see citing works
“These enzymes were studied, as b-HAD activity influences the capacity to oxidize free fatty acids (11, 30), while PFK activity has been used as an index of glycolytic capacity (28, 29).”
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“Insulin resistance is associated with many abnormalities in muscle tissue such as an increase in muscle lipid content, impaired glycogen synthesis, an enzymatic disposition towards anaerobic generation of energy (high PFK/CS ratio), an increase in the proportion of Type 2 muscle fibres and a reduced capillary density…”
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The metabolically healthy but obese individual presents a favorable inflammation profile
Karelis, A. D., Faraj, M., Bastard, J.-P., St-Pierre, D. H., Brochu, M., Prud’homme, D., & Rabasa-Lhoret, R. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0482 · Cited by 579 · see citing works
“Areas of skeletal muscle, fat, and muscle attenuation were calculated by delineating the regions of interest and then computing the surface areas using attenuation range of 190 to 30 HU for fat and 0 to 100 HU for skeletal muscle (21).”
MethodThe role of mitochondria in the pathogenesis of type 2 diabetes
Patti, M.-E., & Corvera, S. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0027 · Cited by 551 · see citing works
“oxidase (COX) activity in the fasting state (107, 108) and”
BackgroundIntramuscular lipid content is increased in obesity and decreased by weight loss
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“(2,3,33) is noteworthy, because they consistently found lower oxidative enzyme activity in vastus lateralis muscle homogenate in relation to obesity and type 2 diabetes (46,47).”
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“Many other factors, including lipid droplet size, location of lipid droplets relative to mitochondria, and muscle oxidative capacity, are all potential determinants of insulin resistance (15,48,54).”
BackgroundThe acute versus the chronic response to exercise
THOMPSON, P. D., CROUSE, S. F., GOODPASTER, B., KELLEY, D., MOYNA, N., & PESCATELLO, L. (2001) · Medicine and Science in Sports and Exercise · doi:10.1097/00005768-200106001-00012 · Cited by 508 · see citing works
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“In these studies, fat accumulation was assessed by muscle biopsies or computerized tomography of the vastus lateralis muscle (7).”
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“related to insulin resistance (10), we examined the”
BackgroundSelf-citationThe potential of endurance exercise-derived exosomes to treat metabolic diseases
Safdar, A., Saleem, A., & Tarnopolsky, M. A. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.76 · Cited by 463 · see citing works
Obesity in Children and Adolescents
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“(30) were the first to report that impaired mitochondrial function might contribute to the reduction in the activity of the oxidative pathway.”
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“Impetus for the present study derives considerably from a prior study in which it was found that glucosetolerant women with visceral obesity had an increased ratio of glycolytic to oxidative enzyme capacity in skeletal muscle and that this was a strong marker of insulin resistance (22).”
InfluentialSelf-citationInsulin Resistance in Morbid Obesity
Greco, A. V., Mingrone, G., Giancaterini, A., Manco, M., Morroni, M., Cinti, S., Granzotto, M., Vettor, R., Camastra, S., & Ferrannini, E. (2002) · Diabetes · doi:10.2337/diabetes.51.1.144 · Cited by 442 · see citing works
“Muscle attenuation on computed tomography scans, believed to reflect intramuscle lipid content, has been reported to be accentuated in obese women (22) and to be reciprocally related to insulin sensitivity (20).”
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“Additionally, muscle attenuation has been found to correlate negatively with aerobic fitness (13) and with the oxidative enzyme capacity of skeletal muscle (16).”
BackgroundSelf-citationEffects of exercise on mitochondrial content and function in aging human skeletal muscle
Menshikova, E. V., Ritov, V. B., Fairfull, L., Ferrell, R. E., Kelley, D. E., & Goodpaster, B. H. (2006) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/61.6.534 · Cited by 398 · see citing works
“A poor capacity for oxidative metabolism within skeletal muscle is also associated with insulin resistance (4) and type 2 diabetes mellitus (5,6).”
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“In accordance with our data from muscle homogenates, reduced oxidative enzyme activity and increased glycolyticto-oxidative enzyme activity has been a consistent finding in skeletal muscle from patients with type 2 diabetes (14,16).”
