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1 Physical Activity Sciences
Laboratory, Laval University, Ste-Foy, Quebec, Canada G1V 4G2;
2 Department of Medicine, ABSTRACT Simoneau, Jean-Aimé, and David E. Kelley. Altered
glycolytic and oxidative capacities of skeletal muscle contribute to
insulin resistance in NIDDM. J. Appl.
Physiol. 83(1): 166-171, 1997.
obesity; non-insulin-dependent diabetes mellitus; muscle enzymes; hexokinase; citrate synthase; phosphofructokinase
INTRODUCTION A GOOD DEAL OF THE FUNCTIONAL DIVERSITY of skeletal
muscle derives from differences of fiber type distribution, and this
also helps determine metabolic diversity of skeletal
muscle. Insulin-stimulated metabolism in skeletal muscle
is influenced by fiber type (10). In regard to pathophysiology, insulin
resistance in men and women correlates with reduced proportions of
slow-twitch, oxidative fibers and increased proportions of fast-twitch,
glycolytic fibers (15). Similarly, aging and physical inactivity, which
are recognized to lead to insulin resistance, are also associated with
diminished oxidative capacity of skeletal muscle (18). Conversely,
increased physical activity, which improves insulin sensitivity,
enhances expression of oxidative enzymes while reducing expression of
glycolytic enzymes (18). Thus relationships between fiber type
distribution and insulin resistance quite likely arise from patterns of
oxidative enzymes and glycolytic enzymes, although capillary density
may also contribute. In support of this postulate, diminished oxidative enzyme capacity of skeletal muscle is a stronger correlate of obesity
than is fiber type per se (21). Also, in a recent collaborative study
between our laboratories (22), a strong relationship was detected in
obese women between insulin resistance of skeletal muscle and the
combination of increased glycolytic and reduced oxidative enzyme
activity. These findings gave impetus for the present investigation,
which was undertaken to examine the hypothesis that proportionality
between enzyme activity of the glycolytic pathway is perturbed in
relation to activity of oxidative enzymes within skeletal muscle of
individuals with non-insulin-dependent diabetes mellitus (NIDDM).
Insulin resistance of skeletal muscle in individuals with NIDDM is
typically more severe than in simple (glucose-tolerant) obesity, and,
additionally, most patients with NIDDM are obese. Thus it is logical to
postulate a similar or more severe altered ratio of glycolytic to
oxidative enzyme capacities in NIDDM. The relatively few prior studies
to examine this issue did indeed find reduced oxidative enzyme capacity
in skeletal muscle of individuals with NIDDM (2, 13, 16, 26). However,
neither the relationship of enzyme activity to insulin sensitivity nor
the proportionality between glycolytic and oxidative capacities was
explicitly addressed. Pette and Hofer (19) were among the
first investigators to articulate the concept that proportionality
between glycolytic and oxidative pathways is a key determinant of the
metabolic potential of skeletal muscle and can be modulated by physical
exercise. The glycolytic-to-oxidative ratio connotes potential for
coordinating glycolytic flux of substrate with capacity for oxidative
phosphorylation. Therefore, the ratio of activities, perhaps more
strongly than the activities of individual enzymes, reflects metabolic
capabilities of skeletal muscle. In the present study, an increased
glycolytic-to-oxidative ratio was observed in skeletal muscle of
individuals with NIDDM and was more severe than the perturbation found
in obesity.
METHODS
The insulin
resistance of skeletal muscle in glucose-tolerant obese individuals is
associated with reduced activity of oxidative enzymes and a
disproportionate increase in activity of glycolytic enzymes. Because
non-insulin-dependent diabetes mellitus (NIDDM) is a disorder
characterized by even more severe insulin resistance of skeletal muscle
and because many individuals with NIDDM are obese, the present study
was undertaken to examine whether decreased oxidative and increased
glycolytic enzyme activities are also present in NIDDM. Percutaneous
biopsy of vatus lateralis muscle was obtained in eight lean (L) and
eight obese (O) nondiabetic subjects and in eight obese NIDDM subjects
and was assayed for marker enzymes of the glycolytic
[phosphofructokinase, glyceraldehyde phosphate dehydrogenase,
hexokinase (HK)] and oxidative pathways [citrate synthase
(CS), cytochrome-c oxidase], as
well as for a glycogenolytic enzyme (glycogen phosphorylase) and a
marker of anaerobic ATP resynthesis (creatine kinase). Insulin
sensitivity was measured by using the euglycemic clamp technique.
