Journal Logo

CLINICAL SCIENCES

Insulin Responsiveness in Metabolic Syndrome after Eight Weeks of Cycle Training

STUART, CHARLES A.1; SOUTH, MARK A.2; LEE, MICHELLE L.3; MCCURRY, MELANIE P.1; HOWELL, MARY E. A.1; RAMSEY, MICHAEL W.2; STONE, MICHAEL H.2

Author Information
Medicine & Science in Sports & Exercise: November 2013 - Volume 45 - Issue 11 - p 2021-2029
doi: 10.1249/MSS.0b013e31829a6ce8
  • Free

Abstract

Obesity and diabetes have increased in prevalence in the United States for the past 20 yr at a near epidemic rate (24,25,37). More than half of all adults are now overweight (BMI > 25 kg·m−2), with some regions having in excess of two thirds of the population being overweight or obese (BMI > 30 kg·m−2). Diabetes has been diagnosed in as many as 13% of adults in several states. Insulin resistance and hyperinsulinemia are key elements of the metabolic syndrome that is marked by visceral obesity, hypertension, hyperlipidemia, hyperglycemia, and coronary heart disease (1,19,26). The metabolic syndrome is a prediabetes condition until fasting hyperglycemia reaches 126 mg·dL−1 (20).

Regular exercise is beneficial to the prevention (21) and management of type 2 diabetes (15,34). Whether the exercise consists predominantly of endurance training or strength training, glycemic control improves (6,12,13). A dose–response relationship for the amount of regular exercise was apparent in a recent report of diabetes incidence among male health professionals (18). Grontved et al. (18) evaluated data from biennially administered detailed questionnaires from more than 32,000 participants over an average of 16 yr. During the time of follow-up, there were 2278 new cases of type 2 diabetes. Regular aerobic exercise or weight training of at least 150 min·wk−1 resulted in 34% and 52% less diabetes, respectively. Men who reported 150 min or more of combined weight training and aerobic exercise had a 59% lower incidence of type 2 diabetes (18). As little as 20 min of weight training per week significantly decreased the diabetes incidence compared with no exercise.

Although there is evidence in healthy individuals for the activation of the mammalian target of rapamycin being crucial for muscle remodeling after weight training and AMP-dependent kinase (AMPK) activation after endurance training (2,36), it is unclear how the muscle hypertrophy and mitochondrial biogenesis cellular pathways are involved in response to either type of exercise alone in persons at high risk for type 2 diabetes. In the absence of weight loss, the impact of stationary cycle training on muscle remodeling and whole-body insulin responsiveness is presented in this report. This study of supervised, increasing-intensity stationary cycle training of metabolic syndrome participants for 8 wk, was designed as a follow-up to a protocol of purely strength training of the same duration and similar energy expenditure that demonstrated no improvement in insulin resistance (22). The hypothesis driving these studies was that predominantly endurance training (with no weight loss) might have more impact than strength training on insulin responsiveness in the metabolic syndrome, and the cellular mechanisms of muscle adaptation would differ from those seen in strength training.

MATERIALS AND METHODS

Materials

Monoclonal antibodies directed against slow-twitch myosin heavy chain were purchased from Millipore (Billerica, MA). ATP synthase antibodies (ab110273) were purchased from Abcam (Cambridge, MA). An alkaline phosphatase-conjugated fast myosin antibody (Sigma clone MY-32 alkaline phosphatase conjugate) was purchased from Sigma-Aldrich (St. Louis, MO). A peroxidase-conjugated rabbit antimouse IgG antibody (315-035-045) was purchased from Jackson ImmunoResearch Laboratories (West Grove, PA). GLUT4 antibodies (AB1049, goat antihuman) were purchased from Chemicon (Temecula, CA). Monoclonal antibodies directed at the human insulin receptor beta subunit (05-1104) were purchased from Millipore. Rabbit polyclonal antibodies directed at the human insulin receptor beta subunit (07-724) were purchased from Millipore. Rabbit polyclonal antibodies directed against human insulin receptor substrate 1 (IRS-1) (no. 2382) were purchased from Cell Signaling (Danvers, MA). Rabbit polyclonal antibodies specific for human IRS-1 phosphorylated at Tyr896 (no. 3070), Ser307 (no. 2491), Ser337(no. 2580), Ser636 (no. 2388), and Ser1101 (no. 2385) were purchased from Cell Signaling.

