Literature Review of the Effects of Exercise on Glucose Metabolism
Objective • The incidence of Type 2 Diabetes mellitus continues to increase around the world. This review attempts to summarize the recent research
Data Sources • A literature review was conducted to identify recent research studies that elucidated the physiological effects of exercise on glucose metabolism and clinical studies showing expected outcomes when recommending an exercise regime to a Type 2 diabetic.
Study Selection •Three studies and one reviews were chosen that elucidate the mechanism by which exercise effects glucose uptake and metabolism in the cell as well as quantify the effects of exercise on glucose cellular uptake. Two studies were selected that demonstrate the outcomes that might be expected and obstacles that may be encountered in the clinical application of exercise in the treatment plan of Type 2 diabetic patients.
Conclusions • While the cellular mechanisms by which glucose uptake is increased are not fully understood, the studies all agree that glucose uptake is increased during sustained exercise and does have a place in the treatment of Type 2 diabetes.
As the number of people diagnosed with Type 2 diabetes continues to increase it has become imperative that health care providers understand the importance that exercise plays in the treatment of this disease and the prevention of its complications including nephropathy, retinopathy, and cardiovascular disease. While pharmaceutical interventions offer an alternative to treatment for Type 2 diabetes, lifestyle intervention is significantly more effective than metformin (Knowler, Barrett-Connor, Fowler, Hamman, Lachin, Walker, et al).
For the first time in 2000, Kristiansen, Gade, Wojtaszewski, Kiens, and Richter demonstrated in eight healthy men aged 20-27 that during conditions when maximal exercise-induced muscle glucose uptake is expected (exercise performed at high intensity with low glycogen concentrations) the glucose uptake is higher in trained compared with untrained muscle. The investigators postulate that this may be due to the higher GLUT-4 protein concentration in trained muscle. They also continue on to say that whatever the molecular nature of the exercise-induced mechanism to increase muscle glucose transport is, it is probably sensitive to the energy status of the muscle cell. In this study the vastus lateralis muscle was “trained” using a supervised endurance training program for 3 weeks based on a one-legged dynamic knee-extensor apparatus and the diet was controlled to ensure low glycogen stores prior to the testing.
J.L. Andersen, Scherling, L.L. Andersen and Dela endeavored to demonstrate the level of glucose uptake in resistance trained skeletal muscle. Studies prior to this one all focused on endurance trained skeletal muscle glucose uptake. The objective of this study was to establish if skeletal muscle specifically adapts qualitatively to a de-training resistance program or if the changes in insulin action are merely due to increases in muscle mass. In this study, seven young, healthy men participated in a heavy resistance training program for 90 days (trained state) and then abstained from training for a 90 day period (de-trained state). The authors concluded that insulin-stimulated glucose uptake rates per unit of muscle mass decrease significantly with de-training. However they did not find any significant correlation between changes in leg glucose uptake rates and changes in muscle mass which supports the conclusion that the effect of resistance training cannot to a mere increase in fat-free mass. Andersen et. al. did find that the onset of insulin action was slower in the detrained state and the major difference in leg glucose handling in the two states of training was a decrease in non-oxidative glucose disposal with de-training. This study was based on the effects of de-training and therefore the training-induced adaptations in glucose metabolism may not be exactly the opposite of those seen with de-training. The study does conclude that in response to the cessation of resistance training, skeletal muscle adapts qualitatively with decreased insulin sensitivity.
A recent study by Juel, Holten, and Dela focused on two monocarboxylate transporter proteins, MCT1 and MCT4. Lactate is released from skeletal muscle in proportion to glucose uptake rates. Lactate leaves the cells via simple diffusion and two transport proteins, MCT1 and MCT4. MCT’s had not previously been measured in Type 2 diabetics. Ten male Caucasian Type 2 diabetic patients and seven male Caucasian controls without a family history of Type 2 diabetes participated in a supervised 6 week (3 times per week lasting no more than 30 minutes per session) single leg strength training program while the other leg remained untrained. A two-step, sequential isoglycemic and hyperinsulinemic clamp was used on fasting subjects. Basal venous and arterial blood measurements were taken and again at 90, 105, and 120 minutes after infusions of glucose (maintaining an isoglycemic environment) and 50 ml of insulin. Muscle biopsies were taken prior to the infusions. The biopsy data showed that MCT1 content in skeletal muscle of Type 2 diabetics is lower compared with healthy controls and strength training resulted in a 48% increase in MCT1 content in the controls and a 75% increase in MCT1 content in Type 2 diabetics. This increase in MCT1 had occurred in response to a low training effect. The increased release was not dependent on the observed larger blood flow rates in the trained leg because the differences between the trained and untrained leg in arterial-femoral venous differences attained statistical significance. MCT4 transporters did not increase in Type 2 diabetics while it does increase in healthy controls. The authors conclude that lactate release from trained muscle is increased during hyperinsulinemia and lactate release rates from muscle are positively correlated with glucose uptake rates.