Activity for glycolytic enzymes (phosphofructokinase, glyceraldehye
phosphate dehydrogenase, HK) was highest in subjects with subjects with NIDDM, following the order of NIDDM > O > L, whereas maximum
velocity for oxidative enzymes (CS,
cytochrome-c oxidase) was lowest in subjects with NIDDM. The ratio between glycolytic and
oxidative enzyme activities within skeletal muscle correlated
negatively with insulin sensitivity. The HK/CS ratio had the strongest
correlation (r = 
0.60, P < 0.01) with insulin
sensitivity. In summary, an imbalance between glycolytic and oxidative
enzyme capacities is present in NIDDM subjects and is more severe than
in obese or lean glucose-tolerant subjects. The altered ratio between
glycolytic and oxidative enzyme activities found in skeletal muscle of
individuals with NIDDM suggests that a dysregulation between
mitochondrial oxidative capacity and capacity for glycolysis is an
important component of the expression of insulin resistance.
Table 1.
Clinical characteristics and insulin sensitivity
Lean Nondiabetic Subjects (5 M/3 F)
Obese
Nondiabetic Subjects (6 M/4 F)
NIDDM Subjects (5 M/3 F)
Age, yr
47 ± 3
47 ± 3
51 ± 3
Weight, kg
72 ± 5
96 ± 6*
104 ± 4*
BMI, kg/m2
23.2 ± 0.8
31.2 ± 1.2*
34.2 ± 1.2*
FPG, mmol/l
5.0 ± 0.2
5.2 ± 0.1
11.3 ± 1.4
Hb A1c, %
5.8 ± 0.2
5.4 ± 0.2
8.0 ± 0.7
Glucose Rd,
µmol · kg
1 · min1
53 ± 6
30 ± 3*
15 ± 2
Glucose
oxidation2,
µmol · kg
1 · min1
17 ± 1
14 ± 2
8 ± 2
Nonoxidative glucose metabolism,
µmol · kg
1 · min1
36 ± 5
16 ± 2*
7 ± 2
Values are means ± SE. M, male; F, female; NIDDM,
non-insulin-dependent diabetes mellitus; BMI, body mass index; FPG,
fasting plasma glucose; Rd, rate of disposal. Normal
range for hemoglobin A1c (Hb A1c) = 4.6-6.3%.
*
P < 0.05 vs. lean subjects.
P < 0.05 vs. nondiabetic subjects.
2 · min1).
After insulin infusion was started, a variable-rate 20% dextrose infusion was used to maintain euglycemia; in NIDDM subjects plasma glucose was allowed to decrease to 90 mg/dl.
D-[3-3H]glucose
was added to the 20% dextrose infusion to maintain stable plasma
glucose specific activity (6). In three of the NIDDM subjects, it was necessary to extend the clamp to maintain at least 60 min of euglycemia. During the final 30 min of insulin infusion, blood
was sampled at 10-min intervals for plasma glucose radioactivity. Data
on collateral positron-emission tomography studies of glucose transport
have been separately reported (12).
80°C and shipped on dry ice to
Laval University (J.-A. Simoneau) for analysis of enzyme activity. Small pieces of the muscle sample (~10 mg) were homogenized in a
glass-glass Duall homogenizer with 39 vol of ice-cold extracting medium
(0.1 M Na-K-phosphate, 2 mM EDTA, pH 7.2). The suspension was
magnetically stirred on ice for 15 min. For hexokinase (HK; EC 2.7.1.1)
determination, Triton X-100 was added to an aliquot of muscle
homogenate to give a final concentration of 1%. After another 15 min
of being stirred on ice, this homogenate was used for assaying HK
activity. The major portion of the initial aliquot was cooled with ice
and sonicated five times for 5 s at 20 W, with pauses of 85 s between
pulses, and the resulting homogenate was used for determination of
activity levels (maximum velocity) of six enzymes.