ResultM <scp>USCLE</scp> T <scp>RIGLYCERIDE AND</scp> I <scp>NSULIN</scp> R <scp>ESISTANCE</scp>
Kelley, D. E., Goodpaster, B. H., & Storlien, L. (2002) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.22.010402.102912 · Cited by 364 · see citing works
Self-citationAMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity.
O’Neill, H. M., Holloway, G. P., & Steinberg, G. R. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.019 · Cited by 364 · 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
“…to lean subjects; with the apparent mitochondrial insufficiencies being most pronounced in the severely obese and/or diabetic conditions (Hulver et al., 2003; Kelley et al., 2002; Kim et al., 2000; Noland et al., 2003; Simoneau et al., 1995; Simoneau and Kelley, 1997; Simoneau et al., 1999).”
BackgroundMuscle as a “Mediator” of Systemic Metabolism
Baskin, K. K., Winders, B. R., & Olson, E. N. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.021 · Cited by 333 · see citing works
“Insulin resistance, a hallmark of metabolic syndrome and diabetes, correlates with a higher composition of fast-twitch myofibers (Simoneau et al., 1995).”
BackgroundWhat is the Relationship Between Exercise and Metabolic Abnormalities?
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Self-citationSkeletal muscle utilization of free fatty acids in women with visceral obesity.
Colberg, S. R., Simoneau, J. A., Thaete, F. L., & Kelley, D. E. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117864 · Cited by 320 · see citing works
“At mid-thigh, a cross-sectional CT scan was obtained, and subcutaneous adipose area was measured electronically (18); for a separate protocol, muscle attenuation was also examined (19).”
BackgroundMethodSelf-citationHemiparetic muscle atrophy and increased intramuscular fat in stroke patients
Ryan, A. S., Dobrovolny, C. L., Smith, G. V., Silver, K. H. C., & Macko, R. F. (2002) · Archives of Physical Medicine and Rehabilitation · doi:10.1053/apmr.2002.36399 · Cited by 325 · see citing works
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BackgroundInfluentialVisceral obesity and metabolic syndrome
Bosello, O., & Zamboni, M. M. (2000) · Obesity Reviews · doi:10.1046/j.1467-789x.2000.00008.x · Cited by 284 · see citing works
“A negative correlation was found between mid-thigh muscle attenuation and insulin stimulated muscle glucose storage; furthermore, muscle glucose storage is negatively correlated with visceral fat (48).”
Backgroundn−3 Fatty acids and the metabolic syndrome
Carpentier, Y., Portois, L., & Malaisse, W. J. (2006) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/83.6.1499s · Cited by 283 · see citing works
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Invited review: activity-induced angiogenesis
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Composition of Skeletal Muscle Evaluated with Computed Tomography
Goodpaster, B. H., Thaete, F. L., & Kelley, D. E. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06416.x · Cited by 257 · see citing works
Self-citationThe effects of obesity on skeletal muscle regeneration
Akhmedov, D., & Berdeaux, R. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00371 · Cited by 241 · see citing works
“Elevated TAG content and increased numbers of lipid droplets have been observed in muscle biopsies from obese people (Simoneau et al., 1995; Malenfant et al., 2001).”
BackgroundInfluentialCassidy, S., Thoma, C., Houghton, D., & Trenell, M. I. (2016) · Diabetologia · doi:10.1007/s00125-016-4106-1 · Cited by 244 · see citing works
“The molecular adaptations to HIIT described above, including raised GLUT-4 content, increased aerobic enzyme capacity and mitochondrial biogenesis, have all been associated with improved peripheral insulin sensitivity [13, 43].”
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“THE CLOSE RELATIONSHIP between muscle lipid content and skeletal muscle insulin resistance has been reported for many years in both animal (32, 40, 41, 56) and human studies (42, 47, 55).”
BackgroundInsulin resistance: a contributing factor to age-related muscle mass loss?
Guillet, C., & Boirie, Y. (2005) · Diabetes & Metabolism · doi:10.1016/s1262-3636(05)73648-x · Cited by 237 · see citing works
“From a metabolic standpoint, insulin resistance is associated with decreased skeletal muscle oxidative capacity in type 2 diabetes [60] and in obesity [61, 62].”
