HIGHLIGHTED TOPICS
Exercise Effects of Muscle Insulin Signaling and Action
Invited Review: Effects of acute exercise and exercise training on insulin resistance

Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona 85721-0093

	ABSTRACT

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Insulin resistance of skeletal muscle glucose transport is a key defect in the development of impaired glucose tolerance and Type 2 diabetes. It is well established that both an acute bout of exercise and chronic endurance exercise training can have beneficial effects on insulin action in insulin-resistant states. This review summarizes the present state of knowledge regarding these effects in the obese Zucker rat, a widely used rodent model of obesity-associated insulin resistance, and in insulin-resistant humans with impaired glucose tolerance or Type 2 diabetes. A single bout of prolonged aerobic exercise (30-60 min at ~60-70% of maximal oxygen consumption) can significantly lower plasma glucose levels, owing to normal contraction-induced stimulation of GLUT-4 glucose transporter translocation and glucose transport activity in insulin-resistant skeletal muscle. However, little is currently known about the effects of acute exercise on muscle insulin signaling in the postexercise state in insulin-resistant individuals. A well-established adaptive response to exercise training in conditions of insulin resistance is improved glucose tolerance and enhanced skeletal muscle insulin sensitivity of glucose transport. This training-induced enhancement of insulin action is associated with upregulation of specific components of the glucose transport system in insulin-resistant muscle and includes increased protein expression of GLUT-4 and insulin receptor substrate-1. It is clear that further investigations are needed to further elucidate the specific molecular mechanisms underlying the beneficial effects of acute exercise and exercise training on the glucose transport system in insulin-resistant mammalian skeletal muscle.

skeletal muscle glucose transport; obese Zucker rat; impaired glucose tolerance; Type 2 diabetes

	INTRODUCTION

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NUMEROUS METABOLIC AND HEMODYNAMIC factors can contribute to the improvements in glucose homeostasis that are seen after acute exercise and exercise training in individuals with insulin resistance. These adaptive responses include enhanced insulin action on the skeletal muscle glucose transport system, reduced hormonal stimulation of hepatic glucose production, improved blood flow to skeletal muscle, and normalization of an abnormal blood lipid profile. This mini-review will focus only on the adaptive responses to exercise of the glucose transport system in skeletal muscle. In this context, one purpose of this article is to examine the present body of knowledge regarding the influence of a single bout of prolonged aerobic [30-60 min at ~60-70% of maximal oxygen consumption (O_2 max)] exercise on whole-body glucose tolerance and on insulin-stimulated skeletal muscle glucose transport activity in conditions of insulin resistance. Moreover, this document will briefly review the effects of endurance exercise training on the skeletal muscle glucose transport system in insulin-resistant states, with a particular emphasis on the beneficial adaptive responses of the protein expression and functionality of insulin signaling factors and of GLUT-4 protein to this intervention. Because of space limitations, coverage will be restricted to the obese Zucker (fa/fa) rat, a widely used rodent model of obesity-associated insulin resistance, and to insulin-resistant humans with impaired glucose tolerance (IGT) or Type 2 diabetes.

	REGULATION OF SKELETAL MUSCLE GLUCOSE TRANSPORT

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Skeletal muscle, which makes up ~40% of the body mass of humans and other mammalian species, is the primary tissue responsible for the peripheral disposal of glucose in response to a glucose or insulin challenge or during an exercise bout (6, 24). Glucose transport into the myocyte is acutely regulated by insulin and insulin-like factors through the activation of a series of intracellular proteins (for a review of insulin signaling and glucose transport activation, see Refs. 103 and 117). Insulin binding to the -subunit of the insulin receptor causes an enhancement of the tyrosine kinase activity of the intracellular -subunits, leading to autophosphorylation of the insulin receptor and to tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). The tyrosine-phosphorylated IRS-1 molecule can then dock with the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase), which in turn activates the p110 catalytic subunit of this enzyme. PI3-kinase catalyzes the production of phosphoinositide moieties, which can subsequently activate 3-phosphoinositide-dependent kinases (PDK), including PDK1. A downstream target of PDK1 is Akt/protein kinase B (Akt/PKB), a serine/threonine kinase. Several lines of investigation support a role of Akt/PKB in the regulation of glucose transport (44, 77, 112), although other studies indicate that Akt/PKB is not involved in this process (76). Clearly, the exact role of Akt/PKB in the glucose transport process in skeletal muscle remains to be defined. The activation of these steps ultimately results in the translocation of a regulatable glucose transporter protein isoform (GLUT-4) to the sarcolemmal membrane and the t tubules, where glucose transport takes place via a facilitative diffusion process. GLUT-4 is only one of several isoforms in a family of facilitative glucose transporter proteins, and available evidence supports the idea that it is the magnitude of GLUT-4 translocation that dictates the capacity of a skeletal muscle to enhance glucose transport activity (53).

Glucose transport into skeletal muscle is also stimulated by an insulin-independent mechanism that is activated by contractions (54, 87), hypoxia (3, 15, 16), nitric oxide (5, 94), and bradykinin (83, 107). The translocation mechanism for increasing plasma membrane GLUT-4 also functions in response to contractions (37, 41), hypoxia (15), nitric oxide (33), and bradykinin (2, 107). It is likely that there is an important role of Ca²⁺ in the activation of glucose transport by these insulin-independent mechanisms (see Refs. 43, 53, and 98 for reviews). Whereas relatively little is currently known about the specific intracellular factors that allow muscle contractions to stimulate GLUT-4 translocation and glucose transport in skeletal muscle, recent evidence supports a role of the activation of 5'-adenosine monophosphate-activated protein kinase (AMP kinase), an enzyme activated by a decrease in cellular energy charge (80).

	DEVELOPMENTAL ASPECTS OF INSULIN RESISTANCE

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Insulin resistance of skeletal muscle glucose transport represents a major defect in the normal maintenance of euglycemia (117). This insulin resistance is frequently accompanied by a variety of metabolic and cardiovascular abnormalities, including hypertension, glucose intolerance, Type 2 diabetes, dyslipidemia, atherosclerosis, and central obesity, a condition referred to as "syndrome X" (92, 93) or the "insulin resistance syndrome" (23). The link among these disorders has been attributed to hyperinsulinemia, a consequence of the insulin resistance (23).