Spectrophotometric techniques were conducted at 30°C, according to
methods previously used (11, 24). The enzymes were citrate synthase
(CS; EC 4.1.3.7), cytochrome-c oxidase (COx; EC 1.9.3.1), phosphofructokinase (PFK; EC 2.7.1.11), glyceraldehyde phosphate dehydrogenase (GAPDH; EC 1.2.1.12), glycogen
phosphorylase (Phos; EC 2.4.1.1), and creatine kinase (CK; EC
2.7.3.2). Values of the enzyme activities are expressed in units of micromoles of substrate per minute per gram of wet weight
tissue (U/g). The intraindividual reproducibility for these measurements has been established (7, 23).
Substrate and hormone assays.
Plasma glucose was measured by using a Yellow Springs Instruments
glucose analyzer, (Yellow Springs, OH). Plasma glucose radioactivity was determined with liquid-scintillation spectrometry after
deproteinizing plasma and evaporating supernatant to dryness to remove
tritiated water. Rates of glucose appearance and utilization
(Rd) were calculated by using the equations of Finegood
(6). Plasma insulin was measured by radioimmunoassay by
using a commercial kit (Insulin RIA 100, Pharmacia Diagnostics,
Uppsala, Sweden).
Statistics.
Data are expressed as means ± SE, unless otherwise indicated.
Analysis of variance was used to examine for significant differences across groups (lean, obese, and NIDDM). To test the hypothesis that
there was a consistent rank order in the four sets of
glycolytic-to-oxidative ratios across the three groups (in the order of
NIDDM > obese > lean), the nonparametric test of Terpstra and
Jonckheere, which tests for a consistent pattern of rank order across
multiple parallel sets of data, was utilized (14). To examine the
relationship between enzyme activity and insulin sensitivity, linear
regression and stepwise multiple regressions were performed by using
statistical software (BBN, Cambridge, MA).
RESULTS
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Relationship of glycolytic and oxidative capacities to insulin sensitivity. There were significant group differences for insulin-stimulated utilization of glucose, oxidation of carbohydrate, and nonoxidative glucose metabolism, as shown in Table 1. Significant and negative relationships (r = about
0.5)
were found between insulin sensitivity (Rd) and the ratios of
glycolytic to oxidative enzyme activities (PFK/CS, GAPDH/CS, HK/CS, and
Phos/CS). In a stepwise, multiple-regression model,
containing individual marker enzymes as well as each
glycolytic-to-oxidative ratio, the HK/CS ratio was the strongest
predictor of insulin resistance
(r = 0.60;
P < 0.01) as shown in Fig.
2. Indeed, after inclusion of the HK/CS ratio, no
additional variance in Rd was explained by stepwise inclusion of other enzyme activities or other
enzyme ratios. Obesity (body mass index) was positively related to
glycolytic enzyme markers (r = 0.33-0.63) and to the glycolytic-to-oxidative ratios
(r = 0.52-0.64) and was
negatively associated with oxidative enzyme markers
(r = 0.24 to
0.39).
DISCUSSION
Insulin resistance within skeletal muscle is a key metabolic perturbation of obesity and NIDDM. The etiology of insulin resistance in obesity and NIDDM is multifactorial, involving interaction among impairments in hormonal signaling, enzyme and transporter activity, substrate availability and competition, modulation of blood flow, and other influences, such as recent physical activity, weight, and diet composition. In recent years, there has been a renewed interest in potential relationships between insulin sensitivity and muscle fiber type distribution (15, 17). In many respects, this interest in muscle morphology and its relationship to substrate metabolism derives from much earlier seminal studies by Pette and Hofer (19) and others (9), who articulated the important regulatory role that is exerted by differences in the expression of energy-producing pathways in skeletal muscle. Functional differentiation of muscle was shown to be strongly related to differences in glycolytic and oxidative enzyme capacities, and plasticity of muscle metabolism was related to changes within enzyme pathways, shown to be capable of more robust change than fiber type distribution per se. The focus of the present study was to test the hypothesis that a disproportionality exists between glycolytic enzyme activities (postulated to be increased) and oxidative enzyme activities (postulated to be decreased) in skeletal muscle of individuals with NIDDM. A corollary was that these pertubations are linked to the expression of insulin resistance, and the findings of the present study support both hypotheses.