Kirwan and del Aguila in an interesting review published in 2003 make a distinction between concentric and eccentric exercise in glucose metabolism. Eccentric exercise is characterized by the muscles lengthening as the tension drops (i.e. prolonged downhill running or marathon running). Eccentric exercise causes extensive muscle damage, muscle soreness, edema, and elevation of plasma myocellular proteins. It appears that this muscle damage initiates a cascade of cellular events leading to decreased insulin sensitivity. TNF- is increased more than 2-fold within 24 hours of eccentric exercise. TNF- increases insulin receptor substrate-1 (IRS-1) serine/threonine phosophorylation which impairs IRS-1 docking to the insulin receptor thus inhibiting insulin signaling. In contrast concentric exercise training results in increasing insulin signaling and GLUT-4 expression and decreasing TNF- expression in skeletal muscle and ultimately enhancing insulin sensitivity. Kirwan and del Aguila conclude by stating that although exercise generally exerts a positive effect on insulin sensitivity, it may paradoxically promote insulin resistance if it causes disruption of muscle cell integrity. The effects of this insulin resistance are transient lasting less than 72 hours and can be avoided by minimizing the lengthening contractions of eccentric exercise during training.
The challenge for the clinician becomes the application of research findings to patient treatment. In the case of a Type 2 diabetic the exercise prescription will improve glucose metabolism and prevent diabetic complications and possibly amount to significant savings in prescription medications. Singapore initiated a National Healthy Lifestyle Programme in 1992. The program has resulted in increases in regular exercise rates among Singaporeans and a leveling off in the prevalence rate of diabetes. Singapore has implemented practice guidelines for physicians that advise a combination of both aerobic and resistance training as part of the exercise prescription for Type 2 diabetics. Lim, Kang, and Stewart state that although resistance training is often neglected this mode of exercise is generally safe and improves HBA1C levels and increases lean body mass. The authors conclude that the reasons for underparticipation in regular exercise include the patients’ lack of knowledge about the benefits of exercise, a lack of motivation, and a lack of clear recommendation from health care professionals. They continue on to say that specific instructions should be given to patients rather than general advice, which does not increase compliance.
Tudor-Locke, Bell, Myers, Harris, Ecclestone, Lauzon and Rodger evaluated a daily physical activity intervention for Type 2 diabetics using a 16-week intervention study with a 24-week follow-up assessment. 47 participants, 24 in the study group and 23 in the control group, had their baseline levels of physical activity assessed by wearing pedometers over three consecutive days during their waking hours while engaging in usual activities. The participants attended four weekly group meetings during which they were trained in pedometer use, the program manual containing goal-setting and problem-solving exercises and calendars for self-monitoring steps/day. No advice was given for diet or glycemic control. In the study group 16 participants attended all 4 group meetings and 8 attended 3 of the 4 sessions. The study group represents approximately 31 minutes of extra walking per day. The authors found an inverse relationship between the change in steps per day and change in blood glucose, HbA1C and triglyceride concentrations in study participants treated with oral hypoglycemic medications. Although they did not collect these data, there may be an interaction between improved insulin secretion (from the medication) and slightly improved insulin sensitivity (from increased exercise). Tudor-Locke et al conclude that the physiological impact of the behavioral change was subtle and appears to be most obvious in persons taking oral hypoglycemic agents.
References
Anderson, J.L., Schjerling, P., Andersen, L.L., & Dela, F. Resistance training and insulin action in humans:effects of de-training. Journal of Physiology. 2003;551:1049-1058.
Fenicchia, L.M., Kanaley, J.A., Azevedo, J.L, Miller, C.S., Weinstock, R.S., Carhart, R.L., & Ploutz-Snyder, L.L. Influence of resistance exercise training on glucose control in women with Type 2 Diabetes. Metabolism. 2004; 53:284-289.
Juel, C., Holten, M.K., & Dela, F. Effects of strength training on muscle lactate release and MCT1 and MCT4 content in healthy and Type 2 diabetic humans. Journal of Physiology. 2003;556:297-304.
Kirwan, J.P. & del Aguila, L.F. Insulin signaling, exercise and cellular integrity.
Kristiansen, S., Gade, J., Wojtaszewski, J.F.P., Kiens, B., & Richter, E.A. Glucose uptake is increased in trained vs. untrained muscle during heavy exercise. Journal of Applied Physiology. 2000;89:1151-1158.
Lim, J.G., Kang, H.J., & Stewart, K.J. Type 2 Diabetes in Singapore: The role of exercise for its prevention and management. Singapore Medical Journal. 2004:45:62-68.
Ryder, J.W., Chilbalin, A.V., & Zierath, J.R. Intracellular mechanisms underlying increases in glucose uptake in response to insulin or exercise in skeletal muscle. Acta Physiol Scand. 2001;171:249-257.
Tudor-Locke, C., Bell, R.C., Myers, A.M., Harris, S.B., Ecclestone, N.A., Lauzon, N. & Rodger, N.W. Controlled outcome evaluation of the First Step Program: a daily physicalactivity intervention for individuals with Type II diabetes. International Journal of Obesity. 2004;28:113-119.
Beth Poindexter N.D.