| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Diabetes and Obesity Research Program (L.K.H., N.T., L.V.C., D.J.C.), Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; Royal Perth Hospital (S.K.G.), School of Medicine and Pharmacology, Perth, Western Australia 6001, Australia; and School of Health Sciences (N.T.), University of Wollongong, Wollongong, New South Wales 2522, Australia
Address all correspondence and requests for reprints to: Dr. Leonie Heilbronn, Garvan Institute for Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia. E-mail: l.heilbronn{at}garvan.org.au.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Methods: Subjects (n =18) were divided into insulin-sensitive (IS) and insulin-resistant (IR) groups by median glucose infusion rate during a hyperinsulinemic euglycemic clamp. Weight, VO2max (maximal aerobic capacity), and percentage body fat were measured before and after 6 continuous weeks of aerobic exercise training at 55–70% VO2max (40 min/session, 4 d/wk).
Results: Age, percentage fat, and VO2max were not different between IS and IR groups at baseline. Expression of the nuclear encoded PGC1
and mitochondrial encoded gene COX1 were significantly lower in the IR group (P < 0.05). Citrate synthase activity and protein levels of subunits from complexes I and III of the respiratory chain were also lower in the IR group (P < 0.05). Insulin sensitivity and aerobic fitness were increased after exercise training in both groups (P < 0.001), and the expression of mitochondrial encoded genes CYTB and COX1 was also increased (P < 0.01). However, there was no change in PGC1 expression, mitochondrial enzyme activity, or protein levels of complexes of the respiratory chain in response to exercise in either group.
Conclusion: This study confirms that IR men have reduced markers of mitochondrial metabolism, independent of fatness and fitness. Moderate exercise training did not alter these markers despite improving fitness and whole body insulin sensitivity. This study suggests that additional mechanisms may be involved in improving insulin resistance after exercise training in obese men.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Mitochondria are the site of oxidative energy production in eukaryotic cells. Mitochondrial biogenesis involves the coordinated action of both nuclear and mitochondrial encoded genomes. Peroxisome profilerator-activated receptor 
coactivator (PGC1), an inducible transcriptional coactivator, has been implicated as a major regulator of the mitochondrial biogenic program. PGC1 interacts with nuclear respiratory factor 1 (NRF1), stimulating transcription of many mitochondrial genes as well as mitochondrial transcription factor A (TFAM), a direct regulator of mitochondrial DNA replication and transcription. A coordinated reduction of the PGC1-responsive genes involved in oxidative phosphorylation was found from vastus lateralis muscle biopsies in nondiabetic relatives of subjects with type 2 diabetes and in subjects with overt type 2 diabetes compared with glucose-tolerant controls (5, 6). Additional investigations have also shown reduced mitochondrial function [as assessed by multiple methods including ATP phosphorylation, mitochondrial size, citrate synthase (CS) activity, rotenone-sensitive nicotinamide adenine dinucleotide:oxygen (NADH:O2) oxidoreductase, and mitochondrial copy number] in nondiabetic relatives of subjects with type 2 diabetes and in subjects with overt type 2 diabetes (4, 7, 8, 9). However, these studies are cross-sectional, and other unmeasured factors may account for some of the observed differences, including gender, age, total body fat mass, visceral fat mass or fitness. In fact, few studies have measured fitness, and there is the possibility that the reduced muscle mitochondrial metabolism observed in more obese individuals may simply be a consequence of more sedentary habits (10).
Another important question that is unresolved is whether mitochondrial dysfunction is an inherent property of insulin-resistant (IR) subjects or whether it is acquired and can be reversed by exercise training. Aerobic exercise training is sufficient to increase mitochondrial enzyme activity and the expression of nuclear-encoded genes involved in regulating mitochondrial transcription including PGC1, NRF1, and TFAM in young and old lean individuals (11, 12), but relatively few studies have investigated this response in obese individuals. Recently, Menshikova et al. (13) observed that dietary restriction in combination with exercise improved mitochondrial metabolism in obese individuals. However, dietary restriction stimulates PGC1 and endothelial nitric oxide synthase expression (14), and therefore the direct effects of exercise alone are unclear.
