During intense exercise glycemia increases and plasma insulin decreases minimally, if at all (Marliss and Vranic. 2002), thus giving an added benefit of insulin activating even more GLUT-4 translocation and further increasing glucose uptake, even if insulin sensitivity is reduced. The increase continues after exercise because this insertion of GLUT-4 means that the glucose transport system is left in a more easily recruitable state following glycogen-depleting exercise, and thus DM sufferers can bypass the defective insulin signalling mechanisms and increase the rates of muscle glucose uptake. This sustained increase in glucose uptake after exercise may also be due to the Insulin-stimulated tyrosine phosphorylation of IRS-1 and –2, thus increasing PI 3-Kinase activity after exercise (Alexander et al. 2000).
Regular aerobic exercise increases insulin sensitivity as it has been shown to increase both affinity and the number of insulin receptors. This is especially useful for DM sufferers because IDDM patients have very little insulin, therefore making that as productive as possible will require less exogenous insulin, also NIDDM patients may experience a return to normal levels of secretion as less is needed to activate the insulin receptors.
Exercise decreases glucosuria and polyuria. Glucosuria is caused by the level of glucose being filtered in the kidneys exceeding the capacity of the tubular cells’ for reabsorption leading to the presence of glucose in the urine, which exerts an osmotic effect that draws water with it. This leads to an increased volume of urine and polyuria. Thus increased muscle glucose uptake following exercise will decrease polyuria and thus excess fluid loss, preventing the reduction in blood volume that can lead to further complications.
Exercise decreases body fat by increasing the amount of calories utilised by the body and augmenting lipolysis. As previously mentioned this will increase the uptake of glucose into muscle cells thus decreasing its deposition into adipose cells, conversion into Triglycerides and the subsequent growth of adipose cells. As obesity is linked with the down regulation of insulin receptors seen in NIDDM, decreasing body fat will restore the amount of IR’s and subsequently insulin sensitivity. Furthermore, NIDDM sufferers will also benefit from decreased hypertension, because the hyperlipidaemia brought about by their liver producing high amounts of Very Low Density LipoProteins (VLDL’s) will be decreased by increased lipolysis of free fatty-acids in the plasma and those within tissues, such as Triglycerides.
Apart from the increase in GLUT-4 expression endurance exercise leads to increased muscle oxidative capacity due to increased activities of the enzymes involved in glucose phosphorylation (hexokinase) and glucose oxidation (citrate synthase)(Kara et al. 2000) further enhancing the uptake and utilisation of glucose during and after exercise.
Exercise decreases the chance of hypertension in DM sufferers because it decreases the chances of hyperinsulinaemia in IDDM sufferers, as they will not need high doses of exogenous insulin. As it is not released evenly after injection it can result in peaks of high levels in the plasma. Exercise also reduces the chance of hypertension in NIDDM, as it will decrease the amount of insulin that needs to be secreted to counteract the desensitisation of its receptors. This is beneficial because acute hyperinsulinaemia induces sodium retention and activates the renin-angiotensin system (Gans et al. 1991) leading to an increase in plasma volume and thus blood pressure. This will also lead to an increase in insulin sensitivity, as displayed by Gans et al (1991) treatment with enalapril, an angiotensin converting enzyme (ACE) inhibitor, increased insulin sensitivity suggesting the renin-angiotensin system decreases insulin sensitivity.
Exercise will also lead to an increased maximal oxygen uptake (VO2max) in both IDDM and NIDDM sufferers, because high levels of glucose can lead to alteration of the haemoglobin molecule reducing its oxygen carrying capacity, thereby a decrease in glucose levels will reverse this.
Although exercise will provide all of the above benefits for both IDDM and NIDDM sufferers, care must be taken with exercise in IDDM sufferers, because it may trigger a potentially dangerous dual response of enhanced glucose uptake and greater exogenous insulin supply due to rapid circulation of injected insulin (McArdle et al. 1996), exacerbating the imbalance between glucose supply and utilisation and result in complications from hypoglycaemia.