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Increased intramuscular lipid storage in the insulin-resistant and endurance-trained state
van Loon, L. J. C., & Goodpaster, B. H. (2006) · Pflügers Archiv · doi:10.1007/s00424-005-1509-0 · Cited by 232 · see citing works
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“This enzyme ratio was also negatively correlated with insulin sensitivity, and is consistent with prior observations that an elevated ratio of glycolytic to oxidative enzyme capacities is a biochemical characteristic of insulin resistant skeletal muscle (55).”
ResultSelf-citationFat content in individual muscle fibers of lean and obese subjects.
Malenfant, P., Joanisse, D., Thériault, R., Goodpaster, B., Kelley, D., & Simoneau, J.-A. (2001) · International Journal of Obesity · doi:10.1038/sj.ijo.0801733 · Cited by 227 · see citing works
Self-citationSkeletal muscle triglyceride levels are inversely related to insulin action
Pan, D. A., Lillioja, S., Kriketos, A. D., Milner, M. R., Baur, L. A., Bogardus, C., Jenkins, A. B., & Storlien, L. H. (1997) · Diabetes · doi:10.2337/diabetes.46.6.983 · Cited by 1,179 · see citing works
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Interaction between free fatty acids and glucose metabolism
Boden, G. H. (2002) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/00075197-200209000-00014 · Cited by 222 · see citing works
Abdominal Obesity, Muscle Composition, and Insulin Resistance in Premenopausal Women
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“Furthermore, a decreased skeletal muscle mitochondrial size or oxidative enzyme activity is related to insulin resistance and Type 2 diabetes (4, 18, 22, 42).”
Skeletal muscle lipid accumulation in obesity, insulin resistance, and type 2 diabetes
Goodpaster, B. H., & Wolf, D. L. (2004) · Pediatric Diabetes · doi:10.1111/j.1399-543x.2004.00071.x · Cited by 206 · see citing works
“reduced rates of fat oxidation across the leg (64), as well as an overall reduction in mitochondrial enzymes involved in oxidative metabolism (53).”
BackgroundUse of intramuscular triacylglycerol as a substrate source during exercise in humans
van Loon, L. J. C. (2004) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00368.2004 · Cited by 205 · see citing works
“The physiological function of this IMTG pool has regained much of its interest over the past few years, because various studies have reported a strong association between elevated plasma FFA availability, IMTG accumulation, and the development of insulin resistance and/or Type 2 diabetes (17, 94, 116, 136, 137, 143, 1…”
BackgroundExosomes as Mediators of the Systemic Adaptations to Endurance Exercise
Safdar, A., & Tarnopolsky, M. A. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a029827 · Cited by 203 · see citing works
“Studies in the last four decades have determined that development of obesity and T2DM are mechanistically linked with skeletal muscle mitochondrial dysfunction (Simoneau et al. 1995; Morino et al. 2005, 2006; Ritov et al. 2010).”
BackgroundEffects of dietary fatty acids on insulin sensitivity and secretion
Manco, M., Calvani, M., & Mingrone, G. (2004) · Diabetes Obesity and Metabolism · doi:10.1111/j.1462-8902.2004.00356.x · Cited by 201 · see citing works
Ryan, A. S., & Nicklas, B. (1999) · International Journal of Obesity · doi:10.1038/sj.ijo.0800777 · Cited by 199 · see citing works
Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity
Menshikova, E. V., Ritov, V. B., Toledo, F. G. S., Ferrell, R. E., Goodpaster, B. H., & Kelley, D. E. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00322.2004 · Cited by 189 · see citing works
“Reduced oxidative enzyme activity in muscle, including smaller mitochondria and reduced electron transport chain (ETC) activity, has been found in obese men and women (2, 17, 20, 33).”