In the present study, we have sought to determine whether overweight and obese IR subjects who had similar fitness and percentage body fat compared with insulin-sensitive (IS) subjects have reduced markers of mitochondrial metabolism. We then investigated the effects of moderate exercise training for 6 wk on these markers.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Sedentary, nonsmoking, nondiabetic overweight and obese male subjects were recruited by public advertisement. Subjects were excluded if they exercised more than 1 h/wk, if weight had changed by more than 2 kg in the preceding 6 months, if they were taking antihypertensive medications, or if they had a personal history of type 2 diabetes or cardiovascular disease. The study protocol was approved by the Human Research Ethics Committee at St. Vincent’s Hospital, Sydney, and subjects provided informed written consent. Similarly to a previous study (15), subjects were divided into IS and IR groups based on median glucose infusion rate [37.1 µmol/kg fat-free mass (FFM)·min] as measured during a hyperinsulinemic euglycemic clamp.
Study design
Subjects were tested at baseline and after 6 wk of exercise training as described previously (16). Postexercise clinic visits were conducted 24–36 h after the last bout of exercise. Subjects fasted overnight before each visit. Weight was measured in light clothing, and height was assessed by a stadiometer. Following this, a vastus lateralis muscle biopsy was performed, the samples were blotted for blood, and any visible fat was removed before they were snap-frozen at –80 C. A standard 120-min hyperinsulinemic euglycemic clamp was then performed with indirect calorimetry (Deltatrac, Datex, Helsinki, Finland), similar to previously described studies (16, 17, 18). Briefly, one cannula was placed in an antecubital vein for infusion of insulin (Novo Nordisk, New South Wales, Australia) and glucose (Baxter, New South Wales, Australia). A second cannula was placed retrograde in a dorsal vein of the contra lateral hand for blood withdrawal, and the hand was placed in a heating pad. Insulin was infused at 50 mU/m2·min, and arterialized glucose was measured at 10-min intervals (YSI 2300, YSI, Inc., Yellow Springs, OH), and a variable infusion of exogenous glucose was given to maintain glucose concentrations at 5.0 mmol/liter. Immediately after the clamp, dual-energy x-ray absorptiometry (Lunar DPX; Lunar Radiation Corp., Madison, WI) and magnetic resonance imaging (General Electric, Milwaukee, WI) scans were performed. Sixteen axial T1-weighted abdominal slices between the levels of T12/L1 and L4/5 were obtained. The right calf was then scanned within an extremity coil, and magnetic resonance spectra were acquired by PRESS sequence (echo time, 135 msec; repetition time, 1500 msec) according to methods described (16). Intramyocellular lipid (IMCL) was expressed as the ratio between the proton resonance areas of intramyocellular lipid methylene and creatinine. Maximal aerobic capacity (VO2max) was assessed using the modified YMCA cycling protocol 1 wk before baseline testing and 1 wk after exercise testing (19). Long chain acylCoA (LCAC) were measured from approximately 100-mg muscle biopsy samples, and RIAs were performed for measurement of fasting serum insulin (Linco Research, St. Charles, MO) according to previously described methods (16).
Exercise program
Subjects were instructed to perform aerobic exercise at 55–70% VO2max as previously described (16). Briefly, subjects exercised by alternating brisk walking and light jogging to achieve a target heart rate range. Subjects exercised 4 d/wk for 40 min per session for 6 consecutive weeks. Subjects recorded exercise details in a diary and had regular monitoring contact. Exercise was interrupted in four subjects due to unforeseen health, occupational, or personal reasons (three in the IS group and one in the IR group). All subjects were tested after 6 wk of uninterrupted exercise training, and therefore subjects were tested after 9.7 ± 0.9 wk (range, 6–15 wk) with a frequency of 4.1 ± 0.2 exercise sessions per week (range, 3–5). There were no statistical differences for any of the variables examined in the four subjects that had interruptions to their exercise training program, and so they were included in the analysis. Subjects were instructed not to change their usual dietary habits as monitored by 3-d diet records.