The most important benefit comes from a combined effect of all the above and is the decreased likelihood of developing long range complications such as peripheral circulatory failure which can lead to gangrene in the toes and feet, low cerebral blood flow which can in turn lead to secondary renal failure due to inadequate filtration pressure. Eventually leading to diseases of the vasculature such as atherosclerotic lesions, heart disease, & strokes, because high levels of glucose and insulin attack the endothelium by binding to proteins (glycosylation). In addition, high levels of glucose cause damage to the nervous system via axon damage. These vascular lesions often develop in the kidneys and lead to diabetic nephropathy because the glucose binds to the proteins of the kidney tubules (glycosylates them) making the tubules more permeable, even to proteins thus causing albuminuria and a decrease in glomerular filtration rate. These vascular lesions can also occur in the eyes, and lead to blindness, because high levels of glucose stimulates the formation of new blood vessel in the retina and vitreous humour of the eye. This can lead to cataracts or these vessels can haemorrhage leading to lesions.
There are several benefits of exercise for DM sufferers and complex mechanisms that underlie them. However only endurance type, glycogen depleting exercise such as jogging or walking have the ability to bestow these benefits. There will also be added benefits of protection against other diseases such as atherosclerosis and osteoporosis that can result from participating in this type of exercise, thus GP’s and other medical practitioners should include relevant exercise regimes in their programmes of treatment for DM sufferers, to decrease the need for exogenous insulin in IDDM sufferers and maybe prevent the need for oral hypoglycaemic drugs which over stress the already weakened β-cells of the pancreas, by stimulating them to increase insulin secretion, and can lead to them ceasing insulin production completely. Thus the patient would require exogenous insulin.
As well as the above physiological benefits from exercise there are also psychological benefits such as: improved self-esteem & self-image, reduced incidence of depression and anxiety, and improved feeling of well-being. These benefits are possibly attributable to the increased release of endogenous opioids during and after exercise, particularly β-endorphins.
References:
Alexander, V et al. (2000). Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: Differential effects on insulin-receptor substrates 1 and 2. Proceedings of the National Academy of Science, 97(1), pp.38-43.
Balon, TW. Nadler, JL. (1997). Evidence that nitric oxide increases glucose transport in skeletal muscle. Journal of Applied Physiology, 82(1), pp.359-363.
Gans, RO. (1991). The effect of angiotensin-I converting enzyme inhibition on insulin action in healthy volunteers. European Journal of Clinical Investigation, 21(5), pp.527-533.
Hayashi, T. Wojtaszewski, JFP. Goodyear, LJ. (1997). Exercise regulation of glucose transport in skeletal muscle. American Journal of Physiology: Endocrinology and Metabolism, 273(6), pp.E1039-E1051.
Kara, R et al. (2000). Effects of exercise training and ACE inhibition on insulin action in rat skeletal muscle. Journal of Applied Physiology, 89(2), pp.687-694.
Marliss, EB. Vranic, M. (2002). Intense exercise has unique effects on both insulin release and its roles in glucoregulation. Diabetes, 51, pp.S271-S283.
McArdle, WD. Katch, FI. Katch, VL. (1996). Exercise Physiology: energy, nutrition, and human performance. 4th Edition, Maryland USA: Williams and Wilkins.
Sherwood, L. (1997). Human Physiology: from cells to systems. 3rd Edition, USA: Wadsworth.