Impetus for the present study derives considerably from a prior study in which it was found that glucose-tolerant 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). The findings in obese, glucose-tolerant individuals of the present study reaffirm these earlier results. The findings also extend these observations because the disproportionality between glycolytic and oxidative enzyme activity was more marked in NIDDM than in obese glucose-tolerant individuals. There have been some prior investigations that have examined skeletal muscle glycolytic and oxidative enzyme activity in NIDDM (2, 13, 16, 26). These studies found that glycolytic capacity was higher, whereas oxidative capacity was reduced, in NIDDM. However, neither the relationship to insulin sensitivity nor the issue of proportionality between glycolytic and oxidative enzyme capacity was specifically addressed. The results of the present study are, therefore, consistent with these previous studies and also can be regarded as consistent with recent data on an increased distribution of fast-twitch, glycolytic fibers in NIDDM (17). Seven skeletal muscle enzymes were assayed for the present study, and for each of these, there was at least a twofold variance in activity across the subjects, who were lean and obese nondiabetic individuals and obese individuals with NIDDM. There were strong within-subject relationships among the four glycolytic enzymes (PFK, GAPDH, HK, and Phos) and a correlation of similar strength between CS and COx; however, no significant correlation (within subject) was observed between glycolytic and oxidative activities. These patterns confirm prior observations regarding coordinated regulation of enzyme activity levels within each pathway yet independent regulation of glycolytic compared with oxidative pathways (19). These findings underscore the conceptual validity of examining proportionality between glycolytic and oxidative enzyme activities as a separate, yet integrative, parameter of skeletal muscle metabolic potential. A high level of within-subject repeatability for determination of enzyme activity has been reported as well (7, 22).
Subjects with NIDDM had the highest ratio of glycolytic to oxidative enzyme activities, with obese and lean nondiabetic subjects manifesting stepwise decrements in these ratios. This pattern for ratios of glycolytic to oxidative enzyme activities emerged so clearly because there were oppositely directed patterns for glycolytic and oxidative enzyme activities. NIDDM subjects had the highest mean value for glycolytic activity and the lowest mean value for oxidative capacity, with obese nondiabetic subjects manifesting intermediate values for each pathway.
The ranges for the oxidative markers, CS and COx, were consistent with levels typically found in sedentary subjects (7). The reduced oxidative capacity of skeletal muscle in NIDDM is consonant with low values for aerobic fitness in many individuals with NIDDM (20). Although none of the participants in the present study reported strenuous or even regular programs of exercise, aerobic fitness was not determined, and it is possible that some of the differences in oxidative capacity observed do indeed reflect differences in fitness or physical activity levels among our volunteers. Capacity for oxidative phosphorylation within skeletal muscle appears to decline with aging but can be improved with physical training. Physical activity, which enhances insulin sensitivity, has the effect of increasing oxidative capacity and reducing glycolytic enzyme activity (9). This type of response is additional, albeit indirect, evidence for a linkage between regulation of insulin sensitivity and proportionality between glycolytic and oxidative pathways. The response to training suggests that as the capacity to replete ATP through oxidative phosphorylation is enhanced, there is less reliance on ATP generation via anaerobic glycolysis. The findings of the present study and those of an earlier study in obese glucose-tolerant women (22) suggest that an opposite pattern occurs in the setting of insulin resistance. This pattern seems to be one characterized by an increased reliance on glycolytic capacity and diminished ability to utilize the higher yielding pathways of oxidative phosphorylation. Additional studies are needed to address the relative contribution of these fundamental aspects of the bioenergetics of skeletal muscle to the various disorders associated with insulin resistance.
Relatively strong correlations were found in the present study between glycolytic-to-oxidative ratios and insulin sensitivity. The mechanisms by which an elevated ratio of glycolytic to oxidative enzyme capacities contributes to insulin resistance are not well established. However, some hypotheses can be proposed, perhaps usefully taking the direction proposed by Gerbitz et al. (8) in their recent review on mitochondrial metabolism and its relationship to insulin resistance. The ratio between glycolytic and oxidative enzyme activities reflects proportionality between cytosolic and mitochondrial capacities for ATP resynthesis. Because, during insulin-stimulated conditions, replenishment of ATP in skeletal muscle is nearly exclusively derived from oxidative phosphorylation, then an impediment within this pathway, or an increased reliance on cytosolic ATP resynthesis, might negatively influence steps that require ready provision of ATP such as glycogen formation or trapping of transported glucose via its phosphorylation. Thus it seems plausible to postulate that alterations within glycolytic and oxidative pathways form a "stage" on which defects in insulin regulation of substrate transport and metabolism are more readily manifest. Alterations in the glycolytic-to-oxidative ratio may dispose skeletal muscle toward lipid accumulation in and around muscle fibers, thereby creating a milieu for substrate competition and contributing to insulin resistance. In a prior study, positive correlation was observed between glycolytic-to-oxidative ratio and muscle attenuation determined by computed tomography, which is a noninvasive parameter of fat accumulation within skeletal muscle (22). Certainly additional research is needed to better understand the mechanisms that account for the associations between the glycolytic-to-oxidative ratio and insulin sensitivity.