The obese Zucker (fa/fa) rat is an animal model of severe skeletal muscle insulin resistance that is also characterized by marked hyperinsulinemia, glucose intolerance, dyslipidemia, and central adiposity (84) and therefore is a suitable animal model of the insulin resistance syndrome. GLUT-4 protein expression in skeletal muscle of the obese Zucker rat is generally not defective (Refs. 35, 36, 63; but also see Ref. 52). However, insulin-stimulated GLUT-4 protein translocation (35, 74) and glucose transport activity (21, 35, 49) are substantially impaired in isolated skeletal muscle from these obese animals. Anai et al. (1) demonstrated that in skeletal muscle from the obese Zucker rat there are significant defects in crucial aspects of the insulin signaling cascade. In hindlimb muscle from insulin-resistant obese Zucker rats, IRS-1 protein expression is 60% less and insulin-stimulated IRS-1 tyrosine phosphorylation is 38% less, despite elevated basal levels, than in muscle from age-matched, insulin-sensitive lean Zucker rats. The amount of the p85 regulatory subunit of PI3-kinase associated with the tyrosine-phosphorylated IRS-1 in the insulin-stimulated state is 29% of lean control levels. Finally, IRS-1-associated PI3-kinase activity in muscle immunoprecipitates from these obese animals is only 54% of the level observed in lean animals (1).

Similar findings have been made in skeletal muscle from insulin-resistant humans. Insulin resistance in Type 2 diabetes, except for that observed in morbidly obese humans (29), is not generally associated with a decreased skeletal muscle level of GLUT-4 protein (117). However, insulin stimulation fails to induce normal GLUT-4 protein translocation to the sarcolemma in skeletal muscle from subjects with Type 2 diabetes (99, 116). Moreover, Goodyear et al. (40) and Björnholm et al. (10) demonstrated that significantly less insulin stimulation of insulin receptor and IRS-1 tyrosine phosphorylation and of IRS-1-immunoprecipitable PI3-kinase activity is detected in muscle from insulin-resistant subjects compared with insulin-sensitive controls. In addition, insulin-stimulated Akt/PKB kinase activity is significantly reduced in skeletal muscle from insulin-resistant Type 2 diabetic subjects (79), although this is not a consistent finding (72). Insulin-stimulated glycogen synthase activity is generally reduced (Refs. 7, 19, 109; but also see Ref. 78), and the reduction in nonoxidative glucose disposal in these individuals is thought to be secondary to defects in glucose transport (19). No reduction in insulin-stimulated mitogen-activated protein kinase (MAP kinase) phosphorylation is detected in incubated muscle preparations from Type 2 diabetic subjects (78). Therefore, there are marked defects in specific signaling proteins and in GLUT-4 protein translocation that define the insulin-resistant state.

	PREMISE FOR EXERCISE AS AN INTERVENTION IN INSULIN RESISTANCE

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It is well established that acute physical activity and endurance exercise training lead to enhancements of insulin-mediated glucose metabolism in healthy individuals and in normal rodent models (see reviews in Refs. 43, 45, 5, and 62). In normal rodent models, moderate- or high-intensity exercise training can improve glucose tolerance (9, 64), whole body insulin sensitivity (65, 66), and insulin action on skeletal muscle glucose transport (48, 96, 97, 105). The protein expression of GLUT-4 appears to play an important role in the capacity of a skeletal muscle for insulin stimulation of glucose transport (47, 69). The increased insulin action on skeletal muscle glucose transport after exercise training is associated with increased GLUT-4 protein expression (42, 48, 88, 96, 97, 101, 105), as well as adaptive responses of enzymes involved in glucose phosphorylation and oxidation (summarized in Refs. 53 and 62). On the bases of these observations, exercise represents an important potential intervention for improving the metabolic status of insulin-resistant individuals.

An improvement in insulin action on skeletal muscle glucose metabolism in insulin-resistant individuals could decrease conversion rates to overt diabetes, as well as reduce cardiovascular mortality. Indeed, the results of the recently concluded Diabetes Prevention Program in the United States convincingly demonstrated that the introduction of a lifestyle modification program, including at least a 7% reduction in body weight and a minimum of 150 min of physical activity per week, could, over a 3-yr period, reduce the incidence of Type 2 diabetes by 58% in individuals at significant risk for the development of the disease (28). These results are essentially identical to those from a recent Finnish study in which a weight-loss and exercise intervention reduced the incidence of Type 2 diabetes in overweight men with IGT (111) and are consistent with earlier epidemiological studies indicating that increased physical activity can prevent the development of Type 2 diabetes in men (46).

	ACUTE EXERCISE AND INSULIN RESISTANCE

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Glucose tolerance and glucose disposal. The various metabolic responses to a single bout of exercise performed by insulin-resistant rodents (primarily the obese Zucker rat) and humans are summarized in Tables 1 and 2, respectively. An acute bout of exercise (30 min at ~70% of O_2 max) by untrained rats does not improve intravenous glucose tolerance (64). Likewise, a single bout of prolonged aerobic exercise (30-60 min at ~60-70% of O_2 max) will normally not improve the diminished glucose tolerance of insulin-resistant Type 2 diabetic subjects, as evaluated with a standard oral glucose tolerance test (95). In contrast, a prior bout of prolonged moderate-intensity exercise (45 min of cycle ergometry at 45% of O_2 max) performed by Type 2 diabetic subjects can reduce the glycemic excursions and elevated plasma insulin levels during the 4-h period after a breakfast meal containing 56% carbohydrate, 30% fat, and 14% protein (81). Interestingly, this exercise effect was not observed when a lunch meal was subsequently consumed 4 h after the breakfast meal (81), indicating the transient nature of this acute exercise effect.