Muscle gene expression
RNA was isolated from approximately 30 mg of tissue using the acid phenol method (20). Primers were designed using MacVector (Sigma Aldrich, New South Wales, Australia) (Table 1
). cDNA was prepared from RNA by use of Superscript II and oligo dT primers (Invitrogen, Victoria, Australia). Real-time quantitative PCR was performed with the Rotorgene 6.0 (Corbett Research, New South Wales, Australia) with Hot Start reaction mix (Roche Applied Science, New South Wales, Australia) in accordance with the manufacturer’s instructions. Samples were run with internal positive and negative controls, and gene product was quantified by comparing samples to known standard concentrations of pure gene product. The threshold cycle value for every sample was measured in duplicate and was normalized to glyceraldehyde-3-phosphate dehydrogenase expression, which was not different between IR and IS groups at baseline and was not altered in response to exercise training.
|
An additional 30 mg of muscle was weighed, and 5% (wt:vol) homogenates were prepared in 50 mmol/liter Tris-HCl, 1 mmol/liter EDTA, and 0.1% Triton X-100 (pH 7.2). After three freeze-thaw cycles, enzyme activities were determined at 30 C using a Spectra Max 250 microplate spectrophotometer (Molecular Devices, Sunnyvale, CA). All assays were conducted in duplicate, and reaction rates were linear for more than 2 min. Cytochrome c oxidase (COX) activity was measured in a reaction mixture containing 100 mmol/liter KH2PO4/K2HPO4 and 0.1 mmol/liter cytochrome c reduced with sodium hydrosulfite (pH 7.0). The rate of change in absorbance was monitored at 550 nm. CS activity was measured in a reaction mixture containing 100 mmol/liter Tris-HCl, 1 mmol/liter MgCl2, 1 mmol/liter EDTA, 0.2 mmol/liter dithio-bis (2-nitrobenzoic acid), 0.3 mmol/liter acetyl CoA, and 0.5 mmol/liter oxaloacetate (omitted for control) (pH 8.2). The rate of change in absorbance was monitored at 412 nm. For ß-hydroxyacyl CoA dehydrogenase (HAD), hexokinase (HK), and phosphofructokinase (PFK), activity was measured at 340 nm after the appearance/disappearance of nicotinamide adenine dinucleotide phosphate. For HAD, the reaction mixture contained 50 mmol/liter imidazole, 0.15 mmol/liter NADH, 0.1 mmol/liter acetoacetyl CoA, 0.175 mM KCl, and 2.0 mM EDTA (pH 7.4). For PFK, the reaction mixture contained 50 mmol/liter imidazole, 5 mM MgCl2, 50 mM KCl, 5 mM ATP, 0.4 mmol/liter NADH, excess aldolase triosephosphate isomerase and -glycerol phosphate dehydrogenase, and 5 mM fructose-6 phospate (omitted for control) (pH 7.4). For HK, the reaction mixture contained 50 mmol/liter imidazole, 8 mM ATP, 8 mmol/liter MgCl2, 0.5 mmol/liter NADP+, excess glucose-6 phosphate dehydrogenase, and 5 mM glucose (omitted for control) (pH 7.4).
Immunoblotting
For protein blots, approximately 20 mg muscle was homogenized in an ice-cold solubilization buffer containing 65 mM Tris (pH 7.4), 150 mM NaCl, 5 mM EDTA, 1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, 10% glycerol, 1 µg/ml aprotinin, 1 µg/ml leupeptin, 10 mM sodium fluoride, 1 mM Na3VO4, and 1 mM phenylmethylsulfonylfluoride. The protein concentration of the supernatants was determined using the Bio-Rad Coomassie dye-binding protein assay (Bio-Rad Laboratories, Hercules, CA). Protein homogenates were prepared in Laemmli buffer (21) and subjected to SDS-PAGE. Proteins were separated on 10% gels transferred to polyvinylidene difluoride membranes (Hybond-P; Amersham Biosciences, Piscataway, NJ) and blocked in 1% BSA. Membranes were probed with MS601, which is an antibody cocktail against the 20-kDa subunit of complex I, the 30-kDa subunit of complex II, the core protein 2 subunit of complex III, subunit II of complex IV, and complex V subunit, respectively (MitoSciences, Eugene, OR). Membranes were incubated with donkey antirabbit horseradish peroxidase, bands were detected by chemiluminescence (PerkinElmer Life Sciences, Boston, MA), and band densities were quantified using IPLab Gel software (Signal Analytics Corp., Vienna, VA). To allow for quantification between blots, an in-house standard was also run on each gel, and protein levels are expressed relative to the standard.
