Regulation

of glucose

R. JAMES Department

transport

BARNARD2 AND JACX F. YOUNGREN of Physiological Science University of Caiifonua,

The entry of glucose into muscle cells is achieved primarily via a carrier-mediated system consisting of protein transport molecules. GLUT-i transporter isoform is normally found in the sarcolemmal (SL) membrane and is thought to be involved in glucose transport under basal conditions. With insulin stimulation, glucose transport is accelerated by translocating GLUT-4 transporters from an intracellular pooi out to the T-tubule and SL membranes. Activation of transporters to increase the turnover number may also be involved, but the evidence is far from conclusive. When insulin binds to its receptor, it autophosphorylates tyrosine and serine residues on the 3-subunit of the receptor. The tyrosine residues are thought to activate tyrosine kinases, which in turn phosphorylate/activate as yet unknown second messengers. Insulin receptor antibodies, however, have been reported to increase glucose transport without increasing kinase activity. Insulin resistance in skeletal muscle is a major characteristic of obesity and diabetes mellitus, especially NIDDM. A decrease in the number of insulin receptors and the ability of insulin to activate receptor tyrosine kinase has been documented in muscle from NIDDM patients. Most studies report no change in the intracellular pool of GLUT-4 transporters available for translocation to the SL. Both the quality and quantity of food consumed can regulate insulin sensitivity. A high-fat, refined sugar diet, similar to the typical U.S. diet, causes insulin resistance when compared with a low-fat, complexcarbohydrate diet. On the other hand, exercise increases insulin sensitivity. After an acute bout of exercise, glucose transport in muscle increases to the same level as with maximum insulin stimulation. Although the number of GLUT-4 transporters in the sarcolemma increases with exercise, neither insulin or its receptor is involved. After an initial acute phase, which may involve calcium as the activator, a secondary phase of increased insulin sensitivity can last for up to a day after exercise. The mechanism responsible for the increased insulin sensitivity with exercise is unknown. Regular exercise training also increases insulin sensitivity, which can be documented several days after the final bout of exercise, and again the mechanism is unknown. An increase in the muscle content of GLUT-4 transporters with training has recently been reported. Even though significant progress has been made in the past few years in understanding glucose transport in skeletal muscle, the mechanisms involved in regulating transport are far from being understood. -Barnard, R. J.; Youngren, J. F. Regulation of glucose transport in skeletal muscle. FASEB J. 6: 3238-3244; 1992. ABSTRACT

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Los Angeles, California

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isrequired to promote entry of glucose into body cells. The transport is achieved by proteins (-45 kDa) and does not require energy. Although insulin was discovered in 1921, it was not until the 1980s that significant advances were made in understanding the mechanism of insulin action at the cellular level. In 1980, Cushman and Wardzala (1) and Suzuki and Kono (2) independently proposed the translocation hypothesis based on studies done with fat cells. Using cytochalasin-B binding to quantitate the number of glucose transporters, they were able to demonstrate a translocation of transporters from an intracellular pool to the plasma membrane after insulin stimulation. In 1982, several laboratories reported that the insulin receptor contains tyrosine residues that undergo autophosphorylation upon exposure to insulin and can also phosphorylate other proteins (3, 4). Serine residues are also phosphorylated, but there is no evidence to suggest any involvement in glucose transport. In 1988, James et al. (5) provided evidence for the existence of different types of facilitative glucose transporters. To date, five different isoforms of facilitative glucose transporters have been identified as well as a sodium/glucose cotransporter (6). Because GLUT-I and GLUT-4 transporter isoforms have both been shown to reside in fat cells and to be responsive to insulin stimulation, it has been assumed that both isoforms are also involved in skeletal muscle glucose transport. In fact, mRNA and protein for both transporter isoforms have been reported for skeletal muscle (7-10). Using immunohistochemical techniques, Kahn et al. (7) recently reported that GLUT-i in soleus muscle was found in penneurial cells and not in muscle fibers. However, Klip and Marette (11) recently reported that by using immunofluorescence, GLUT-I could be detected in the plasma membrane. GLUT-i protein has been identified in highly purified sarcolemmal membranes but not in intracellular membranes (12, 13). If the GLUT-i found in SL membranes was the result of contamination from the penneurial cells, it should be found in both plasma and intracellular membranes. Klip and P#{226}quet (14) have concluded that it is highly unlikely that the amount of GLUT-I identified in SL membranes could be the result of contamination by perineural cells. In addition, GLUT-i transporter has been detected immunologically in rat L6 muscle cells and human muscle cells maintained in culture (14). Thus, the bulk of evidence still suggests that GLUT-l and GLUT-4 are both found in skeletal muscle. Some evidence suggests that there is more than