View this table: [in this window] [in a new window]   Table 1.   Summary of effects of acute exercise or exercise training on whole body glucose disposal and skeletal muscle insulin action in insulin-resistant rodent models

View this table: [in this window] [in a new window]   Table 2.   Summary of effects of acute exercise or exercise training on whole-body glucose disposal and skeletal muscle insulin action in insulin-resistant humans

It is, however, well established that, during a single bout of physical activity, a significant glucose-lowering effect in obese rodents (38) and in Type 2 diabetic individuals can be elicited (58, 81, 86, 114). Plasma insulin is also reduced in these individuals during the exercise bout (86). Whole body glucose disposal during a euglycemic, hyperinsulinemic clamp can also be enhanced in obese rats after a single bout of exercise (14, 38, 89) and is associated with an increase in insulin-stimulated glucose transport in skeletal muscle (89). The effect of acute exercise on glycemia is likely due to the ability of contractile activity to activate skeletal muscle glucose transport, as this pathway appears to be normal in animal models of insulin resistance (11, 12, 30, 49, 73) or in Type 2 diabetic subjects (3, 68). In addition, the enhanced glucose transport activity resulting from the exercise bout by Type 2 diabetic humans persists into the immediate postexercise period (27, 58, 85) and is associated with enhanced insulin sensitivity immediately after (85) and 20 h after (27) exercise. At 24 h after exercise, the enhanced insulin sensitivity was not observed (22). The mechanisms for these responses of Type 2 diabetic subjects to acute exercise are currently unknown.

Skeletal muscle glucose transport and insulin signaling. One underlying cellular mechanism for this glucose-lowering effect of acute exercise in insulin resistance has been addressed in a study of exercise-induced GLUT-4 translocation in a cohort of Type 2 diabetic individuals (68). Immediately after a single bout of exercise (45-60 min of cycling at 60-70% of O_2 max), there was a 74 ± 20% increase in plasma membrane GLUT-4 protein in vastus lateralis muscle, which was nearly identical to the postexercise increase (71 ± 18%) seen in nondiabetic subjects. Protein expression of GLUT-4 was not enhanced by this single bout of exercise (68). Consistent with this finding are the results of King et al. (73), which demonstrated that the exercise-induced translocation of glucose transporter protein in skeletal muscle of the obese Zucker rat was not different from that in lean animals. Therefore, a single bout of moderate-intensity exercise can increase muscle glucose transport via a normal induction of GLUT-4 translocation into the plasma membrane (68, 73).

The longer term effect of a single bout of exercise on insulin signaling in insulin-resistant skeletal muscle is less definitive. Twenty-four hours after a single exercise session (1 h of cycle ergometer exercise at 65% of O_2 max) performed by Type 2 diabetic subjects, the response to insulin of skeletal muscle tyrosine phosphorylation of the insulin receptor and of IRS-1 was significantly enhanced (22). However, insulin stimulation of IRS-1-associated PI3-kinase activity was not enhanced by the prior exercise, and at this time point whole body insulin-stimulated glucose disposal (assessed with a euglycemic, hyperinsulinemic clamp) was not increased relative to the sedentary state (22). It is clear that further investigations, incorporating shorter postexercise time points, are needed to elucidate the mechanisms whereby acute exercise can augment skeletal muscle glucose uptake by insulin-resistant skeletal muscle.

	CHRONIC EXERCISE AND INSULIN RESISTANCE

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Glucose tolerance and glucose disposal. The adaptive responses of whole body and skeletal muscle glucose metabolism to an increase in physical activity by insulin-resistant rodents are shown in Table 1, and those observed in insulin-resistant humans are displayed in Table 2. As mentioned previously, one characteristic feature of the abnormal metabolic state of obese Zucker rats is glucose intolerance. In one of the first investigations of the potential beneficial effects of exercise training that used this animal model of obesity-associated insulin resistance, Becker-Zimmermann et al. (8) demonstrated that mild exercise training (treadmill running) by older (25-wk-old) obese Zucker rats could significantly improve glucose disposal during an oral glucose tolerance test and reduce the exaggerated insulin response to a glucose challenge. Moreover, these investigators showed that exercise training by younger (7-wk-old) obese Zucker rats could prevent the deterioration of glucose tolerance experienced by these animals as they develop into adulthood (8). This exercise training-induced improvement in the whole body insulin sensitivity of obese Zucker rats was soon confirmed with swim training (113). Several subsequent investigations also demonstrated that the impaired whole body glucose tolerance (20, 100, 106) and the reduced insulin sensitivity at the whole body (20, 52, 100, 106) and hindlimb (primarily skeletal muscle) levels (60, 61, 115) of the obese Zucker rat can be substantially improved by aerobic exercise training.

The impaired whole body glucose metabolism in humans with IGT or Type 2 diabetes can likewise be beneficially modified by exercise training (67). Endurance exercise training leads to improvements in glucose tolerance (59, 95) and whole body insulin-mediated glucose disposal (25) in insulin-resistant subjects with IGT or Type 2 diabetes. Interestingly, Eriksson et al. (32) reported that a chronic circuit training regimen, in which resistance-type exercises are performed, also enhances insulin-mediated whole-body glucose disposal in insulin-resistant subjects with IGT.

Skeletal muscle glucose transport and insulin signaling. Several investigations have convincingly shown that skeletal muscle is the primary cellular locus for the beneficial adaptive responses of whole body insulin sensitivity to exercise training by the obese Zucker rat. Moderate- and high-intensity aerobic training results in an increased maximal aerobic capacity (20, 100, 106, 110) and in greater locomotor skeletal muscle levels of enzymes involved in glucose catabolism (e.g., hexokinase and citrate synthase) (4, 13, 20, 100, 106, 110). The enhanced exercise training-induced glucose tolerance and glucose disposal in the obese Zucker rat are primarily due to adaptations in the insulin-dependent glucose transport system in skeletal muscle. Exercise training leads to enhanced insulin action on glucose transport in locomotor muscles of the perfused hindquarter (4, 13, 20, 60, 61, 115) and in isolated, incubated locomotor skeletal muscles (34, 100, 106). Two critical adaptive responses that underlie the enhanced insulin-stimulated glucose transport activity after exercise training in these animals are an upregulation of GLUT-4 protein expression (4, 13, 34, 36, 52, 100, 104, 106) and increased GLUT-4 translocation (13) and cell surface GLUT-4 (34) after insulin stimulation.