Subject selection

Eighteen sedentary subjects were recruited. None of the subjects had performed regular exercise for at least 1 yr. The research protocol and the consent documents were approved by the institutional review board of the East Tennessee State University. Each subject provided written informed consent. Sedentary subjects were recruited into two groups: high risk for type 2 diabetes (BMI ≥ 30 kg·m−2 and a family history of type 2 diabetes) and low risk for type 2 diabetes (BMI < 30 kg·m−2, no family history of type 2 diabetes). The 11 subjects at high risk for diabetes qualified for the designation “metabolic syndrome,” as set forward by the International Diabetes Federation (1). Each of these had BMI greater than 30 kg·m−2, waist circumference greater than 102 cm (40 inches), insulin resistance by euglycemic clamp, and dyslipidemia (triglycerides > 150 mg·dL−1, HDL < 40 mg·dL−1 in men or 50 mg·dL−1 in women) and/or hypertension (systolic blood pressure > 130 mm Hg).

The exercise intervention

All subjects performed their exercise training in groups of two to six, typically side by side, on SCIFIT cycle ergometers (model ISO1000; SCIFIT Systems Inc., Tulsa, OK) in the ETSU Sport and Exercise Science Laboratory under the direct supervision of an exercise science graduate student. Subjects were instructed to maintain a cadence of 75–85 rpm. After 5 min of light cycling warm-up (50 W), four 5-min sets at the weekly target intensity setting were alternated with 1-min light cycling periods at reduced intensity (50 W). The target intensities (W) for weeks 1–8 were 100, 110, 120, 100, 125, 135, 145, and 120. These sessions took place on Monday and Tuesday and Thursday and Friday in assigned afternoon time slots with Wednesday being designated for midsection training. Participants performed midsection exercises consisting of crunches, bells, and windshield wipers during the 8-wk intervention. Each exercise was performed on Wednesdays with one set of each exercise being performed during the first week and an additional set of 10 repetitions being added each week until reaching a total of three sets for each exercise. Target intensity settings were increased at weeks 1–3 and weeks 5–7, with reduced loads being prescribed on weeks 4 and 8 in an attempt to reduce potential for overtraining and to manage fatigue. Heavy and light days were also used to further enhance recovery and manage fatigue. Two minutes of light cycling (50 W) was performed as a cooldown after the target sets were finished. All postmeasures of anthropometrics and muscle biopsies were performed 24–48 h after the last exercise session.

A 3-d diet diary was reviewed with each subject by a nutrition intern supervised by nutrition faculty. The verified data were analyzed using Nutrition Pro software (Axxya Systems, Stafford, TX) to quantify daily caloric intake and average diet composition. Subjects were instructed to increase food consumption by 250–750 calories per day. If weight measured weekly deviated by more than 1 kg from the initial weight, a nutritionist counseled the subject to make further adjustments.

Subject assessments

Body composition was measured by air displacement plethysmography (BodPod, Concord, CA). Blood pressures were the average of duplicates performed after sitting quietly for a minimum of 10 min. Glucose, insulin, HbA1c, and cholesterol measurements were performed in a clinical laboratory from serum obtained after an overnight fast (minimum of 10 h). Maximal oxygen consumption (V˙O2max) and respiratory exchange ratio were analyzed using a TrueOne 2400 Metabolic Measurement System (ParvoMedics, Sandy, UT) and a SCIFIT cycle ergometer. Fat oxidation was calculated from the baseline respiratory exchange ratio by the method of Frayn (17).

Muscle biopsies

Percutaneous needle biopsies of vastus lateralis were performed after an overnight fast and 2 h of quiet recumbency as previously described, using a Bergstrom-Stille 5-mm muscle biopsy needle with suction (33). The sample was divided in two, with one piece frozen immediately in liquid nitrogen for later analysis and the second piece mounted on cork and quickly frozen in a slurry of isopentane cooled by liquid nitrogen for sectioning and microscope slide preparation.

Euglycemic hyperinsulinemic clamp

After a 2-h baseline period, a single infusion of regular insulin was performed at 15 mU·m−2·min−1 for 2 h to achieve a physiological increment in insulin concentration of approximately 50 μU·mL−1 (350 pmol·mL−1). The glucose infusion rate necessary to maintain the blood glucose at 85 ± 5 mg·dL−1 (4.72 ± 0.28 mmol·L−1) was generally stable by 60 min, and the last 30 min of the 120-min insulin infusion was used to calculate the steady-state glucose infusion rate (SSGIR) to quantify insulin sensitivity as previously described (32).

Quantification of muscle fiber type composition and fiber size

Fiber composition was determined using methods described by Behan et al. (4). Fresh biopsy material was immediately mounted on cork for transverse sectioning and frozen in a slurry of isopentane cooled in liquid nitrogen. All sections were coded and then quantified independently by two observers who were unaware of which subject the image represented. All fiber size data for the current study were calculated using the minimum diameter measured for each fiber (11).

Immunoblots

Immunoblots to assess the content of the insulin receptor beta subunit, IRS-1, IRS-1 pTyr896, IRS-1 pSer307, IRS-1 pSer337, IRS-1 pSer636, IRS-1 pSer1101, GLUT4, and ATP synthase were performed using muscle homogenates are previously described (22). Studies of GLUT4 and ATP synthase used 10% polyacrylamide minigels (Pierce, Rockford, IL), whereas all of the IRS-1 studies used NuPAGE Novex Tris–acetate 3%–8% gels from Invitrogen (Carlsbad, CA).