1This review is based, in part, on the symposium “Regulation of Glucose Transport in Skeletal Muscle” presented by The American Physiological Society (and sponsored by the APS Endocrinology and Metabolism Section) at the 75th Annual Meeting of the Federation of American Societies for Experimental Biology in Atlanta, Georgia, April 24, 1991. 2To whom correspondence: should be addressed, at: Department of Physiological Science, 1804 Life Sciences, University of California, 405 Hilgard Ave., Los Angeles, CA 90024-1527, USA.

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one pool of intracellularGLUT-4 transporters and that different mechanisms may be involved in their translocation to the SL. However, Rodnick et al. (15), using immunocytochemical techniques, have recently reported that GLUT-4 is present in tubulovesicular structures clustered in the transgolgi reticulum and that these transporters are translocated to the sarcolemma with either insulin stimulation or exercise. Skeletal muscle is the most important target tissue for insulin in the regulation of blood glucose. Euglycemic clamp studies have shown that approximately 75% of the glucose removed from the blood goes into skeletal muscle and that insulin resistance in skeletal muscle is one of the primary characteristics of diabetes mellitus (16). Thus, attention has recently focused on the regulation of glucose transport in skeletal muscle. In addition to insulin, exercise has been shown to stimulate the glucose transport system. Diet also plays an important role in regulating the sensitivity of insulin and is an important aspect in the treatment of diabetes mellitus. The purpose of this review is to discuss the cellularlevel mechanisms involved in the regulation of glucose transport in skeletal muscle. Although several studies using cultured muscle cells have been reported, it is clear that this model is different from intact muscle (14); thus, these studies are not included. It has recently been demonstrated that glucose transport capacity is different in different skeletal muscle fiber types (10, 13, 17). Slow-twitch oxidative and fasttwitch oxidative glycolytic fibers have slightly higher basal rates of glucose uptake than do fast-twitch glycolytic fibers. GLUT-I has been reported to be lower in the fast glycolytic fibers (13). Insulin-stimulated glucose uptake is much higher in slow oxidative and fast oxidative glycolytic fibers compared with fast glycolytic fibers. The difference is due, in part, to a lower number of insulin receptors in the fast glycolytic fibers (18). There appears to be no difference in insulin receptor tyrosine kinase activity in receptors from different fiber types (18). There also appears to be larger intracellular pools of glucose transporters in the more insulin-responsive fibers (10, 13). Kern et al. (10) reported that the GLUT-4 content was approximately fivefold higher in red (fast-twitch oxidative glycolytic) than white (fast-twitch glycolytic) muscle. MECHANISM

OF

INSULIN

ACTION

Several laboratories have recently developed isolated sarcolemmal (SL)3 membrane preparations to study the glucose transport system. The advantages and difficulties of this approach have been discussed in detail by Klip (19). The SL vesicle preparation has been shown to contain insulin receptors as well as glucose transporters. The vesicles are osmotically active and exhibit stereospecific D-glucose transport. These vesicles contain T-tubule membranes, which are also thought to play a role in glucose transport (20). Insulin does not stimulate glucose transport when added to the vesicle preparation; however, when insulin is injected into animals before SL vesicle are isolated, the enhanced glucose transport can be demonstrated in the SL vesicle preparation. Stennlicht et al. (2i) found that the Vm for glucose transport was increased by 3.2-fold after maximum insulin stimulation, with no change in Km. The number of glucose transporters, as assessed by cytochalasin-B binding, increased by only 1.7-fold, with no change in Kd. These results led Sternlicht et al. (21) to conclude that insulin increased glucose transport by both translocation and activation of glucose transporters (Fig. 1). Similar results were reported by Klip et al. (22) and Goodyear et al. (13). These results, however, may be due to inherent problems of cross-contamination