Exercise training of animals with normal insulin signaling leads to an enhancement of specific steps in the insulin signaling cascade, including increased mRNA and protein expression and functionality of the insulin receptor, IRS-1, PI3-kinase, and MAP kinase [extracellular-regulated kinase 1 (ERK1)] (17, 70, 71). However, much less is known regarding the adaptive responses to exercise training of the insulin signaling pathway in muscle of the obese Zucker rat. Exercise training of these insulin-resistant animals leads to upregulation of insulin receptor tyrosine phosphorylation (52) and enhanced IRS-1 protein expression (102) with no alteration in protein expression of insulin receptor -subunit (52, 102), the p85 subunit of PI3-kinase (52, 102), or Akt/PKB (52). However, in a recent study by Christ et al. (18), 7 wk of exercise training by obese Zucker rats did not cause any increases in insulin action on insulin receptor or IRS-1 tyrosine phosphorylation, PI3-kinase activity, or Akt/PKB serine phosphorylation.

Muscle contractions lead to activation of ERK1/2, isoforms of MAP kinase (39), and there is speculation that increases in MAP kinase signaling may be associated with several exercise-associated adaptive responses in skeletal muscle (82, 98). Interestingly, exercise training by obese Zucker rats leads to upregulation of ERK2 protein expression (90). This finding raises the intriguing possibility that enhanced signal transduction through the MAP kinase signaling cascade may play an important role in the increased expression of glucose catabolic enzymes, GLUT-4, and insulin signaling proteins after exercise training by the obese Zucker rat.

Our knowledge of the underlying mechanisms for the beneficial effects of exercise training on insulin-resistant human skeletal muscle is much less extensive. Endurance exercise training also leads to improvements in insulin action on skeletal muscle glucose metabolism in insulin-resistant human subjects with IGT (95) or Type 2 diabetes (59, 95). Six weeks of exercise training by insulin-resistant offspring of human Type 2 diabetic subjects was associated with an enhancement of insulin-stimulated glucose transport and phosphorylation in skeletal muscle (91). As in rodent models of insulin resistance, an important molecular mechanism for the adaptive response to training by middle-aged men (55, 57) and by human Type 2 diabetic subjects (26, 59) is the upregulation of GLUT-4 protein expression in skeletal muscle. Whether exercise training can enhance insulin-stimulated GLUT-4 translocation in insulin-resistant human muscle is not presently known.

Exercise training by insulin-sensitive humans results in upregulation of insulin-stimulated PI3-kinase activity, both in longitudinal (56) and in cross-sectional (75) studies. These studies support a role of altered protein expression and functionality of insulin signaling factors in the enhanced insulin sensitivity of human skeletal muscle after exercise training. However, it has recently been shown that 1 wk of exercise training (60 min/day at 70% of peak oxygen consumption) did not enhance insulin stimulation of PI3-kinase activity or Akt/PKB activity in vastus lateralis muscle of middle-aged men (~58 yr old and presumably insulin resistant) (108). Other potential adaptive responses of the insulin signaling cascade in insulin-resistant skeletal muscle to regular exercise are currently unknown.

	EXERCISE AND INSULIN RESISTANCE: FUTURE DIRECTIONS

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The beneficial effects of an acute bout of exercise and of chronic exercise training on insulin action in insulin-resistant states are well established. However, there is a relative paucity of information on the specific molecular mechanisms in the skeletal muscle glucose transport system to explain these exercise effects. How contractile activity by skeletal muscle causes an enhancement of insulin sensitivity is not clear. Particularly intriguing is the very recent finding that components of the kallikrein-kininogen system may play a role in the development of enhanced insulin sensitivity after contractions by muscles from insulin-sensitive rats (31). This information is especially relevant in light of findings that treatment of insulin-resistant obese Zucker rats with bradykinin, a product of the kallikrein-kininogen system, can enhance whole body glucose tolerance (50) and insulin action on skeletal muscle glucose transport (50, 51). An important area of future investigation would be the potential interactions between products of the kallikrein-kininogen system, including bradykinin, and insulin signaling factors in insulin-resistant skeletal muscle.

A critical aspect that must be addressed in future investigations is a better understanding of the underlying mechanisms for upregulation of GLUT-4 protein and of specific insulin signaling factors after exercise training by insulin-resistant rodent models, such as the obese Zucker rat, and by humans with IGT and Type 2 diabetes. Specifically, the potential roles of increased intracellular Ca²⁺ and Ca²⁺-activated pathways, such as the MAP kinase pathway, and of a chronically altered energy charge, such as the activation of AMP kinase, in these exercise training-induced responses in insulin-resistant skeletal muscle require further investigation. The elucidation of these mechanisms will assist clinicians and exercise physiologists in the design of the most effective exercise regimens for the improvement of insulin action in insulin-resistant human subjects with IGT and Type 2 diabetes.

	FOOTNOTES

Address for reprint requests and other correspondence: E. J. Henriksen, Dept. of Physiology, Ina E. Gittings Bldg. 93, Univ. of Arizona, Tucson, AZ 85721-0093 (E-mail: ejhenrik{at}u.arizona.edu).

10.1152/japplphysiol.01219.2001

	REFERENCES

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1.   Anai, M, Funaki M, Ogihara T, Terasaki J, Inukai K, Katagiri H, Fukushima Y, Yazaki Y, Kikuchi M, Oka Y, and Asano T. Altered expression levels and impaired steps in pathways to phosphatidylinositol-3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats. Diabetes 47: 13-23, 1998.

2.   Asahi, Y, Hayashi H, Wang L, and Ebina Y. Fluoromicroscopic detection of myc-tagged GLUT4 on the cell surface. Co-localization of the translocated GLUT4 with rearranged actin by insulin treatment in CHO cells and L6 myotube. J Med Invest 46: 192-199, 1999.

3.   Azevedo, JL, Carey JO, Pories WJ, Morris PG, and Dohm GL. Hypoxia stimulates glucose transport in insulin-resistant human skeletal muscle. Diabetes 44: 695-698, 1995.

4.   Banks, EA, Brozinick JT, Jr, Yaspelkis BB, III, Kang HY, and Ivy JL. Muscle glucose transport, GLUT-4 content, and degree of exercise training in obese Zucker rats. Am J Physiol Endocrinol Metab 263: E1010-E1015, 1992.

5.   Balon, TW, and Nadler JL. Evidence that nitric oxide increases glucose transport in skeletal muscle. J Appl Physiol 82: 359-363, 1997.

6.   Baron, AD, Brechtel G, Wallace P, and Edelman SV. Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans. Am J Physiol Endocrinol Metab 255: E769-E774, 1988.