Immunohistochemistry

Immunohistochemical studies were performed as previously described (31). Images were generated using a Leica confocal microscope system. The image signal intensity of individual fibers was quantified using Quantity One image analysis software from Bio-Rad (Hercules, CA). Fiber type was determined in the corresponding confocal image labeled with antibodies specific for either slow-twitch myosin heavy chain or fast-twitch myosin heavy chain.

Statistics

All data are displayed as mean ± SEM, except as explicitly indicated. Comparing data between the two groups was performed using the independent t-test except as noted. Comparisons of data before and after training were done using the paired t-test. A P value of less than 0.05 was considered significant. Statistical procedures were performed using SigmaPlot version 12.2 from Systat Software (San Jose, California).

RESULTS

Subject characteristics

The characteristics of the control and metabolic syndrome participants are displayed in Table 1. There were 11 metabolic syndrome subjects (5 of whom were females) and 7 sedentary controls (5 of whom were females). The mean age of the metabolic syndrome group was 44 ± 4 yr (range, 23–54 yr), and that of the control group was 41 ± 4 yr (range, 29–55 yr). Shown in Table 1 are the P values for comparisons of before and after training in both groups, and in the rightmost column are the results of t-tests comparing the metabolic syndrome baseline data to the control subject baseline measurements. Of the variables displayed in this table, only the V˙O2max was significantly increased by the training in the metabolic syndrome subjects. Among the control subjects, the V˙O2max increased, and the peak power from strength testing also increased. Most of the key pretraining characteristics of the metabolic syndrome subjects were quite different from those of the control group, with the exceptions of the strength testing data, blood pressures, and lipid data. In metabolic syndrome subjects, fasting glucose concentration averaged 9% higher, and fasting insulin was 257% of the control group value. The HDL cholesterol concentrations were higher in the control subjects than the metabolic syndrome subjects. The dietary calories per day calculated from the 3-d diet diary were 35% more in the metabolic syndrome group, but this difference was not statistically significant. The proportion of calories from fat was 39% higher (P = 0.011). The respiratory exchange ratio tended to decrease after training, and the calculated fat oxidation tended to increase in both groups, although not statistically significantly different.

TABLE 1
TABLE 1:
Subject characterization and response to 8 wk of stationary cycle training.

Whole-body insulin responsiveness was not increased by cycle training

Seven control subjects and 11 metabolic syndrome subjects had euglycemic clamp studies performed before and after 8 wk of increasing duration and intensity stationary cycle training. In both groups, some subjects improved and others did not change or their insulin responsiveness declined. The mean SSGIR was unchanged in both groups. The individual subject data are shown in Figure 1. Interestingly, the control subjects who improved their insulin responsiveness were those who started at lower baseline responsiveness, whereas among the metabolic syndrome subjects, the lower baseline subjects showed little or no improvement.

FIGURE 1
FIGURE 1:
Insulin responsiveness quantified by euglycemic insulin clamps was not increased by 8 wk of supervised stationary cycle training. This graph plots the pre- and posttraining SSGIR for 7 sedentary control subjects (open circles) and 11 subjects with the metabolic syndrome (black filled circles). The mean and SE values for the two groups before and after training are also plotted. The SSGIR of the metabolic syndrome group was 29% of the corresponding insulin responsiveness quantified in the control group both in the baseline study and after training.

Our subjects’ data on insulin resistance can be expressed by many different calculated indicators as described in detail by Ferranini et al. (16) from the European Group for the Study of Insulin Resistance. When the insulin clamp glucose infusion data were expressed as “M” (μmol·min−1·kg−1 fat-free mass), differences between our groups before and after exercise training were amplified. Controls increased from 47.7 ± 5.6 to 87.1 ± 19.7, and metabolic syndrome subjects decreased from 17.4 ± 2.3 to 12.9 ± 2.7. Further, if the insulin sensitivity index (ISI) were calculated as the ratio of “M” to fasting insulin (16), there would be further separation of the group data. The controls averaged 17.5 ± 3.9 pretraining and 34.7 ± 12.1 posttraining, with the metabolic syndrome group changing from 1.98 ± 0.68 to 2.12 ± 1.33 after training. The insulin clamp data expressed by these two alternative calculations suggest that the controls improved their insulin responsiveness but the metabolic syndrome group did not. When using these data to calculate homeostatic model assessment for insulin resistance (HOMA IR) (23), similar trends in training effects were present, but the changes were not statistically significant. The control subjects’ HOMA IR decreased from 1.32 ± 0.45 to 0.99 ± 0.23, and metabolic syndrome subjects increased from 3.29 ± 0.47 to 5.62 ± 1.77.