Proc. Natl. Acad. Sci.Vol. 97, Issue 1, 38-43, January 4, 2000
Applied Biological Sciences
Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: Differential effects on insulin-receptor substrates 1 and 2
Alexander V. Chibalin, Mei Yu, Jeffrey W. Ryder, Xiao Mei Song, Dana Galuska, Anna Krook, Harriet Wallberg-Henriksson, and Juleen R. Zierath
Department of Surgical Sciences, Karolinska Hospital, S-171 76, and the Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77, Stockholm, Sweden
Communicated by Vernon R. Young, Massachusetts Institute of Technology, Cambridge, MA, November 18, 1999 (received for review April 1, 1999)
Abstract
Level of physical activity is linked to improved glucose homeostasis. We determined whether exercise alters the expression and/or activity of proteins involved in insulin-signal transduction in skeletal muscle. Wistar rats swam 6 h per day for 1 or 5 days. Epitrochlearis muscles were excised 16 h after the last exercise bout, and were incubated with or without insulin (120 nM). Insulin-stimulated glucose transport increased 30% and 50% after 1 and 5 days of exercise, respectively. Glycogen content increased 2- and 4-fold after 1 and 5 days of exercise, with no change in glycogen synthase expression. Protein expression of the glucose transporter GLUT4 and the insulin receptor increased 2-fold after 1 day, with no further change after 5 days of exercise. Insulin-stimulated receptor tyrosine phosphorylation increased 2-fold after 5 days of exercise. Insulin-stimulated tyrosine phosphorylation of insulin-receptor substrate (IRS) 1 and associated phosphatidylinositol (PI) 3-kinase activity increased 2.5- and 3.5-fold after 1 and 5 days of exercise, despite reduced (50%) IRS-1 protein content after 5 days of exercise. After 1 day of exercise, IRS-2 protein expression increased 2.6-fold and basal and insulin-stimulated IRS-2 associated PI 3-kinase activity increased 2.8-fold and 9-fold, respectively. In contrast to IRS-1, IRS-2 expression and associated PI 3-kinase activity normalized to sedentary levels after 5 days of exercise. Insulin-stimulated Akt phosphorylation increased 5-fold after 5 days of exercise. In conclusion, increased insulin-stimulated glucose transport after exercise is not limited to increased GLUT4 expression. Exercise leads to increased expression and function of several proteins involved in insulin-signal transduction. Furthermore, the differential response of IRS-1 and IRS-2 to exercise suggests that these molecules have specialized, rather than redundant, roles in insulin signaling in skeletal muscle.
Journal of Applied Physiology
Vol. 82, No. 1, pp. 359-363, January 1997
Evidence that nitric oxide increases glucose transport in skeletal muscle
Thomas W. Balon Jerry L. Nadler
(With the Technical Assistance of Arnie Jasman)
Department of Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, Duarte, California 91010
ABSTRACT
Balon, Thomas W., and Jerry L. Nadler. Evidence that nitric oxide increases glucose transport in skeletal muscle. J. Appl. Physiol. 82(1): 359-363, 1997.Nitric oxide synthase (NOS) is expressed in skeletal muscle. However, the role of nitric oxide (NO) in glucose transport in this tissue remains unclear. To determine the role of NO in modulating glucose transport, 2-deoxyglucose (2-DG) transport was measured in rat extensor digitorum longus (EDL) muscles that were exposed to either a maximally stimulating concentration of insulin or to an electrical stimulation protocol, in the presence of NG-monomethyl-L-arginine, a NOS inhibitor. In addition, EDL preparations were exposed to sodium nitroprusside (SNP), an NO donor, in the presence of submaximal and maximally stimulating concentrations of insulin. NOS inhibition reduced both basal and exercise-enhanced 2-DG transport but had no effect on insulin-stimulated 2-DG transport. Furthermore, SNP increased 2-DG transport in a dose-responsive manner. The effects of SNP and insulin on 2-DG transport were additive when insulin was present in physiological but not in pharmacological concentrations. Chronic treadmill training increased protein expression of both type I and type III NOS in soleus muscle homogenates. Our results suggest that NO may be a potential mediator of exercise-induced glucose transport.
Eur J Clin Invest 1991 Oct;21(5):527-33
The effect of angiotensin-I converting enzyme inhibition on insulin action in healthy volunteers.