Statistics
Data were analyzed using Statview 5 (SAS Institute, Cary, NC). Data are presented as means ± SEM unless otherwise stated, and significance was set at P < 0.05. One-way ANOVA was performed to test for differences in baseline variables between IS and IR groups, and the change from baseline with intervention was analyzed by repeated measures with intervention and group as interaction terms in the model.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Subject characteristics at baseline are presented in Table 2. As expected, the IR group had significantly lower insulin sensitivity as measured during the hyperinsulinemic clamp. Fasting insulin was also significantly increased in the IR group. Weight, percent body fat, visceral fat, respiratory quotient (RQ), and VO2max were not significantly different between IS and IR groups.
|
The expression of the nuclear encoded gene PGC1 was lower in IR subjects at baseline (P < 0.01; Fig. 1), and a trend toward reduced NRF1 expression was also observed (P = 0.07). TFAM expression was not significantly different between groups. Mitochondrial encoded gene COX1 was also significantly lower (P < 0.01), but CYTB expression was not statistically lower between IS and IR groups (P = 0.13). Two IS subjects had high expression of CYTB, and removal of these outliers did not statistically alter this result. Additionally, nuclear encoded UCP3 expression was significantly lower in IR subjects (P < 0.01). CS activity was also lower in the IR group (136 ± 8 vs. 112 ± 6 nmol/mg protein·min; P = 0.03), and COX activity tended to be lower (61 ± 14 vs. 38 ± 4 nmol/mg protein·min; P = 0.1), but there were no differences for enzymes involved in glucose and fat metabolism (HAD, PFK, HK) between groups (data not shown). We also measured the protein content of subunits of each of the five complexes of the respiratory chain. Although protein levels were lower in the IR group compared with the IS group for each subunit measured, this was statistically significant for complexes I and III only (Fig. 2; P < 0.03).
|
|
Consistent with the role of PGC1 as a master metabolic regulator of mitochondrial biogenesis, we also observed significant correlations between PCG1 and NRF1 (r2 = 0.44; P = 0.01), COX1 (r2 = 0.64; P = 0.008), and CYTB (r2 = 0.72; P = 0.001). Significant correlations were also observed between glucose infusion rate and expression of PGC1 (r2 = 0.28; P = 0.02) and UCP3 (r2 = 0.25; P = 0.03). CS and COX activity were also related to insulin-stimulated glucose infusion rate (Fig. 3). However, no relationships were observed between any of the markers of mitochondrial metabolism and IMCL or the active lipid metabolite, LCAC.