Cycle training induces changes in muscle fiber composition and fiber diameters. Muscle fiber composition was different in baseline assessments, and changes induced by stationary cycle training were in opposite directions for the controls and metabolic syndrome subject groups as shown in Figure 2A. The metabolic syndrome subjects had lower type 1, higher type 2a, and lower type 2× fiber proportions in vastus lateralis pretraining. After 8 wk of training, the control subject group muscle had a decrease in type 2× fibers and an increase in type 2a fiber content, suggesting the training caused a shift away from purely strength, fast-twitch fibers. In contrast, metabolic syndrome trained muscle appeared to have shifted toward strength-power fibers because there were lower type 1 and higher type 2× fiber proportions.

FIGURE 2
FIGURE 2:
Change in muscle fiber composition and in fiber size after 8 wk of cycle training. A, The fiber composition of pretraining and posttraining biopsies of vastus lateralis muscle in sedentary controls and in subjects with the metabolic syndrome. Shown here are the mean and SEM of the percent of each of the three principal fiber types as quantified by the slow-twitch/fast-twitch myosin antibody technique of Behan et al. (4). *Significantly different posttraining (P < 0.05, paired t-test). +Significant pretraining difference from the corresponding fiber type proportion in the control group (P < 0.05, independent t-test). B, The fiber diameter data derived as described in the Materials and Methods section. *Significant difference from baseline (P < 0.05, paired t-test). In the metabolic syndrome group, type 1 fiber type diameter increased by 15% after training.

Fiber size, shown in Figure 2B as fiber diameter, was not different between the controls and the type 1 and type 2× fibers of the metabolic syndrome subjects in the baseline biopsies. Size did not change after training in the control subjects, but it increased significantly in type 1 fibers in the metabolic syndrome subjects.

Eight weeks of the cycle training of metabolic syndrome subjects increased insulin receptor and GLUT4 expression in vastus lateralis muscle

To evaluate the mechanisms underlying potential improvement in whole-body insulin responsiveness in exercise trained subjects, the expression of three key elements of the insulin pathway in muscle were quantified. Figure 3 displays changes in the expression of insulin receptors, IRS-1, and GLUT4 after supervised stationary cycle training for 8 wk. Both groups exhibited increases in insulin receptor expression after training. GLUT4 was increased in metabolic syndrome muscle. IRS-1 expression was higher in baseline metabolic syndrome muscle and significantly decreased after training.

FIGURE 3
FIGURE 3:
The impact of exercise training on the muscle expression of the insulin receptor, IRS-1, and GLUT4. A–C, Images of examples of immunoblots of the insulin receptor beta subunit, IRS-1, and GLUT4, respectively, expressed in muscle from biopsies of our subjects. Each lane of polyacrylamide gels contained a sample with 10 μg of protein from muscle homogenate. Each sample was run in four separate experiments. The mean expression for each subject’s sample quantified on an arbitrary scale relative to a reference muscle sample was then averaged with the mean expression of the other subjects in the group. These data were then expressed in the graph of panel D in proportion to the control baseline data for each of the three factors that were quantified. *Significantly different from baseline (P < 0.05, paired t-test). +Baseline data that are different from the control subjects (P < 0.05, independent t-test).

Exercise training increased the expression of activated AMPK and mitochondria in muscle fibers

Postexercise training improvement in maximal oxygen uptake seen in our subjects was likely due in part to increased mitochondria in muscle. The activation of AMPK is a necessary step in the exercise-related activation of mitochondrial biogenesis, and the quantification of the expression of mitochondrial enzyme ATP synthase will reflect substantial changes in mitochondrial production. Eight weeks of stationary cycle training more than doubled the expression of phosphorylated AMPK in both type 1 and type 2× muscle fibers in both controls and metabolic syndrome subjects as shown in Figure 4. These data are from immunohistochemical studies as previously described for GLUT4 and activated mammalian target of rapamycin (31). Unexpectedly, ATP synthase expression was significantly greater in metabolic syndrome type 2× fibers than that in type 1 fibers (P = 0.039, paired t). This relative trend also appeared in the sedentary control muscle, but the difference did not achieve statistical significance. ATP synthase expression increased in metabolic syndrome type 2× muscle fibers by immunohistochemisty (Fig. 4) and trended toward an increase in type 1 in metabolic syndrome and in type 1 and type 2 fibers in controls.