BackgroundSelf-citationEndurance Training and Obesity
Venables, M., & Jeukendrup, A. E. (2008) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e31815f256f · Cited by 189 · see citing works
“There is a great deal of evidence to show that intramuscular triglyceride (IMTG) concentrations are elevated in obesity and type 2 diabetes mellitus (15,16, 33,42), possibly because of an inability to oxidize lipids”
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“…glucose transporter 4 (GLUT4) expression have all been independently associated with improved insulin sensitivity (Hughes et al. 1993; Simoneau et al. 1995; Heilbronn et al. 2007) and short-term sprint interval training (Burgomaster et al. 2005, 2006, 2007, 2008; Gibala et al. 2006;…”
BackgroundHeilbronn, L. K., Gan, S. K., Turner, N., Campbell, L. V., & Chisholm, D. J. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2210 · Cited by 184 · see citing works
Afifi, M., Almaghrabi, O. A., & Kadasa, N. M. S. (2015) · BioMed Research International · doi:10.1155/2015/153573 · Cited by 182 · see citing works
“It is well known that diabetes mellitus has the ability to induce an oxidative stress in many tissues [33].”
BackgroundDeterminants of intramyocellular triglyceride turnover: implications for insulin sensitivity
Moro, C., Bajpeyi, S., & Smith, S. R. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00624.2007 · Cited by 179 · see citing works
“A reduction in fatty acid oxidation in skeletal muscle has been reported in obese and type 2 diabetic individuals in postabsorptive conditions (9, 10, 65, 112).”
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“In fact, decreased lipid oxidation in both of these conditions has been linked to an impaired capacity of lipolytic and oxidative enzymes in skeletal muscle (4, 17, 34) and therefore may also be influenced by the ovarian hormones.”
BackgroundExercise training increases intramyocellular lipid and oxidative capacity in older adults
Pruchnic, R., Katsiaras, A., He, J., Kelley, D. E., Winters, C., & Goodpaster, B. H. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00459.2003 · Cited by 177 · see citing works
“This is also consistent with reports that insulin-resistant skeletal muscle is characterized by lower oxidative capacity (50, 51) and lower postabsorptive rates of fatty acid oxidation (29).”
ResultSelf-citationPeterson, M. D., Gordon, P. M., & Hurvitz, E. A. (2012) · Obesity Reviews · doi:10.1111/j.1467-789x.2012.01052.x · Cited by 176 · see citing works
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“In older studies, muscle tissue triglycerides have been quantified using methods which do not distinguish between IMCL and extramyocellular fat in muscle tissue, including biochemical extraction(14) and Hounsfield attenuation on computer tomography scans of thigh muscle.(15,16) These measures of total muscle lipid sho…”
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Self-citation
- Authors
- Simoneau, J., Colberg, S. R., Thaete, F. L., & Kelley, D. E.
- Affiliations
- University of Pittsburgh (US)
- Veterans Health Administration (US)
- Corresponding author
- Kelley, David E.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 1995-02
- Volume
- 9
- Issue
- 2
- Pages
- 273-278
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W1592900851
- Cited by
- 362
- References
- 0
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 9 · 2023: 4 · 2022: 12 · 2021: 8 · 2020: 10 · 2019: 8 · 2018: 11 · 2017: 15 · 2016: 12 · 2015: 14 · 2014: 8 · 2013: 12 · 2012: 16
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p30dk046204-15)
- National Institute of Diabetes and Digestive and Kidney Diseases (1P30DK-46204)
- National Center for Research Resources (M01RR000056, 5 MO1 RR 00056)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- skeletal muscle insulin sensitivity, insulin resistance, obesity, muscle composition, muscle fiber typing, glycolytic enzymes, oxidative enzymes, muscle fat content, regional fat distribution, vastus lateralis, aerobic metabolism, anaerobic metabolism, women
- MeSH terms
- Adenosine Triphosphatases, Adipose Tissue, Adult, Aerobiosis, Blood Glucose, Citrate (si)-Synthase, Creatine Kinase, Electron Transport Complex IV, Female, Glucose, Glyceraldehyde-3-Phosphate Dehydrogenases, Phosphorylases, Glycolysis, Hexokinase, Humans, Infusions, Intravenous, Insulin, Obesity, Phosphofructokinase-1, Thinness, Tomography, X-Ray Computed, 3-Hydroxyacyl CoA Dehydrogenases, Glucose Clamp Technique, Body Mass Index, Muscle, Skeletal, Muscle Fibers, Skeletal
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