Gans RO, Bilo HJ, Nauta JJ, Popp-Snijders C, Heine RJ, Donker AJ.
Department of Medicine, Free University Hospital, Amsterdam, The Netherlands.
Acute hyperinsulinaemia, achieving insulin levels within the physiological range, induces sodium retention. At the same time an activation of the renin-angiotensin system occurs, with a rise in plasma renin activity (PRA) and angiotensin-II level but no change in plasma aldosterone. After administration of higher, pharmacological doses of insulin an increase in systolic blood pressure and heart rate can also be observed, while further increases in PRA and angiotensin-II are noted. To determine whether angiotensin-II is involved in observed insulin actions, we studied the renal and cardiovascular effects of three dosages of insulin (50 (Ins I), 300 (Ins II) and 500 (Ins III) mU kg-1 h-1) in healthy subjects after one week of treatment with the angiotensin-I converting enzyme inhibitor enalapril (10 mg twice a day), using the euglycaemic clamp technique. Control data were obtained from two previously conducted experiments in the same subjects, one with infusion of insulin and one with the insulin solvent only. The effect of insulin on fractional sodium excretion, blood pressure and heart rate was unaffected by enalapril, which precludes any involvement of the renin-angiotensin system with regard to these aspects of insulin action. Insulin sensitivity increased significantly during treatment with enalapril (with enalapril: Ins I: 11.3 +/- 3.0, Ins II: 20.0 +/- 3.4 and Ins III: 20.6 +/- 3.9 mg kg-1 min-1 glucose (mean +/- SD); without enalapril: Ins I: 8.7 +/- 2.3, Ins II: 13.7 +/- 3.0 and Ins III: 15.5 +/- 3.1 mg kg-1 min-1 glucose; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Physiol Endocrinol Metab Vol. 273, Issue 6, E1039-E1051, December 1997
Exercise regulation of glucose transport in skeletal muscle
Tatsuya Hayashi1, Jørgen F. P. Wojtaszewski2, and Laurie J. Goodyear1
1 Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215; and 2 Copenhagen Muscle Research Centre, August Krogh Institute, University of Copenhagen, DK-2100 Copenhagen, Denmark
ABSTRACT
Exercise increases the rate of glucose uptake into the contracting skeletal muscles. This effect of exercise is similar to the action of insulin on glucose uptake, and the mechanism through which both stimuli increase skeletal muscle glucose uptake involves the translocation of GLUT-4 glucose transporters to the plasma membrane and transverse tubules. Most studies suggest that exercise and insulin recruit distinct GLUT-4-containing vesicles and/or mobilize different "pools" of GLUT-4 proteins originating from unique intracellular locations. There are different intracellular signaling pathways that lead to insulin- and exercise-stimulated GLUT-4 translocation. Insulin utilizes a phosphatidylinositol 3-kinase-dependent mechanism, whereas the exercise signal may be initiated by calcium release from the sarcoplasmic reticulum leading to the activation of other signaling intermediaries, and there is also evidence for autocrine- or paracrine-mediated activation of transport. The period after exercise is characterized by increased sensitivity of muscle glucose uptake to insulin, which can be substantially prolonged in the face of carbohydrate deprivation. The ability of exercise to utilize insulin-independent mechanisms to increase glucose uptake in skeletal muscle has important clinical implications, especially for patients with diseases that are associated with peripheral insulin resistance, such as non-insulin-dependent diabetes mellitus.