FIGURE 4
FIGURE 4:
Fiber-specific changes in the expression of activated AMPK and mitochondrial marker ATP synthase. Because it was anticipated that exercise that was primarily endurance training would impact mitochondrial biogenesis, muscle AMPK activation and ATP synthase expression were quantified. Sections of muscle from each subject pre- and posttraining were incubated with a monoclonal antibody against slow-twitch myosin heavy chain to identify the type 1 fibers on the section. A second rabbit polyclonal antibody against either phospho-AMPK or ATP synthase was added and incubated overnight at 4°C. Fluorescent tagged antirabbit IgG and antimouse IgG were added after the primary incubation, and dual color images were obtained using a Leica confocal microscope. The signal intensity generated with either the phospho-AMPK or the ATP synthase antibody for the identified fiber type was quantified using digital imaging software (Quantity One from BioRad). At least 30 fibers had the signal intensity quantified for each antigen. A, The data for the control and metabolic syndrome subjects before and after training in the type 1 fibers. The expression of phospho-AMPK tended to be lower in the type 2× fibers for both controls and metabolic syndrome subjects, but ATP synthase expression appeared higher in type 2× fibers. The activated AMPK was twofold increased after training for both groups in both fiber types. The ATP synthase was significantly increased by training in type 2× only in the metabolic syndrome group, indicating training-induced increased mitochondrial production, albeit not nearly to the level of increased activated AMPK. *Significant posttraining increase in expression compared with corresponding baseline (P < 0.05, paired t-test). #Significant difference between type 2× fiber and type 1 fiber expression (P < 0.05, paired t).

Immunoblots of muscle homogenates (data not shown) demonstrated a 16% lower pretraining expression of ATP synthase in metabolic syndrome subjects’ muscle (P = 0.040). There was a 9% increase posttraining in controls (P = 0.038) and a 12% increase posttraining in metabolic syndrome subjects (P = 0.055).

Muscle IRS-1 phosphorylation before and after exercise training

The phosphorylation of IRS-1 at tyrosine 896 is critical in the signal pathway activated by insulin interaction with its cell surface receptor. Previous studies have shown that the excess phosphorylation of IRS-1 at one of a few key serines can inhibit the ability of the insulin receptor tyrosine kinase to phosphorylate the tyrosine at 896. We hypothesized that beneficial exercise training might decrease the inhibitory serine phosphorylation and enhance the phosphorylation at Tyr896. Figure 5 summarizes the impact of cycle training for 8 wk on the phosphorylation of IRS-1 at Tyr896, Ser337, and Ser636. All muscle biopsies in these studies were performed after an overnight fast, and thus circulating insulin concentrations were minimized in both groups (see Table 1). In spite of a higher expression of total IRS-1 (Fig. 3), the phosphorylation of IRS-1 at tyrosine 896 was not increased in metabolic syndrome muscle, either pretraining or posttraining. In contrast, phosphorylation at serines 337 and 636 were increased compared with control subject phosphorylation at these sites. Training did not change the phosphorylation level at Ser636 but tended to increase the phosphorylation at Ser337, although this training-related difference was not significant in either group.

FIGURE 5
FIGURE 5:
Cycle training impact on tyrosine and serine phosphorylation of muscle IRS-1. A–C, Typical immunoblot images of muscle homogenates probed with antibodies specific for phospho-Tyr896, phospho-Ser337, and phospho-Ser636, respectively. Immunoblot images like these were evaluated for signal strength using digital analysis software for each subject in four separate experiments. D, Summary of the results of these analyses. In the pretraining samples, Tyr896 phosphorylation was not different, but phosphorylation at Ser337 and Ser636 were approximately 50% higher in the metabolic syndrome muscle samples. The exercise training protocol did not decrease the amount of phosphorylation at Ser337 or Ser636, and there appears to be a trend toward increased phosphorylation at Ser337 in both controls and metabolic syndrome muscle. +Difference from the corresponding control subject data (P < 0.05).

DISCUSSION

The study described in this report was designed to use stationary cycle training as a predominantly endurance exercise training intervention to decrease insulin resistance in participants who were at high risk for type 2 diabetes because they met the criteria for the metabolic syndrome. This protocol, like its predecessor using only strength training (22), successfully adjusted caloric intake to prevent weight loss. Like the previous strength training of 8 wk duration, less than half of the subjects improved their insulin responsiveness, measured by euglycemic insulin clamps, but the others either showed no change or decreased their insulin responsiveness. These mixed individual results caused the group data to be unchanged. Thus, with this duration and intensity of closely supervised exercise training, either endurance or strength, no improvement in insulin resistance can be anticipated in such interventions in the absence of weight loss.