|
Three subjects did not complete the study [IS (n = 1), IR (n = 2)], and so postexercise analyses are presented on 15 subjects. The effects of exercise on body weight, fat oxidation, body composition, fitness and insulin sensitivity were previously reported (16). Briefly, body weight was not significantly changed in response to training, although total body fat and sc abdominal fat were reduced by 4 ± 1% (P = 0.05) in both groups. Fasting RQ was also reduced in IS and IR groups by 5 and 4%, respectively (P = 0.03). However, the change in RQ (or metabolic flexibility) in response to insulin infusion was not different after exercise training. Visceral fat, IMCL, and LCAC were not significantly altered by exercise training in either group, but significant increases were observed in insulin sensitivity and VO2max (Table 3). We examined markers of mitochondrial metabolism before and after exercise to determine whether they were associated with improvements in insulin sensitivity. We observed that mitochondrial encoded genes COX1 and CYTB were increased in response to exercise in both groups with no differences observed between groups (P < 0.001; Table 3). Nuclear encoded genes PGC1 and TFAM were not significantly altered, although a tendency toward increased NRF1 expression was observed (P = 0.06). Mitochondrial enzyme activities and protein levels of subunits of the respiratory chain were not significantly changed by exercise (Table 3). However, we did observe relationships between the increase in protein levels of complexes III and V and the increase in glucose infusion rate and VO2max (Fig. 4).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
and COX1, indicating reduced mitochondrial biogenesis. Importantly, CS activity, a marker of mitochondrial content and function (23), was also reduced. Although COX activity was not statistically different between groups, we observed that subjects with lower levels of COX activity were more IR. We saw no difference in activities of enzymes that represent glycolysis (HK, PFK) and the ß-oxidation pathway (HAD). In support of the gene expression and mitochondrial activity findings, we also observed that protein subunits from complexes I and III were significantly lower in the IR group, suggesting reduced mitochondrial density. Together, these findings support previous results that IR subjects have impaired mitochondrial metabolism. Interestingly, no difference was found in IMCLs between IR and IS groups. This contradicts earlier studies showing increased lipid deposition within skeletal muscle (1, 4, 24) but is supported by other studies investigating relatives of subjects with type 2 diabetes (25) and overweight subjects (26). IMCLs are probably a marker for more active lipid metabolites that impair insulin signaling (27), but we also observed no differences in fasting LCAC and no relationship between fasting LCAC or IMCL and measures of mitochondrial metabolism. Together, these results suggest that mitochondrial dysfunction may be associated with insulin sensitivity by an alternative mechanism. Potential mechanisms include altered production of reactive oxygen species (28) and increased damage to proteins, DNA, and lipids or altered insulin signaling to AMP kinase (29). UCP3 has previously been proposed to lower the proton gradient of the respiratory chain (30), preventing excessive reactive oxygen species production in the mitochondria and thus mitochondrial damage. In accordance with this, we observed lower UCP3 expression in IR subjects in this study. Other studies have reported decreased UCP3 expression and protein in subjects with impaired glucose tolerance and overt type 2 diabetes (31). However, it is possible that other lipid moieties, ceramide, and diacylglycerol have a greater relationship with these markers of mitochondrial metabolism, but there was insufficient biopsy material to measure these metabolites in the current study.
The majority of mitochondrial proteins are derived from the nuclear genome, necessitating the transcription of genes, the translation of mRNA into protein, the targeting of protein to a mitochondrial compartment via import machinery, and the assembly of multisubunit enzyme complexes in the respiratory chain. Six weeks of exercise has previously been noted to be sufficient to evoke a new steady state of mitochondrial biogenesis, a process generally associated with a 50–100% increase in mitochondrial content in skeletal muscle in lean healthy subjects (32). In the current study, PGC1 expression was not altered after exercise training. However, the posttraining muscle biopsies were taken approximately 36 h after the final exercise bout, and PGC1 expression has previously been shown to be reduced to basal levels 4 h after a single exercise bout (33). In support of an effect of exercise training on mitochondrial biogenesis, we observed increased expression of mitochondrial encoded genes COX1 and CYTB, which are downstream targets of PGC1. However, the protein levels of subunits of the respiratory chain were not statistically increased after exercise training, although subjects who tended to increase insulin sensitivity and fitness also tended to increase the protein levels of subunits from complexes III and V. Of note, the subunit of complex I, which was lower in IR subjects, was not related to the change in insulin sensitivity. Whether this reflects an intrinsic defect in this subunit in obese subjects in response to exercise training requires further investigation.
