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Glucose Homeostasis

Glucose intolerance and decreased insulin sensitivity are independent risk factors for CVD (Hurley and Hagberg 1998). Abnormal glucose homeostasis is associated with worsened lipid lipoprotein profiles and an increased risk for the development of hypertension and type 2 diabetes (Hurley and Hagberg 1998, Warburton et al. 2001b, 2001a). It is well-established that habitual physical activity is an effective primary preventative strategy against insulin resistance and type 2 diabetes in the general population (Warburton et al. 2006). Although comparatively less information is available for SCI, it appears that exercise training programs are effective in improving glucose homeostasis (Hjeltnes et al. 1998, Chilibeck et al. 1999, de Groot et al. 2003, Phillips et al. 2004, Mahoney et al. 2005, Jeon et al. 2010). Key terms used when assessing glucose homeostasis are provided in Table 10.

Table 10 : Glucose Homeostasis Key Terms

Oral Glucose Tolerance Test (OGTT)·     Involves the ingestion of glucose and the subsequent serial blood analysis of glucose levels to determine the rate of blood glucose removal. Common test used in the diagnosis of diabetes.
Insulin Sensitivity·     Refers to the sensitivity of target cells (muscle, hepatic cells and adipose) to insulin.
Blood Glucose·     Refers to blood levels of glucose (a simple sugar, carbohydrate). High fasting blood glucose levels reflects pre-diabetic or diabetic conditions.
Blood Insulin·     Refers to blood levels of insulin (a hormone that regulates carbohydrate metabolism).
Glucose Transporters

(GLUT-4)

·     Glucose transporters are important membrane proteins that facilitate the transport of glucose through the cellular membrane. GLUT4 is an insulin-regulated glucose transporter located in adipose and muscle tissues.
Glycogen Synthase·     Enzyme involved in the synthesis of glycogen from glucose.
Hexokinase·     An enzyme that acts during carbohydrate metabolism. In the first step of glycolysis, hexokinase phosphorylates (transfers phosphate from ATP) glucose to prepare it for subsequent breakdown for use in energy production.
Citrate Synthase·     Citrate synthase is an important enzyme in the Citric Acid Cycle (Krebs cycle).
Phosphofructokinase·     Phosphofructokinase (PFK) is an important regulatory enzyme of glycolysis.

Table 11 : Effects of Exercise Training on Glucose Metabolism in Persons with Spinal Cord Injury

Author, Year; Country

Score

Research Design

Sample Size

MethodsOutcomes
de Groot et al. 2003;

Netherlands

PEDro = 7

RCT

Level 1

N = 6

 

 

Population: 4 male, 2 female, C5-L1, AIS A (n = 1), B (n = 1), and C (n = 4), age 36 yrs, 116 d post-injury.

Treatment: Randomized to low-intensity (50%–60% HRR) or high-intensity (70%–80% HRR) arm ergometry, 20 min/d, 3 d/wk, 8 wks.

Outcome Measures: VO2peak, insulin sensitivity, blood glucose.

1.      There was a significant difference in insulin sensitivity between groups, with a non-significant decline in the high-intensity group and a significant improvement in the low-intensity group with training.

2.      A positive correlation between VO2peak and insulin sensitivity (r = 0.68, p = 0.02).

Jeon et al. 2010;

Canada

Pre-post

Level 4

N = 6

Population: 6 male participants with paraplegia participated in the study (mean age, 48.6 ± 6.0 y; mean weight, 70.1 ± 3.3 kg; injury levels between T4-5 and T10).

Treatment: 12 weeks of FES-rowing exercise training 3 to 4 times a week (600–800 kcal).

Outcome measures: VO2peak, plasma leptin, insulin, and glucose levels, insulin sensitivity, body composition.

1.     VO2peak increased from 21.4 ± 1.2 to 23.1 ± 0.8 mL∙kg-1∙min-1 (P = 0.048).

2.     Plasma leptin levels were significantly decreased after the training (pre: 6.91 ± 1.82 ng∙dL-1 vs. post: 4.72 ± 1.04 ng∙dL-1; P = 0.046).

3.     Plasma glucose and leptin levels were significantly decreased after exercise training by 10% and 28% (P = 0.028), respectively.

4.     Plasma glucose, Leptin levels and Whole body fat decreased but did not reach statistical significance.

Mahoney et al. 2005;

USA

Pre-post

Level 4

N = 5

 

Population: 5 males, complete SCI, C5-T10, AIS grade A, age 35.6 yrs, 13.4 yrs post-injury.

Treatment: Home-based neuromuscular electric stimulation-induced resistance exercise training, 2 d/wk, 12 wks.

Outcome Measures: quadriceps femoris muscle cross-sectional area, plasma glucose, insulin.

1.    All participants had normal fasting glucose levels before and after training.

2.    There were no significant changes in blood glucose or insulin with training. However, there was a trend towards reduced plasma glucose levels (p = 0.074).

Phillips et al. 2004;

Canada

Pre-post

Level 4

N = 9

 

Population: 8 male, 1 female, incomplete AIS C, C4-T12, 8.1 yrs post-injury.

Treatment: Body-weight–supported treadmill walking, 3 d/wk, 6 months.

Outcome Measures: whole-body dual-energy X-ray absorptiometry (to capture body composition and bone density), GLUT4 protein abundance, hexokinase activity, oral glucose tolerance tests, glucose oxidation, CO2 breath analysis.