Several studies have shown that combined endurance and resistance training provided the best response in glycemic control and improved insulin sensitivity. Many of these studies did not keep the time and effort constant between the comparison groups, making it hard to be confident that it was the type of exercise rather than just total time spent or energy expended that was the critical variable. Sigal et al. (28) evaluated the impact of exercise training (aerobic, resistance, or combined) on HbA1c in 251 adults with type 2 diabetes. Resistance training was approximately 120 min·wk−1, aerobic training was 135 min·wk−1, and combined training totaled approximately 250 min·wk−1. All three training groups improved their HbA1c, but combined training did the best with a change of −0.97%, aerobic training improved by −0.51%, and the resistance training group improved by −0.38%. The starting weights averaged 101.5 kg, with resistance training losing an average of 1.1 kg, and the aerobic and the combined groups averaged a loss of 2.6 kg. Because the time of exercise also correlated with change in HbA1c, the type of exercise alone cannot be concluded from their data to have an advantage of one over the other. Church et al. (7) performed exercise training for 9 months on 262 men and women with type 2 diabetes at the Pennington Biomedical Research Center in Baton Rouge. Volunteers were randomly assigned to no exercise, resistance exercise, aerobic exercise, or combined aerobic and resistance. All three exercise training groups lost weight, body fat, and waist circumference. All three exercise training groups decreased their HbA1c (−0.16%, −0.24%, and −0.34%, respectively), but only the combined exercise group achieved statistical significance. V˙O2max increased significantly only in the combined exercise group. Strength increased in the resistance and the combined groups, but not in the aerobic training only group. Cuff et al. (9) at the University of British Columbia evaluated the impact of adding resistance training to aerobic training in older women with type 2 diabetes. Ten subjects with combined resistance and aerobic training for 16 wk were compared with nine women with aerobic training only and nine women who did not train. Euglycemic clamp testing showed more improvement in the combined training group than that in the aerobic only group (+1.82 vs +0.55 mg·kg−1·min−1). Both groups were demonstrated by CT to have less visceral fat coincident with weight loss (−2.9 and −1.2, compared with +2.0 kg in the untrained control group).

Davidson et al. (10) measured exercise training-related improvement in insulin responsiveness with euglycemic clamps in 136 sedentary older subjects who did not have diabetes. The glucose infusion rate data showed that the largest enhancement of insulin responsiveness occurred in the combined training group. Resistance training alone was not significantly different from nontrained controls, but substituting resistance training for a portion of the aerobic training time resulted in substantially higher enhancement of insulin responsiveness than the aerobic training that it replaced (10). These investigators concluded that the combined training was the optimal protocol.

The comparison of aerobic and resistance exercise training for subjects with the metabolic syndrome were carried out in the STRRIDE-AT/RT study (3,29). There were 196 participants age 18–70 yr participating. Resistance training was 45–60 min, 3 d·wk−1, and aerobic training was approximately 120 min·wk−1, equivalent to running 12 miles. The combined program added the two programs together, requiring twice the time and energy expenditure. A metabolic syndrome score was calculated from measures of HDL, triglycerides, fasting glucose concentration, waist circumference, and blood pressure. The scores improved with aerobic and combined training but did not improve with resistance training alone (3). V˙O2max increased in all three groups (3), but weight loss, decreased visceral fat, and improved insulin responsiveness by HOMA occurred only in the aerobic only and the aerobic plus resistance groups (29).

Stensvold et al. (30) also compared exercise modalities in treatment of men and women with the metabolic syndrome. They had 11 volunteers in each group where they trained for 12 wk, three times per week, at either aerobic, strength, combined exercise, or no intervention. With no weight loss, all three exercise groups had a decrease in waist circumference. Strength increased in the strength trained and the combined groups. V˙O2max increased in the aerobic and the combined groups, but not in the strength group. Insulin resistance, quantified by HOMA, did not change significantly (30).

Villareal et al. (5,35) at Washington University evaluated diet-induced weight loss, exercise alone, and exercise with weight loss in older obese subjects in a program to reduce frailty. The duration of the study was 1 yr, with the exercise being combined aerobic and strength training. Insulin sensitivity was quantified using an ISI calculated from insulin and glucose measurements from an oral glucose tolerance test. Weight loss and exercise showed the largest improvement in physical function in these subjects, all of whom had some impairment at baseline (35). Weight loss occurred in the diet and diet plus exercise groups. ISI improved 70% in the diet group and 86% in the diet plus exercise group but did not change in the control or exercise only groups (5).

A randomized controlled study of weight loss by diet or by aerobic exercise only was reported by Ross et al. (27) from Kingston, Ontario. Fifty-two obese men were randomized to diet only, exercise without weight loss, exercise-induce weight loss, and no intervention controls for a duration of 12 wk. A weight loss of 7 kg (∼8% of body weight) in both weight loss groups resulted in improved euglycemic clamp-quantified insulin responsiveness of 43% in diet only and 64% in weight loss by exercise (27). Aerobic exercise with no weight loss improved insulin responsiveness by 31%, but this change did not achieve statistical significance. MRI-quantified visceral fat improved significantly in the diet only, exercise-induced weight loss, and exercise without weight loss groups (−28%, −28%, and −12%, respectively) (27).