7.   Beck-Nielsen, H, Vaag A, Damsbo P, Handberg A, Nielsen OH, Henriksen JE, and Thye-Ronn P. Insulin resistance in skeletal muscles in patience with NIDDM. Diabetes Care 15: 418-429, 1992.

8.   Becker-Zimmermann, K, Berger M, Berchtold P, Gries FA, Herberg L, and Schwenen M. Treadmill training improves intravenous glucose tolerance and insulin sensitivity in fatty Zucker rats. Diabetologia 22: 468-474, 1982.

9.   Berger, M, Kemmer FW, Becker K, Herberg L, Schwenen M, Gjinavci A, and Berchtold P. Effect of physical training on glucose tolerance and on glucose metabolism of skeletal muscle in anaesthetized normal rats. Diabetologia 16: 179-184, 1979.

10.   Björnholm, M, Kawano Y, Lehtihet M, and Zierath JR. Insulin receptor substrate-1 phosphorylation and phosphatidylinositol-3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 46: 524-527, 1997.

11.   Brozinick, JT, Jr, Etgen GJ, Yaspelkis BB, III, and Ivy JL. Contraction-activated glucose uptake is normal in insulin-resistant muscle of the obese Zucker rat. J Appl Physiol 73: 382-387, 1992.

12.   Brozinick, JT, Jr, Etgen GJ, Yaspelkis BB, III, and Ivy JL. Glucose uptake and GLUT-4 protein distribution in skeletal muscle of obese Zucker rat. Am J Physiol Regulatory Integrative Comp Physiol 267: R236-R243, 1994.

13.   Brozinick, JT, Jr, Etgen GJ, Yaspelkis BB, III, Kang HY, and Ivy JL. Effects of exercise training on muscle GLUT-4 protein content and translocation in obese Zucker rats. Am J Physiol Endocrinol Metab 265: E419-E427, 1993.

14.   Burstein, R, Zissholtz A, Zick-Bachar Y, Epstein Y, Shapiro Y, and Karnieli E. Glucose uptake by adipocytes of obese rats: effect of one bout of acute exercise. Can J Physiol Pharmacol 70: 1473-1476, 1992.

15.   Cartee, GD, Douen AG, Ramlal T, Klip A, and Holloszy JO. Stimulation of glucose transport in skeletal muscle by hypoxia. J Appl Physiol 70: 1593-1600, 1991.

16.   Chaudry, IH, and Gould MK. Effect of externally added ATP on glucose uptake by isolated rat soleus muscle. Biochim Biophys Acta 196: 327-335, 1970.

17.   Chibalin, AV, Yu M, Ryder JW, Song XM, Galuska D, Krook A, Wallberg-Henriksson H, and Zierath JR. 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. Proc Natl Acad Sci USA 97: 38-43, 2000.

18.   Christ, CY, Hunt D, Hancock J, Garcia-Macedo R, Mandarino LJ, and Ivy JL. Exercise training improves muscle insulin resistance but not insulin receptor signaling in obese Zucker rats. J Appl Physiol 92: 736-744, 2002.

19.   Cline, GW, Petersen KF, Krssak M, Shen J, Hundal RS, Trajanoski Z, Inzucchi S, Dresner A, Rothman DL, and Shulman GI. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med 341: 240-246, 1999.

20.   Cortez, MY, Torgan CE, Brozinick JT, Jr, and Ivy JL. Insulin resistance of obese Zucker rats exercise trained at two different intensities. Am J Physiol Endocrinol Metab 261: E613-E619, 1991.

21.   Crettaz, M, Prentki M, Zaninetti D, and Jeanrenaud B. Insulin resistance in soleus muscle from obese Zucker rats: involvement of several defective sites. Biochem J 186: 525-534, 1980.

22.   Cusi, K, Maezona K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, and Mandarino LJ. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 105: 311-320, 2000.

23.   DeFronzo, RA, and Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14: 173-194, 1991.

24.   DeFronzo, RA, Ferrannini E, Hendler R, Felig P, and Wahren J. Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 32: 32-45, 1983.

25.   Dela, F, Larsen JJ, Mikenes KJ, Ploug T, Petersen LN, and Galbo H. Insulin-stimulated muscle glucose clearance in patients with NIDDM. Effects of one-legged physical training. Diabetes 44: 1010-1020, 1995.

26.   Dela, F, Ploug T, Handberg A, Petersen LN, Larsen JJ, Mikenes KJ, and Galbo H. Physical training increases muscle GLUT4 protein and mRNA in patients with NIDDM. Diabetes 43: 862-865, 1994.

27.   Devlin, JT, Hirshman M, Horton ED, and Horton ES. Enhanced peripheral and splanchnic insulin sensitivity in NIDDM men after single bout of exercise. Diabetes 36: 434-439, 1987.

28.   Diabetes Prevention Program Research Group. Reduction of the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346: 393-403, 2002.

29.   Dohm, GL, Elton CW, Friedman JE, Pilch PF, Pories WJ, Atkinson SM, and Caro JF. Decreased expression of glucose transporter in muscle from insulin-resistant patients. Am J Physiol Endocrinol Metab 260: E459-E463, 1991.

30.   Dolan, PL, Tapscott EB, Dorton PJ, and Dohm GL. Contractile activity restores insulin responsiveness in skeletal muscle of obese Zucker rats. Biochem J 289: 423-426, 1993.

31.   Dumke, CL, Kim J, Arias EB, and Cartee GD. Role of kallikrein-kininogen system in insulin-stimulated glucose transport after muscle contractions. J Appl Physiol 92: 657-664, 2002.

32.   Eriksson, J, Tuominen J, Valle T, Sundberg S, Sovijari A, Lindholm H, Tuomilehto J, and Koivisto V. Aerobic endurance exercise or circuit-type resistance training for individuals with impaired glucose tolerance? Horm Metab Res 30: 37-41, 1998.

33.   Etgen, GJ, Fryburg DA, and Gibbs EM. Nitric oxide stimulates skeletal muscle glucose transport through a calcium/contraction- and phosphatidylinositol-3-kinase-independent pathway. Diabetes 46: 1915-1919, 1997.

34.   Etgen, GJ, Jensen J, Wilson CM, Hunt DG, Cushman SW, and Ivy JL. Exercise training reverses insulin resistance in muscle by enhanced recruitment of GLUT-4 to the cell surface. Am J Physiol Endocrinol Metab 272: E864-E869, 1997.