In the present study, the HK/CS ratio emerged as the strongest correlate of insulin resistance. An impairment of insulin-stimulated glucose phosphorylation has recently been described to be a key defect within skeletal muscle of patients with NIDDM (12). HK serves a pivotal role in glucose transport and metabolism, by trapping glucose through phosphorylation. In the great majority of patients with NIDDM, the structure of HK II is normal (5). Reduced expression of skeletal muscle HK II mRNA in NIDDM has been reported (25). Nevertheless the mechanism of impaired glucose phosphorylation in NIDDM remains uncertain, and one consideration should be that functional capacity of HK is reduced due to diminished efficiency in providing ATP (27). This inefficiency in supplying ATP to HK might be due to altered mitochondrial binding of HK (1, 3), a diminished supply of ATP due to reduced oxidative enzyme capacity, or combined impairments impeding glucose phosphorylation. These are intriguing possibilities and particularly pertinent to the present study because these are potential mechanisms by which mitochondrial dysfunction, or poor coordination of cytosolic and mitochondrial metabolism, could adversely affect insulin-stimulated glucose metabolism. The present findings that the HK/CS ratio is a marker of insulin resistance suggests that the functional and physical coupling between HK capacity and mitochondrial oxidative capacity may be important aspects to examine as mechanisms of impaired glucose phosphorylation and insulin resistance in NIDDM.
In summary, skeletal muscle of patients with NIDDM, and, to a milder degree, skeletal muscle of obese glucose-tolerant individuals, has been found be manifest an increased ratio of glycolytic to oxidative enzyme capacities, an imbalance that is correlated to insulin resistance.
ACKNOWLEDGEMENTS
We are grateful to our research volunteers and to the nursing, dietary, and technician staff at the General Clinical Research Center. We also acknowlegde the technical expertise of Yves Gélinas of Laval University.
FOOTNOTES
Address for reprint requests: D. E. Kelley, Univ. of Pittsburgh School of Medicine, Div. of Endocrinology and Metabolism, E-1140 Biomedical Science Tower, Pittsburgh, PA 15261.
Received 20 August 1996; accepted in final form 3 March 1997.
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I. R. Lanza, D. K. Short, K. R. Short, S. Raghavakaimal, R. Basu, M. J. Joyner, J. P. McConnell, and K. S. Nair Endurance Exercise as a Countermeasure for Aging Diabetes, November 1, 2008; 57(11): 2933 - 2942. [Abstract] [Full Text] [PDF]
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A. Jaleel, K. R. Short, Y. W. Asmann, K. A. Klaus, D. M. Morse, G. C. Ford, and K. S. Nair In vivo measurement of synthesis rate of individual skeletal muscle mitochondrial proteins Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1255 - E1268. [Abstract] [Full Text] [PDF]
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 L. P Turcotte and J. S Fisher Skeletal Muscle Insulin Resistance: Roles of Fatty Acid Metabolism and Exercise Physical Therapy, November 1, 2008; 88(11): 1279 - 1296. [Abstract] [Full Text] [PDF]
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 A.-L. Tardy, C. Giraudet, P. Rousset, J.-P. Rigaudiere, B. Laillet, S. Chalancon, J. Salles, O. Loreau, J.-M. Chardigny, and B. Morio Effects of trans MUFA from dairy and industrial sources on muscle mitochondrial function and insulin sensitivity J. Lipid Res., July 1, 2008; 49(7): 1445 - 1455. [Abstract] [Full Text] [PDF]
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 H M De Feyter, N M A van den Broek, S F E Praet, K Nicolay, L J C van Loon, and J J Prompers Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction Eur. J. Endocrinol., May 1, 2008; 158(5): 643 - 653. [Abstract] [Full Text] [PDF]
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J. R. Berggren, K. E. Boyle, W. H. Chapman, and J. A. Houmard Skeletal muscle lipid oxidation and obesity: influence of weight loss and exercise Am J Physiol Endocrinol Metab, April 1, 2008; 294(4): E726 - E732. [Abstract] [Full Text] [PDF]