The exercise intervention studies reviewed above are consistent with our finding that the impact on insulin resistance of exercise training without weight loss is minimal. Comparisons of types of exercise effectiveness suggest that with weight loss, a combination of aerobic and resistance training is usually associated with the most improvement in glycemic control in type 2 diabetes subjects or in insulin responsiveness in nondiabetic subjects with the metabolic syndrome. Typically, however, the time spent exercising is least with resistance and most with combined training, making time and/or volume of exercise an important variable. This often makes it difficult to determine whether it is the type of exercise or the time spent that is the factor determining the effectiveness of an exercise program.

Muscle fiber composition in metabolic syndrome subjects was different from sedentary controls with decreased slow-twitch (type 1) fibers and increased fast-twitch (type 2) fibers, particularly the mixed fibers (type 2a). Does this predominance of strength (type 2) fibers make metabolic syndrome subjects better suited to strength training than endurance training? The results from this study and our previous study (22) suggest that there was no advantage to strength training, in so far as improvement in insulin responsiveness is concerned. Studies from other investigators that allowed weight loss generally ranked combination training better than endurance and strength training the least effective at improving insulin responsiveness or diabetes glycemic control. Whether these comparisons of exercise protocols actually reflect the type of exercise or only the sum of time and effort is not clear because workloads were generally not matched in the different protocols that were compared.

The data included in this report and our previous evaluation of strength training without weight loss (22) suggest that 8 wk of increasing intensity exercise training alone is largely futile at decreasing the risk for diabetes (decreasing insulin resistance). The current 8-wk cycle training intervention was designed to approximate the volume load and energy expenditure of the 8-wk resistance training protocol (22). Both cycle training and strength training can increase aerobic fitness (V˙O2max), and there were trends toward increasing fat oxidation and lowering blood pressure (Table 1). Strength training increased muscle mass and strength. If weight loss is the critical factor in improving insulin responsiveness, then regular exercise will be additive or even synergistic with a decrease in dietary calories, if a negative energy balance persists. The impact of regular exercise on weight loss, if not compensated during the remainder of the day, will at least be increased energy expenditure and may have other beneficial effects such as decreasing the leptin resistance that is nearly always present in human obesity (8). Unfortunately, exercise training alone at the volume we selected is largely futile in the metabolic syndrome.

Stationary cycle training in metabolic syndrome and controls increased muscle insulin receptor and activated AMPK substantially, but GLUT4 and mitochondria were only modestly affected by the training intervention. The question arises whether the duration of the training period was inadequate to overcome the individual subject’s previous sedentary lifestyle or is weight loss necessary in order for exercise training to exert its full effect on the insulin-stimulated glucose uptake pathway in muscle. Further, is weight loss necessary to overcome obesity-related inhibition of exercise training modulation of muscle mitochondrial biogenesis or muscle fiber hypertrophy? Elite runners are substantially more insulin responsive than healthy control subjects (14). Long-term training is likely part of this, but genetically determined advantages may underlie the higher insulin sensitivity seen in advanced and elite athletes.

Eight weeks of moderate stationary cycle training without weight loss is not effective at decreasing the insulin resistance (a surrogate for diabetes risk) characteristic of the metabolic syndrome. Some key components of muscle remodeling increased robustly (insulin receptors, phospho-AMPK), but others did not, suggesting impairment downstream in the pathways normally involved in muscle adaptation.

These studies were funded by the National Institutes of Health (grant no. DK080488) to Stuart, Stone, and Ramsey.

The authors thank the subjects who volunteered for these studies and the students who coached them through the training, for without their participation and motivation, these data would not be available. Research nurse Susie Cooper Whitaker was very important in the recruitment, retention, and coordination of these studies.

The authors have no conflicts of interest to disclose.

The results of the present study do not constitute endorsement by the American College of Sports Medicine.

ClincalTrials.gov identifier: NCT00727779.