35.   Etgen, GJ, Wilson CM, Jensen J, Cushman SW, and Ivy JL. Glucose transport and cell surface GLUT-4 protein in skeletal muscle of the obese Zucker rat. Am J Physiol Endocrinol Metab 271: E294-E301, 1996.

36.   Friedman, JE, Sherman WM, Reed MJ, Elton CW, and Dohm GL. Exercise training increases glucose transporter protein GLUT-4 in skeletal muscle of obese Zucker (fa/fa) rats. FEBS Lett 268: 13-16, 1990.

37.   Gao, J, Ren J, Gulve EA, and Holloszy JO. Additive effect of contractions and insulin on GLUT-4 translocation into the sarcolemma. J Appl Physiol 77: 1587-1601, 1994.

38.   Gao, J, Sherman WM, McCune SA, and Osei K. Effects of acute running exercise on whole body insulin action in obese male SHHF/Mcc-facp rats. J Appl Physiol 77: 534-541, 1994.

39.   Goodyear, LJ, Chang PY, Sherwood DJ, Dufresne SD, and Moller DE. Effects of exercise and insulin on mitogen-activated protein kinase signaling pathways in rat skeletal muscle. Am J Physiol Endocrinol Metab 271: E403-E408, 1996.

40.   Goodyear, LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, and Dohm GL. Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 95: 2195-2204, 1995.

41.   Goodyear, LJ, Hirshman MF, and Horton ES. Exercise-induced translocation of skeletal muscle glucose transporters. Am J Physiol Endocrinol Metab 261: E795-E799, 1991.

42.   Goodyear, LJ, Hirshman MF, Valyou PM, and Horton ES. Glucose transporter number, function, and subcellular distribution in rat skeletal muscle after exercise training. Diabetes 41: 1091-1099, 1992.

43.   Goodyear, LJ, and Kahn BB. Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 49: 235-261, 1998.

44.   Hajduch, E, Alessi DR, Hemmings BA, and Hundal HS. Constitutive activation of protein kinase B by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells. Diabetes 47: 1006-1013, 1998.

45.   Hayashi, T, Wojtaszewski JF, and Goodyear LJ. Exercise regulation of glucose transport in skeletal muscle. Am J Physiol Endocrinol Metab 273: E1039-E1051, 1997.

46.   Helmrich, SP, Ragland DR, Leung RW, and Paffenbarger RS. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 325: 147-152, 1991.

47.   Henriksen, EJ, Bourey RE, Rodnick KJ, Koranyi L, Permutt MA, and Holloszy JO. Glucose transporter protein content and glucose transport capacity in rat skeletal muscles. Am J Physiol Endocrinol Metab 259: E593-E598, 1990.

48.   Henriksen, EJ, and Halseth AE. Early alterations in soleus GLUT-4, glucose transport, and glycogen in voluntary running rats. J Appl Physiol 76: 1862-1867, 1994.

49.   Henriksen, EJ, and Jacob S. Effects of captopril on glucose transport activity in skeletal muscle of obese Zucker rats. Metabolism 44: 267-272, 1995.

50.   Henriksen, EJ, Jacob S, Fogt DL, and Dietze GJ. Effect of chronic bradykinin administration on insulin action in an animal model of insulin resistance. Am J Physiol Regulatory Integrative Comp Physiol 275: R40-R45, 1998.

51.   Henriksen, EJ, Jacob S, Kinnick TR, Youngblood EB, Schmit MB, and Dietze GJ. ACE inhibition and glucose transport in insulin-resistant muscle: roles of bradykinin and nitric oxide. Am J Physiol Regulatory Integrative Comp Physiol 277: R332-R336, 1999.

52.   Hevener, AL, Reichart D, and Olefsky J. Exercise and thiazolidinedione therapy normalize insulin action in the obese Zucker fatty rat. Diabetes 49: 2154-2159, 2000.

53.   Holloszy, JO, and Hansen PA. Regulation of glucose transport into skeletal muscle. Rev Physiol Biochem Pharmacol 128: 99-193, 1996.

54.   Holloszy, JO, and Narahara HT. Studies of tissue permeability. X changes in permeability to 3-methylglucose associated with contraction of frog muscle. J Biol Chem 240: 3493-3500, 1965.

55.   Houmard, JA, Egan PC, Neufer PD, Friedman JE, Wheeler WS, Israel RG, and Dohm GL. Elevated skeletal muscle glucose transporter levels in exercise-trained middle-aged men. Am J Physiol Endocrinol Metab 261: E437-E443, 1991.

56.   Houmard, JA, Shaw CD, Hickey MS, and Tanner CJ. Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in human skeletal muscle. Am J Physiol Endocrinol Metab 277: E1055-E1060, 1999.

57.   Houmard, JA, Shinebarger MH, Dolan PL, Leggett-Frazier N, Bruner RK, McCammon MR, Israel RG, and Dohm GL. Exercise training increases GLUT-4 protein concentration in previously sedentary middle-aged men. Am J Physiol Endocrinol Metab 264: E896-E901, 1993.

58.   Hübingen, A, Franzen A, and Gries FA. Hormonal and metabolic responses to physical exercise in hyperinsulinaemic and nonhyperinsulinaemic type 2 diabetics. Diabetes Res Clin Pract 4: 57-61, 1987.

59.   Hughes, VA, Fiatarone MA, Fielding RA, Kahn BB, Ferrara CM, Shepherd P, Fisher EC, Wolfe RR, Elahi D, and Evans WJ. Exercise increases muscle GLUT4 levels and insulin action in subjects with impaired glucose tolerance. Am J Physiol Endocrinol Metab 264: E855-E862, 1993.

60.   Ivy, JL, Brozinick JT, Jr, Torgan CE, and Kastello GM. Skeletal muscle glucose transport in obese Zucker rats after exercise training. J Appl Physiol 66: 2635-2641, 1989.

61.   Ivy, JL, Sherman WM, Cutler CL, and Katz AL. Exercise and diet reduce muscle insulin resistance in obese Zucker rat. Am J Physiol Endocrinol Metab 251: E299-E305, 1986.

62.   Ivy, JL, Zderic TW, and Fogt DL. Prevention and treatment of non-insulin-dependent diabetes mellitus. Exerc Sport Sci Rev 27: 1-35, 1999.