Although there was a tendency toward an increase in some markers of mitochondrial density and increased mitochondrial biogenesis, we observed no changes in mitochondrial enzyme activity in response to moderate exercise training and no change in IMCL. In the absence of measures of mitochondrial oxygen consumption, CS and COX activities are considered acceptable alternatives to measure mitochondrial function, and due to assembly of multisubunit enzyme complexes in the respiratory chain are generally regarded to be more representative of mitochondrial function than gene expression or protein alone (34, 35). These results therefore suggest that there may be a defect in the ability to increase mitochondrial metabolism in overweight and obese subjects in response to 6 wk of moderate exercise training. This study contradicts findings by Menshikova et al. (13) who observed an increase in mitochondrial enzyme activity from vastus lateralis biopsies after 16 wk of aerobic exercise training and calorie restriction in obese men and women. Discrepancies between these studies may be due to the length of exercise training periods that were employed, differences in exercise intensity, or location of mitochondria. When interpreting the results of the present study, consideration should be given to the small number of subjects that were tested and the lack of a lean control group to confirm these findings. In addition, subjects were tested approximately 36 h after the last exercise bout and, although this is a fairly standard length of time before testing in the literature, the insulin-sensitizing effects of the last bout of exercise can persist for up to 3 d (36). Finally, it should be pointed out that the muscle biopsies were taken from the vastus lateralis, and greater changes may have been evident from other muscle groups, such as the soleus or gastrocnemius because these muscles would have been recruited more with the type of exercise employed. In support of our findings, an increasing number of studies have reported no changes in IMCL in response to moderate levels of exercise training or weight loss, despite marked improvements in insulin sensitivity (9, 26, 37). Furthermore, Civitarese et al. (14) recently showed no change in CS after 6 months of supervised exercise training and weight loss in overweight individuals. Studies in untrained subjects have also shown that changes in VO2max are detected before changes in CS (19) and disassociations between the change in mitochondrial oxidative capacity and insulin sensitivity are previously reported in the elderly (11) and in subjects with type 2 diabetes (38) in response to exercise training.
In summary, IR obese men had reduced markers of mitochondrial metabolism, including reduced expression of PGC1 and COX1, reduced protein levels of subunits of the respiratory chain, and reduced CS activity at baseline compared with relatively IS obese men that had similar fatness and fitness. The level of exercise undertaken in this study is, we believe, representative of an achievable goal by obese individuals on a free-living basis. We observed modest increases in insulin sensitivity and fitness after exercise with increased expression of mitochondrial encoded genes, but this was observed without changes in IMCL or markers of mitochondrial density and/or enzyme activity. This study suggests that additional mechanisms may also mediate improved insulin sensitivity in the obese. It would be of interest to measure the effects of exercise training on capillary recruitment in IR individuals in future studies. Recent studies show that glucose uptake under insulin-stimulated conditions is also dependent on the rate of delivery (39) and exercise increases capillary recruitment in rodents (37).
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Disclosure Summary: L.K.H., N.T., D.J.C., L.V.C., and S.K.G. have nothing to declare.
First Published Online January 23, 2007
Abbreviations: COX, Cytochrome C oxidase; COX1, COX subunit 1; CS, citrate synthase; CytB, cytochrome B; FFM, fat-free mass; HAD, ß-hydroxyacyl CoA dehydrogenase; HK, hexokinase; IR, insulin resistant; IMCL, intramyocellular lipid; IS, insulin sensitive; LCAC, long chain acyl CoA; NADH, nicotinamide adenine dinucleotide; NRF1, nuclear respiratory factor-1; PFK, phosphofructokinase; PGC1, peroxisome proliferator-activated receptor- coactivator-1; RQ, respiratory quotient; TFAM, mitochondrial transcription factor A; UCP3, uncoupling protein 3; VO2max, maximal aerobic capacity.
Received October 10, 2006.
Accepted January 11, 2007.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
]-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273[CrossRef][Medline]This article has been cited by other articles:
 |
|
 |
|
  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]
|
|
|
|
 |
|
 J. J. Dube, F. Amati, M. Stefanovic-Racic, F. G. S. Toledo, S. E. Sauers, and B. H. Goodpaster Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited Am J Physiol Endocrinol Metab, May 1, 2008; 294(5): E882 - E888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 L. K. Heilbronn, S. Gregersen, D. Shirkhedkar, D. Hu, and L. V. Campbell Impaired Fat Oxidation After a Single High-Fat Meal in Insulin-Sensitive Nondiabetic Individuals With a Family History of Type 2 Diabetes Diabetes, August 1, 2007; 56(8): 2046 - 2053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Schrauwen Of the Fit and the Fat: Mitochondrial Abnormalities and Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1229 - 1231. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
) subjects.