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 J. P. Thyfault Setting the stage: possible mechanisms by which acute contraction restores insulin sensitivity in muscle Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2008; 294(4): R1103 - R1110. [Abstract] [Full Text] [PDF]
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J. A. Houmard Intramuscular lipid oxidation and obesity Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2008; 294(4): R1111 - R1116. [Abstract] [Full Text] [PDF]
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 L. Metz, J. Mercier, A. Tremblay, N. Almeras, and D. R. Joanisse Effect of weight loss on lactate transporter expression in skeletal muscle of obese subjects J Appl Physiol, March 1, 2008; 104(3): 633 - 638. [Abstract] [Full Text] [PDF]
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 A. E. Civitarese and E. Ravussin Minireview: Mitochondrial Energetics and Insulin Resistance Endocrinology, March 1, 2008; 149(3): 950 - 954. [Abstract] [Full Text] [PDF]
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T. A. Bauer, J. E.B. Reusch, M. Levi, and J. G. Regensteiner Skeletal Muscle Deoxygenation After the Onset of Moderate Exercise Suggests Slowed Microvascular Blood Flow Kinetics in Type 2 Diabetes Diabetes Care, November 1, 2007; 30(11): 2880 - 2885. [Abstract] [Full Text] [PDF]
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L. Didier, B. Yerby, R. Deacon, and J. Gao Diet-induced modulation of mitochondrial activity in rat muscle Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1169 - E1177. [Abstract] [Full Text] [PDF]
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 I. Pagel-Langenickel, D. R. Schwartz, R. A. Arena, D. C. Minerbi, D. Thor. Johnson, M. A. Waclawiw, R. O. Cannon III, R. S. Balaban, D. J. Tripodi, and M. N. Sack A discordance in rosiglitazone mediated insulin sensitization and skeletal muscle mitochondrial content/activity in Type 2 diabetes mellitus Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2659 - H2666. [Abstract] [Full Text] [PDF]
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M. Mogensen, K. Sahlin, M. Fernstrom, D. Glintborg, B. F. Vind, H. Beck-Nielsen, and K. Hojlund Mitochondrial Respiration Is Decreased in Skeletal Muscle of Patients With Type 2 Diabetes Diabetes, June 1, 2007; 56(6): 1592 - 1599. [Abstract] [Full Text] [PDF]
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C. B. Jensen, H. Storgaard, S. Madsbad, E. A. Richter, and A. A. Vaag Altered Skeletal Muscle Fiber Composition and Size Precede Whole-Body Insulin Resistance in Young Men with Low Birth Weight J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1530 - 1534. [Abstract] [Full Text] [PDF]
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B. Ukropcova, O. Sereda, L. de Jonge, I. Bogacka, T. Nguyen, H. Xie, G. A. Bray, and S. R. Smith Family History of Diabetes Links Impaired Substrate Switching and Reduced Mitochondrial Content in Skeletal Muscle Diabetes, March 1, 2007; 56(3): 720 - 727. [Abstract] [Full Text] [PDF]
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 F. W. Booth and S. J. Lees Fundamental questions about genes, inactivity, and chronic diseases Physiol Genomics, January 17, 2007; 28(2): 146 - 157. [Abstract] [Full Text] [PDF]
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B. Sirikul, B. A. Gower, G. R. Hunter, D. E. Larson-Meyer, and B. R. Newcomer Relationship between insulin sensitivity and in vivo mitochondrial function in skeletal muscle Am J Physiol Endocrinol Metab, October 1, 2006; 291(4): E724 - E728. [Abstract] [Full Text] [PDF]
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L. Puricelli, E. Iori, R. Millioni, G. Arrigoni, P. James, M. Vedovato, and P. Tessari Proteome Analysis of Cultured Fibroblasts from Type 1 Diabetic Patients and Normal Subjects J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3507 - 3514. [Abstract] [Full Text] [PDF]