63.   Jacob, S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ, Dietze GJ, and Henriksen EJ. The antioxidant -lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. Diabetes 45: 1024-1029, 1996.

64.   James, DE, Burleigh KM, Kraegen EW, and Chisholm DJ. Effect of acute exercise and prolonged training on insulin response to intravenous glucose in vivo in rat. J Appl Physiol 55: 1660-1664, 1983.

65.   James, DE, Kraegen EW, and Chisholm DJ. Effect of exercise training on whole-body insulin sensitivity and responsiveness. J Appl Physiol 56: 1217-1222, 1984.

66.   James, DE, Kraegen EW, and Chisholm DJ. Effects of exercise training on in vivo insulin action in individual tissues of the rat. J Clin Invest 76: 657-666, 1985.

67.   Kelley, DE, and Goodpaster BH. Effects of physical activity on insulin action and glucose tolerance in obesity. Med Sci Sports Exerc 31, Suppl: S619-S623, 1999.

68.   Kennedy, JW, Hirshman MF, Gervino EV, Ocel JV, Forse RA, Hoenig SJ, Aronson D, Goodyear LJ, and Horton ES. Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes. Diabetes 48: 1192-1197, 1999.

69.   Kern, M, Wells JA, Stephens JM, Elton CW, Friedman JE, Tapscott EB, Pekala PH, and Dohm GL. Insulin responsiveness in skeletal muscle is determined by glucose transporter (Glut4) protein level. Biochem J 270: 397-400, 1990.

70.   Kim, Y, Inoue T, Nakajima R, Nakae K, Tamura T, Tokuyama K, and Suzuki M. Effects of endurance training on gene expression of insulin signal transduction pathway. Biochem Biophys Res Commun 210: 766-773, 1995.

71.   Kim, YB, Inoue T, Nakajima R, Shirai-Morishita Y, Tokuyama K, and Suzuki M. Effect of long-term exercise on gene expression of insulin signaling pathway intermediates in skeletal muscle. Biochem Biophys Res Commun 254: 720-727, 1999.

72.   Kim, YB, Nikoulina SE, Ciaraldi TP, Henry RR, and Kahn BB. Normal insulin-dependent activation of AKT/protein kinase B, with diminished activation of phosphoinositide 3-kinase activity, in muscle in type 2 diabetes. J Clin Invest 104: 733-741, 1999.

73.   King, PA, Betts JJ, Horton ED, and Horton ES. Exercise, unlike insulin, promotes glucose transporter translocation in obese Zucker rat muscle. Am J Physiol Regulatory Integrative Comp Physiol 265: R447-R452, 1993.

74.   King, PA, Horton ED, Hirshman MF, and Horton ES. Insulin resistance in obese Zucker rat (fa/fa) is associated with a failure of glucose transporter translocation. J Clin Invest 90: 1568-1575, 1992.

75.   Kirwan, JP, del Aguila LF, Hernandez JM, Williamson DL, O'Gorman DJ, Lewis R, and Krishnan RK. Regular exercise enhances insulin activation of IRS-1-associated PI3-kinase in human skeletal muscle. J Appl Physiol 88: 797-803, 2000.

76.   Kitamura, T, Ogawa W, Sakaue H, Hino Y, Kuroda S, Takata M, Matsumoto M, Maeda T, Konishi H, Kikkawa U, and Kasuga M. Requirement for activation of the serine-threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but not of glucose transport. Mol Cell Biol 18: 3708-3717, 1998.

77.   Kohn, AD, Summers SA, Birnbaum MJ, and Roth RA. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulated glucose uptake and glucose transporter 4 translocation. J Biol Chem 271: 31372-31378, 1996.

78.   Krook, A, Björnholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG, Wallberg-Henriksson H, and Zierath JR. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49: 284-292, 2000.

79.   Krook, A, Roth RA, Jiang XJ, Zierath JR, and Wallberg-Henriksson H. Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. Diabetes 47: 1281-1286, 1998.

80.   Kurth-Kraczek, EJ, Hirshman MF, Goodyear LJ, and Winder WW. 5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes 48: 1667-1671, 1999.

81.   Larsen, JJS, Dela F, Kjaer M, and Galbo H. The effect of moderate exercise on postprandial glucose homeostasis in NIDDM patients. Diabetologia 40: 447-453, 1997.

82.   MacLean, PS, Zheng D, and Dohm GL. Muscle glucose transporter (GLUT 4) gene expression during exercise. Exerc Sport Sci Rev 28: 148-152, 2000.

83.   Mann, WR, Villauer EB, Barilla D, Battle B, Dunning BE, and Balkan B. Effects of bradykinin on glucose metabolism in isolated rat soleus muscle and on blood glucose levels in Ob/Ob mice (Abstract). Diabetes 44: 133A, 1995.

84.   Mathe, D. Dyslipidemia and diabetes: animal models. Diabetes Metab 21: 106-111, 1995.

85.   Minuk, HL, Vranic M, Marliss EB, and Hanna AK. Glucoregulatory and metabolic response to exercise in obese noninsulin-dependent diabetes. Am J Physiol Endocrinol Metab 240: E458-E464, 1981.

86.   Musi, N, Fujii N, Hirshman MF, Ekberg I, Fröberg S, Ljungqvist O, Thorell A, and Goodyear LJ. AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes 50: 921-927, 2001.

87.   Nesher, R, Karl IE, and Kipnis DM. Dissociation of effects of insulin and contraction on glucose transport in rat epitrochlearis muscle. Am J Physiol Cell Physiol 249: C226-C232, 1985.

88.   Neufer, PD, Shinebarger MH, and Dohm GL. Effect of training and detraining on skeletal muscle glucose transporter (GLUT4) content in rats. Can J Physiol Pharmacol 70: 1286-1290, 1992.

89.   Oakes, ND, Bell KS, Furler SM, Camilleri S, Saha AK, Ruderman NB, Chisholm DJ, and Kraegen EW. Diet-induced muscle insulin resistance in rats is ameliorated by acute dietary lipid withdrawal or a single bout of exercise: parallel relationship between insulin stimulation of glucose uptake and suppression of long-chain fatty acyl-CoA. Diabetes 46: 2022-2028, 1997.