J APPL PHYSIOL 89(2):687-694
Vol. 89, Issue 2, 687-694, August 2000
Effects of exercise training and ACE inhibition on insulin action in rat skeletal muscle
Kara R. Foianini, Michelle S. Steen, Tyson R. Kinnick, Melanie B. Schmit, Erik B. Youngblood, and Erik J. Henriksen
Muscle Metabolism Laboratory, Department of Physiology, University of Arizona, Tucson, Arizona 85721-0093
ABSTRACT
Our laboratory has demonstrated (Steen MS, Foianini KR, Youngblood EB, Kinnick TR, Jacob S, and Henriksen EJ, J Appl Physiol 86: 2044-2051, 1999) that exercise training and treatment with the angiotensin-converting enzyme (ACE) inhibitor trandolapril interact to improve insulin action in insulin-resistant obese Zucker rats. The present study was undertaken to determine whether a similar interactive effect of these interventions is manifest in an animal model of normal insulin sensitivity. Lean Zucker (Fa/) rats were assigned to either a sedentary, trandolapril-treated (1 mg · kg1 · day1 for 6 wk), exercise-trained (treadmill running for 6 wk), or combined trandolapril-treated and exercise-trained group. Exercise training alone or in combination with trandolapril significantly (P < 0.05) increased peak oxygen consumption by 26-32%. Compared with sedentary controls, exercise training alone or in combination with ACE inhibitor caused smaller areas under the curve for glucose (27-37%) and insulin (41-44%) responses during an oral glucose tolerance test. Exercise training alone or in combination with trandolapril also improved insulin-stimulated glucose transport in isolated epitrochlearis (33-50%) and soleus (58-66%) muscles. The increases due to exercise training alone or in combination with trandolapril were associated with enhanced muscle GLUT-4 protein levels and total hexokinase activities. However, there was no interactive effect of exercise training and ACE inhibition observed on insulin action. These results indicate that, in rats with normal insulin sensitivity, exercise training improves oral glucose tolerance and insulin-stimulated muscle glucose transport, whereas ACE inhibition has no effect. Moreover, the beneficial interactive effects of exercise training and ACE inhibition on these parameters are not apparent in lean Zucker rats and, therefore, are restricted to conditions of insulin resistance.
Diabetes 51:S271-S283, 2002
Intense Exercise Has Unique Effects on Both Insulin Release and Its Roles in Glucoregulation
Implications for Diabetes
Errol B. Marliss1, and Mladen Vranic2
1 McGill Nutrition and Food Science Centre, McGill University Health Centre/Royal Victoria Hospital, Montreal, Quebec, Canada
2 Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada
In intense exercise (>80% VO2max), unlike at lesser intensities, glucose is the exclusive muscle fuel. It must be mobilized from muscle and liver glycogen in both the fed and fasted states. Therefore, regulation of glucose production (GP) and glucose utilization (GU) have to be different from exercise at <60% VO2max, in which it is established that the portal glucagon-to-insulin ratio causes the less than or equal to twofold increase in GP. GU is subject to complex regulation by insulin, plasma glucose, alternate substrates, other humoral factors, and muscle factors. At lower intensities, plasma glucose is constant during postabsorptive exercise and declines during postprandial exercise (and often in persons with diabetes). During such exercise, insulin secretion is inhibited by ß-cell -adrenergic receptor activation. In contrast, in intense exercise, GP rises seven- to eightfold and GU rises three- to fourfold; therefore, glycemia increases and plasma insulin decreases minimally, if at all. Indeed, even an increase in insulin during -blockade or during a pancreatic clamp does not prevent this response, nor does pre-exercise hyperinsulinemia due to a prior meal or glucose infusion. At exhaustion, GU initially decreases more than GP, which leads to greater hyperglycemia, requiring a substantial rise in insulin for 40–60 min to restore pre-exercise levels. Absence of this response in type 1 diabetes leads to sustained hyperglycemia, and mimicking it by intravenous infusion restores the normal response. Compelling evidence supports the conclusion that the marked catecholamine responses to intense exercise are responsible for both the GP increment (that occurs even during glucose infusion and postprandially) and the restrained increase of GU. These responses are normal in persons with type 1 diabetes, who often report exercise-induced hyperglycemia, and in whom the clinical challenge is to reproduce the recovery period hyperinsulinemia. Intense exercise in type 2 diabetes requires additional study.