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 E. Chanseaume, C. Malpuech-Brugere, V. Patrac, G. Bielicki, P. Rousset, K. Couturier, J. Salles, J.-P. Renou, Y. Boirie, and B. Morio Diets High in Sugar, Fat, and Energy Induce Muscle Type-Specific Adaptations in Mitochondrial Functions in Rats J. Nutr., August 1, 2006; 136(8): 2194 - 2200. [Abstract] [Full Text] [PDF]
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 N. Tiffin, E. Adie, F. Turner, H. G. Brunner, M. A. van Driel, M. Oti, N. Lopez-Bigas, C. Ouzounis, C. Perez-Iratxeta, M. A. Andrade-Navarro, et al. Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes Nucleic Acids Res., June 6, 2006; 34(10): 3067 - 3081. [Abstract] [Full Text] [PDF]
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T. Ostergard, J. L. Andersen, B. Nyholm, S. Lund, K.S. Nair, B. Saltin, and O. Schmitz Impact of exercise training on insulin sensitivity, physical fitness, and muscle oxidative capacity in first-degree relatives of type 2 diabetic patients Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E998 - E1005. [Abstract] [Full Text] [PDF]
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A. Oberbach, Y. Bossenz, S. Lehmann, J. Niebauer, V. Adams, R. Paschke, M. R. Schon, M. Bluher, and K. Punkt Altered Fiber Distribution and Fiber-Specific Glycolytic and Oxidative Enzyme Activity in Skeletal Muscle of Patients With Type 2 Diabetes Diabetes Care, April 1, 2006; 29(4): 895 - 900. [Abstract] [Full Text] [PDF]
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B. Kiens Skeletal Muscle Lipid Metabolism in Exercise and Insulin Resistance Physiol Rev, January 1, 2006; 86(1): 205 - 243. [Abstract] [Full Text] [PDF]
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B.-S. Cha, T. P. Ciaraldi, K.-S. Park, L. Carter, S. R. Mudaliar, and R. R. Henry Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPAR{gamma} agonists Am J Physiol Endocrinol Metab, July 1, 2005; 289(1): E151 - E159. [Abstract] [Full Text] [PDF]
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D. S. Hittel, Y. Hathout, E. P. Hoffman, and J. A. Houmard Proteome Analysis of Skeletal Muscle From Obese and Morbidly Obese Women Diabetes, May 1, 2005; 54(5): 1283 - 1288. [Abstract] [Full Text] [PDF]
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 S. Y. Park, G. H. Choi, H. I. Choi, J. Ryu, C. Y. Jung, and W. Lee Depletion of Mitochondrial DNA Causes Impaired Glucose Utilization and Insulin Resistance in L6 GLUT4myc Myocytes J. Biol. Chem., March 18, 2005; 280(11): 9855 - 9864. [Abstract] [Full Text] [PDF]
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V. B. Ritov, E. V. Menshikova, J. He, R. E. Ferrell, B. H. Goodpaster, and D. E. Kelley Deficiency of Subsarcolemmal Mitochondria in Obesity and Type 2 Diabetes Diabetes, January 1, 2005; 54(1): 8 - 14. [Abstract] [Full Text] [PDF]
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D. S. Hittel, W. E. Kraus, C. J. Tanner, J. A. Houmard, and E. P. Hoffman Exercise training increases electron and substrate shuttling proteins in muscle of overweight men and women with the metabolic syndrome J Appl Physiol, January 1, 2005; 98(1): 168 - 179. [Abstract] [Full Text] [PDF]
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G. Perdomo, S. R. Commerford, A.-M. T. Richard, S. H. Adams, B. E. Corkey, R. M. O'Doherty, and N. F. Brown Increased {beta}-Oxidation in Muscle Cells Enhances Insulin-stimulated Glucose Metabolism and Protects against Fatty Acid-induced Insulin Resistance Despite Intramyocellular Lipid Accumulation J. Biol. Chem., June 25, 2004; 279(26): 27177 - 27186. [Abstract] [Full Text] [PDF]
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D.-H. Han, L. A. Nolte, J.-S. Ju, T. Coleman, J. O. Holloszy, and C. F. Semenkovich UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E347 - E353. [Abstract] [Full Text]
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C. R. Bruce, M. J. Anderson, A. L. Carey, D. G. Newman, A. Bonen, A. D. Kriketos, G. J. Cooney, and J. A. Hawley Muscle Oxidative Capacity Is a Better Predictor of Insulin Sensitivity than Lipid Status J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5444 - 5451. [Abstract] [Full Text] [PDF]