1.    Reduction in the area under the curve for glucose (-15%) and insulin (-33%).

2.    The oxidation of exogenous (ingested) glucose and endogenous (liver) glucose increased (68% and 36.8%, respectively) after training.

3.    Training resulted in increased muscle glycogen, GLUT-4 content (glucose transporter) (126%), and hexokinase II enzyme activity (49%).

Jeon et al. 2002;

Canada

Pre-post

Level 4

N = 7

 

Population: 5 male, 2 female, motor complete, C5-T10, ages 30-53 yrs, 3–40 yrs post-injury.

Treatment: FES leg-cycle training, 30 min/d, 3 d/wk, 8 wks.

Outcome Measures: oral glucose tolerance test (OGTT), glucose and insulin levels, glucose utilization, insulin sensitivity and levels.

1.    There were significantly lower (14.3%) 2-hr OGTT glucose levels after 8 wk of training.

2.    Glucose utilization was higher for all 3 participants and insulin sensitivity was higher for 2 of the 3 participants during posttraining 2-hr clamp test.

Mohr et al. 2001;

Denmark

Pre-post

Level 4

N = 10

Population: 8 male, 2 female, 6 tetraplegia, 4 paraplegia, C6-T4, age 35 yrs, 12 yrs post-injury.

Treatment: FES cycling, 30 min/d, 3 d/wk, 12 months; 7 participants completed an additional 6 months (1 d/wk).

Outcome Measures: insulin-stimulated glucose uptake, oral glucose tolerance test (OGTT), GLUT 4 glucose transporter protein.

1.    Insulin-stimulated glucose uptake rates increased after intensive training.

2.    With the reduction in training, insulin sensitivity decreased to a similar level as before training. GLUT-4 increased by 105% after intense training and decreased again with the training reduction. The participants had impaired glucose tolerance before and after training, and neither glucose tolerance nor insulin responses to OGTT were significantly altered by training.

Chilibeck et al. 1999;

Canada

Pre-post

Level 4

N = 5

Population: 4 male, 1 female, motor complete C5-T8, ages 31–50 yrs, 3–25 yrs post-injury.

Treatment: FES leg-cycle ergometry training, 30 min/d, 3 d/wk, 8 wks.

Outcome Measures: glucose transporters (GLUT-4, GLUT-1), oral glucose tolerance test, citrate synthase.

1.    Training resulted in increases in GLUT-1 (52%) and GLUT-4 (72%).

2.    There was a training-induced increase in citrate synthase activity (56%) and an improvement in the insulin sensitivity index as determined from oral glucose tolerance test.

Hjeltnes et al. 1998;

Sweden

Pre-post

Level 4

N = 5

 

Population: 5 males, C5-C7, all complete AIS A, age 35 yrs, 10 yrs post-injury.

Treatment: Electrically stimulated leg cycling exercise, 7 d/wk, 8 wks.

Outcome Measures: peripheral insulin sensitivity, whole body glucose utilization, glucose transport, phosphofructokinase, citrate synthase, hexokinase, glycogen synthase, blood glucose, plasma insulin.

1.      After training, insulin-mediated glucose disposal was increased by 33%. There was a 2.1-fold increase in insulin-stimulated glucose transport.

2.    Training led to marked increases in protein expression of GLUT4 (glucose transporter) (378%), glycogen synthase (526%), and hexokinase II (204%) in the vastus lateralis muscle.

3.    Hexokinase II activity increased 25% after training.

Discussion

The majority of the data is from experimental non-RCT trials. A search of the literature revealed eight investigations (n = 54). This included one RCT (de Groot et al. 2003) and seven experimental non-RCT (pre-post) trials (Hjeltnes et al. 1998, Chilibeck et al. 1999, Mohr et al. 2001, Jeon et al. 2002, Phillips et al. 2004, Mahoney et al. 2005, Jeon et al. 2010). The single RCT involved the randomization to two different forms of exercise, and, as such, an exercise condition served as the control (Table 11). The majority (six) of these trials examined the effectiveness of FES training.

Similar to other studies in the field of SCI research, this area of investigation is limited by the lack of quality RCTs. Moreover, the majority of the research relates to the effects of FES training. Limited work has been conducted using aerobic and/or resistance exercise training. As a whole, however, these studies are consistent and reveal several important findings. For instance, the improvements in glucose homeostasis may be the result of increased lean body mass (and associated changes in insulin sensitivity) and increased expression of GLUT-4, glycogen synthase, and hexokinase in exercised muscle.

Consistent with findings in able-bodied individuals (Warburton et al. 2001b, 2001a), the improvement in glucose homeostasis after exercise interventions (e.g., aerobic training or FES) does not appear to be related solely to decreases in body adiposity and/or increases in VO2max. This is due to the fact that significant improvements in glucose homeostasis can occur with minor changes in body composition (weight and fat to muscle ratios) and/or aerobic fitness.

It is also important to note that there appears to be a minimal volume of exercise required for improvements in glucose homeostasis. For instance, Mohr et al. (2001) revealed that beneficial changes in insulin sensitivity and GLUT-4 protein observed during a three days/week FES training program were not maintained when FES training was reduced.

Conclusion

  • Aerobic and FES exercise training may lead to clinically significant improvements in glucose homeostasis in persons with SCI. Preliminary evidence indicates that a minimum of 30 min of moderate intensity training on 3 days per week is required to achieve and/or maintain the benefits from exercise training.