90.   Osman, AA, Hancock J, Hunt DG, Ivy JL, and Mandarino LJ. Exercise training increases ERK2 activity in skeletal muscle of obese Zucker rats. J Appl Physiol 90: 454-460, 2001.

91.   Perseghin, G, Price TB, Petersen KF, Roden M, Cline CW, Gerow K, Rothman DL, and Shulman GI. Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med 335: 1357-1362, 1996.

92.   Reaven, GM. Role of insulin resistance in human disease. Diabetes 37: 1595-1607, 1988.

93.   Reaven, GM. Role of insulin resistance in human disease (Syndrome X): an expanded definition. Annu Rev Med 44: 121-131, 1993.

94.   Roberts, CK, Barnard RJ, Scheck SH, and Balon TW. Exercise-stimulated glucose transport in skeletal muscle is nitric oxide dependent. Am J Physiol Endocrinol Metab 273: E220-E225, 1997.

95.   Rogers, MA, Yamamoto C, King DS, Hagberg JM, Ehsani AA, and Holloszy JO. Improvements in glucose tolerance after 1 week of exercise in patients with mild NIDDM. Diabetes Care 11: 613-618, 1988.

96.   Rodnick, KJ, Henriksen EJ, James DE, and Holloszy JO. Exercise training, glucose transporters, and glucose transport in rat skeletal muscles. Am J Physiol Cell Physiol 262: C9-C14, 1992.

97.   Rodnick, KJ, Holloszy JO, Mondon CE, and James DE. Effects of exercise training on insulin-regulatable glucose-transporter protein levels in rat skeletal muscle. Diabetes 39: 1425-1429, 1990.

98.   Ryder, JW, Chibalin AV, and Zierath JR. Intracellular mechanisms underlying increases in glucose uptake in response to insulin or exercise in skeletal muscle. Acta Physiol Scand 171: 249-257, 2001.

99.   Ryder, JW, Yang J, Galuska D, Rincon J, Björnholm M, Krook A, Lund S, Pedersen O, Wallberg-Henriksson H, Zierath JR, and Holman GD. Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 2 diabetic patients. Diabetes 49: 647-654, 2000.

100.   Saengsirisuwan, V, Kinnick TR, Schmit MB, and Henriksen EJ. Interactions of exercise training and -lipoic acid on glucose transport in obese Zucker rat. J Appl Physiol 91: 145-153, 2001.

101.   Saengsirisuwan, V, Perez FR, Kinnick TR, and Henriksen EJ. Effects of exercise training and antioxidant R-(+)-lipoic acid on glucose transport in insulin-sensitive rat skeletal muscle. J Appl Physiol 92: 50-58, 2002.

102.  Saengsirisuwan V, Perez FR, Maier T, and Henriksen EJ. Exercise training and lipoic acid upregulate IRS-1 protein expression in muscle of obese Zucker rats (Abstract). Med Sci Sports Exerc. In press.

103.   Shepherd, PR, and Kahn BB. Glucose transporters and insulin action. Implications for insulin resistance and diabetes mellitus. N Engl J Med 341: 248-257, 1999.

104.   Sherman, WM, Friedman JE, Gao JP, Reed MJ, Elton CW, and Dohm GL. Glycemia and exercise training alter glucose transport and GLUT4 in the Zucker rat. Med Sci Sports Exerc 25: 341-348, 1993.

105.   Slentz, CA, Gulve EA, Rodnick KJ, Henriksen EJ, Youn JH, and Holloszy JO. Glucose transporters and maximal transport are increased in endurance-trained rat soleus. J Appl Physiol 73: 486-492, 1992.

106.   Steen, MS, Foianini KR, Youngblood EB, Kinnick TR, Jacob S, and Henriksen EJ. Interactions of exercise training and ACE inhibition on insulin action in obese Zucker rats. J Appl Physiol 86: 2044-2051, 1999.

107.   Taguchi, T, Kishikawa H, Motoshima H, Sakai K, Nishiyama T, Yoshizato K, Shirakami A, Toyonaga T, Shirontani T, Araki E, and Shichiri M. Involvement of bradykinin in acute exercise-induced increase of glucose uptake and GLUT-4 translocation in skeletal muscle: studies in normal and diabetic humans and rats. Metabolism 49: 920-930, 2000.

108.   Tanner, CJ, Koves TR, Cortright RL, Pories WJ, Kim YB, Kahn BB, Dohm GL, and Houmard JA. Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in middle-aged men. Am J Physiol Endocrinol Metab 282: E147-E153, 2002.

109.   Thornburn, AW, Gumbiner B, Bulacan F, Wallace P, and Henry RR. Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake. J Clin Invest 85: 522-529, 1990.

110.   Torgan, CE, Brozinick JT, Jr, Kastello GM, and Ivy JL. Muscle morphological and biochemical adaptations to training in obese Zucker rats. J Appl Physiol 67: 1807-1813, 1989.

111.   Tuomilehto, J, Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Aunola S, Cepaitis Z, Moltchanov V, Hakumaki M, Mannelin M, Martikkala V, Sundvall J, and Uusitupa M. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344: 1343-1350, 2001.

112.   Ueki, K, Yamamoto-Honda R, Kaburagi Y, Yamauchi T, Tobe K, Burgering BMT, Coffer PJ, Komuro I, Akanuma Y, Yazaki Y, and Kadowaki T. Potential role of protein kinase B in insulin-induced glucose transport, glycogen synthesis, and protein synthesis. J Biol Chem 273: 5315-5322, 1998.

113.   Walberg, JL, Upton D, and Stern JS. Exercise training improves insulin sensitivity in the obese Zucker rat. Metabolism 33: 1075-1079, 1984.

114.   Wallberg-Henriksson, H. Exercise and diabetes mellitus. Exerc Sport Sci Rev 20: 339-369, 1992.

115.   Willems, MET, Brozinick JT, Jr, Torgan CE, Cortez MY, and Ivy JL. Muscle glucose uptake at two difference intensities. J Appl Physiol 70: 36-42, 1991.

116.   Zierath, JR, He L, Guma A, Odegaard-Wahlstrom E, Klip A, and Wallberg-Henriksson H. Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM. Diabetologia 39: 1180-1189, 1996.

117.   Zierath, JR, Krook A, and Wallberg-Henriksson H. Insulin action and insulin resistance in human skeletal muscle. Diabetologia 43: 821-835, 2000.