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K. R. Short, J. L. Vittone, M. L. Bigelow, D. N. Proctor, R. A. Rizza, J. M. Coenen-Schimke, and K. S. Nair Impact of Aerobic Exercise Training on Age-Related Changes in Insulin Sensitivity and Muscle Oxidative Capacity Diabetes, August 1, 2003; 52(8): 1888 - 1896. [Abstract] [Full Text] [PDF]
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M. A. Selak, B. T. Storey, I. Peterside, and R. A. Simmons Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats Am J Physiol Endocrinol Metab, July 1, 2003; 285(1): E130 - E137. [Abstract] [Full Text] [PDF]
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C. S. Stump, K. R. Short, M. L. Bigelow, J. M. Schimke, and K. S. Nair Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts PNAS, June 24, 2003; 100(13): 7996 - 8001. [Abstract] [Full Text] [PDF]
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G. J. Crowther, J. M. Milstein, S. A. Jubrias, M. J. Kushmerick, R. K. Gronka, and K. E. Conley Altered energetic properties in skeletal muscle of men with well-controlled insulin-dependent (type 1) diabetes Am J Physiol Endocrinol Metab, April 1, 2003; 284(4): E655 - E662. [Abstract] [Full Text] [PDF]
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J. C. Baldi, J. L. Aoina, H. C. Oxenham, W. Bagg, and R. N. Doughty Reduced exercise arteriovenous O2 difference in Type 2 diabetes J Appl Physiol, March 1, 2003; 94(3): 1033 - 1038. [Abstract] [Full Text] [PDF]
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S. R. Stannard, M. W. Thompson, K. Fairbairn, B. Huard, T. Sachinwalla, and C. H. Thompson Fasting for 72 h increases intramyocellular lipid content in nondiabetic, physically fit men Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1185 - E1191. [Abstract] [Full Text] [PDF]
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D. E. Kelley, J. He, E. V. Menshikova, and V. B. Ritov Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes Diabetes, October 1, 2002; 51(10): 2944 - 2950. [Abstract] [Full Text] [PDF]
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C. J. Tanner, H. A. Barakat, G. L. Dohm, W. J. Pories, K. G. MacDonald, P. R. G. Cunningham, M. S. Swanson, and J. A. Houmard Muscle fiber type is associated with obesity and weight loss Am J Physiol Endocrinol Metab, June 1, 2002; 282(6): E1191 - E1196. [Abstract] [Full Text] [PDF]
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D. E. Kelley and B. H. Goodpaster Skeletal Muscle Triglyceride: An aspect of regional adiposity and insulin resistance Diabetes Care, May 1, 2001; 24(5): 933 - 941. [Abstract] [Full Text]
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J. He, S. Watkins, and D. E. Kelley Skeletal Muscle Lipid Content and Oxidative Enzyme Activity in Relation to Muscle Fiber Type in Type 2 Diabetes and Obesity Diabetes, April 1, 2001; 50(4): 817 - 823. [Abstract] [Full Text]
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J.-Y. Kim, R. C. Hickner, R. L. Cortright, G. L. Dohm, and J. A. Houmard Lipid oxidation is reduced in obese human skeletal muscle Am J Physiol Endocrinol Metab, November 1, 2000; 279(5): E1039 - E1044. [Abstract] [Full Text] [PDF]
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D. E. Kelley, B. Goodpaster, R. R. Wing, and J.-A. Simoneau Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss Am J Physiol Endocrinol Metab, December 1, 1999; 277(6): E1130 - E1141. [Abstract] [Full Text] [PDF]
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J. G. Regensteiner, T. A. Bauer, J. E. B. Reusch, S. L. Brandenburg, J. M. Sippel, A. M. Vogelsong, S. Smith, E. E. Wolfel, R. H. Eckel, and W. R. Hiatt Abnormal oxygen uptake kinetic responses in women with type II diabetes mellitus J Appl Physiol, July 1, 1998; 85(1): 310 - 317. [Abstract] [Full Text] [PDF]
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