REFERENCES

1. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome–a new worldwide definition. Lancet. 2005; 366: 1059–62.
2. Baar K. Training for endurance and strength: lessons from cell signaling. Med Sci Sports Exerc. 2006; 38 (11): 1939–44.
3. Bateman LA, Slentz CA, Willis LH, et al. Comparison of aerobic versus resistance exercise training effects on metabolic syndrome (from the Studies of a Targeted Risk Reduction Intervention Through Defined Exercise—STRRIDE-AT/RT). Am J Cardiol. 2011; 108: 838–44.
4. Behan WM, Cossar DW, Madden HA, McKay IC. Validation of a simple, rapid, and economical technique for distinguishing type 1 and 2 fibres in fixed and frozen skeletal muscle. J Clin Pathol. 2002; 55: 375–80.
5. Bouchonville MF, Shah K, Armamento-Villareal R, Sinacore DR, Qualls C, Villareal DT. Weight loss, excercise, or both and cardiometabolic risk factors in obese older adults: results of a randomized controlled trial. Endoc Rev. 2012; 33: S18–1.
6. Cauza E, Hanusch-Enserer U, Strasser B, et al. The relative benefits of endurance and strength training on the metabolic factors and muscle function of people with type 2 diabetes mellitus. Arch Phys Med Rehabil. 2005; 86: 1527–33.
7. Church TS, Blair SN, Cocreham S, et al. Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2010; 304: 2253–62.
8. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreative-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996; 334: 292–5.
9. Cuff DJ, Meneilly GS, Martin A, Ignaszewski A, Tildesley HD, Frohlich JJ. Effective exercise modality to reduce insulin resistance in women with type 2 diabetes. Diabetes Care. 2003; 26: 2977–82.
10. Davidson LE, Hudson R, Kilpatrick K, et al. Effects of exercise modality on insulin resistance and functional limitation in older adults: a randomized controlled trial. Arch Intern Med 2009; 169: 122–31.
11. Dubowitz V, Sewry CA, Lane R. Normalmuscle. In: Houston MJ, Cook L, editors. Muscle Biopsy: A Practical Approach. Philadelphia: Saunders Elsevier; 2007. pp. 41–74.
12. Dunstan DW, Daly RM, Owen N, et al. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes. Diabetes Care. 2002; 25: 1729–36.
13. Dunstan DW, Puddey IB, Beilin LJ, Burke V, Morton AR, Stanton KG. Effects of a short-term circuit weight training program on glycaemic control in NIDDM. Diabetes Res Clin Pract. 1998; 40: 53–61.
14. Ebeling P, Bourey R, Koranyi L, et al. Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity. J Clin Invest. 1993; 92: 1623–31.
15. Eriksson JG. Exercise and the treatment of type 2 diabetes mellitus. An update. Sports Med. 1999; 27: 381–91.
16. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest. 1997; 100: 1166–73.
17. Frayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol. 1983; 55: 628–34.
18. Grontved A, Rimm EB, Willett WC, Andersen LB, Hu FB. A prospective study of weight training and risk of type 2 diabetes mellitus in men. Arch Intern Med. 2012; 172: 1–7.
19. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004; 109: 433–8.
20. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005; 28: 2289–2304.
21. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002; 346: 393–403.
22. Layne AS, Nasrallah S, South MA, et al. Impaired muscle AMPK activation in the metabolic syndrome may attenuate improved insulin action after exercise training. J Clin Endocrinol Metab. 2011; 96: 1815–26.
23. Mather KJ, Hunt AE, Steinberg HO, et al. Repeatability characteristics of simple indices of insulin resistance: implications for research applications. J Clin Endocrinol Metab. 2001; 86: 5457–64.
24. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001; 286: 1195–1200.
25. Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991–1998. JAMA. 1999; 282: 1519–22.
26. Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988; 37: 1595–1607.
27. Ross R, Dagnone D, Jones PJ, et al. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med. 2000; 133: 92–103.
28. Sigal RJ, Kenny GP, Boule NG, et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med. 2007; 147: 357–69.
29. Slentz CA, Bateman LA, Willis LH, et al. Effects of aerobic vs. resistance training on visceral and liver fat stores, liver enzymes, and insulin resistance by HOMA in overweight adults from STRRIDE AT/RT. Am J Physiol Endocrinol Metab. 2011; 301: E1033–9.
30. Stensvold D, Tjonna AE, Skaug EA, et al. Strength training versus aerobic interval training to modify risk factors of metabolic syndrome. J Appl Physiol. 2010; 108: 804–10.
31. Stuart CA, Howell ME, Baker JD, et al. Cycle training increased GLUT4 and activation of mammalian target of rapamycin in fast twitch muscle fibers. Med Sci Sports Exerc. 2010; 42 (1): 96–106.
32. Stuart CA, Howell ME, Zhang Y, Yin D. Insulin-stimulated translocation of glucose transporter (GLUT) 12 parallels that of GLUT4 in normal muscle. J Clin Endocrinol Metab. 2009; 94: 3535–42.
33. Stuart CA, Yin D, Howell MEA, Dykes RJ, Laffan JJ, Ferrando AA. Hexose transporter mRNAs for GLUT4, GLUT5, and GLUT12 predominate in human muscle. Am J Physiol Endocrinol Metab. 2006; 291: E1067–73.
34. Tresierras MA, Balady GJ. Resistance training in the treatment of diabetes and obesity: mechanisms and outcomes. J Cardiopulm Rehabil Prev. 2009; 29: 67–75.
35. Villareal DT, Chode S, Parimi N, et al. Weight loss, exercise, or both and physical function in obese older adults. N Engl J Med. 2011; 364: 1218–29.
36. Wilkinson SB, Phillips SM, Atherton PJ, et al. Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle. J. Physiol. 2008; 586: 3701–17.
37. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001; 414: 782–7.
Keywords:

INSULIN RESISTANCE; METABOLIC SYNDROME; EUGLYCEMIC CLAMP; EXERCISE TRAINING

© 2013 American College of Sports Medicine