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Muscle

Cell

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to

of GLUT-4 transportersfrom an intracellular pool to the T-tubules and sarcolemma has been well documented. Activation of transporters has been suggested but not well documented. Details are provided in the text. increase

during cellular fractionization or due to the possibility that the GLUT-4 transporter has a higher turnover number than the GLUT-i transporter. More recent studies using glucose transporter antibodies have shown that after insulin stimulation the GLUT-4 isoform is translocated from an intracellular pool to the T-tubule and SL membranes (13, 15, 20, 23-25). If activation of transporters does indeed occur, it is not known whether the activation involves both GLUT-i and GLUT-4 transporters. Changes in transport activity without a change in glucose transporter distribution have been well documented for isolated fat cells (26, 27), and recent studies with 3T3-Li adipocytes have suggested that the GLUT-i isoform may be activated by insulin (28). King et al. (29) recently reported that the Vm for glucose transport in response to insulin stimulation was reduced by almost 50% in SL membranes from obese Zucker rats. Although there was some insulin stimulation, there was no recruitment of GLUT-4 transporters to the SL. Thus, King et al. (29) concluded that the insulin stimulation was due solely to activation of transporters. With maximum insulin stimulation, the microsomal pool of transporters (GLUT-4) is not completely translocated to the SL membrane. In fact, studies by Hirshman et al. (23) and by Goodyear et al. (25) with both cytochalasin-B binding and GLUT-4 antibodies have shown that less than 50% of the microsomal pool is translocated after insulin stimulation. This may be due to different intracellular pools of GLUT-4 transporters, with only one responding to insulin. These results also suggest that activation of the insulin receptor/the second messenger system are rate limiting for insulin action as opposed to the intracellular pool of GLUT-4 transporters. Insulin receptors isolated from skeletal muscle during euglycemic clamps at low and high doses of insulin dearly show activation of the tyrosine kinase, which is thought to activate a second messenger system (30).

3Abbreviations: diabetes mellitus;

SL, sarcolemmal; N1DDM, IDDM, insulin-dependent

non-insulin-dependent diabetes mellitus.

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However, insulin receptor antibodies have been reported to increase glucose transport in IM-9 lymphocytes without stimulating insulin receptor autophosphorylation and kinase activity (31). It is not known if the same effect can be demonstrated in skeletal muscle. The second messenger responsible for transmitting the signal from the insulin receptor to the intracellular pool of transporters is unknown at this time (32). In summary, insulin increases glucose transport in skeletal muscle by more than threefold. GLUT-4 transporters are translocated from an intracellular pool to the SL membrane. Activation of transporters normally present in SL may also be involved but this has not been well documented. Insulin binding to its receptor results in autophosphorylation of tyrosine residues and increased tyrosine kinase activity, which is thought to be involved in the activation of a second messenger system. However, the exact mechanisms responsible for translocation/activation of transporters are not understood at this time.

EFFECTS Acute

OF

EXERCISE

exercise

Electrical stimulation of muscle or a single bout of exercise via treadmill running or swimming has been shown to increase glucose uptake in numerous studies, as reviewed by Ivy (33). The effect of exercise consists of two phases (34). The initial effect lasts for a few hours and does not require the presence of insulin. The duration of this phase seems to be correlated with glycogen resynthesis and can be prolonged by dietary manipulation to delay glycogen resynthesis (34, 35). After the initial acute increase in glucose transport, there is a secondary phase in which insulin sensitivity is enhanced for several additional hours. Annuzzi et al. (36) observed the effect 24 h after exercise and showed that the effect was specific for the muscle involved in exercise. The exact mechanisms involved in the enhanced glucose uptake with acute exercise are still not completely understood. Using an isolated SL vesicle preparation, Sternlicht et al. (37) reported an increase in transport Vmax with no change in Km after observing a treadmill run of 45 mm. They found no increase in cytochalasin-B binding in the SL vesicles and concluded that the increase in Vm was due solely to activation of glucose transporters. Several papers, however, have reported an increase in cytochalasin-B binding in SL vesicles with acute exercise (38-41). King et al. (11) measured transport and cytochalasin-B binding and found that the increase in transport was far greater than the increase in cytochalasin-B binding; they concluded that acute exercise increases glucose transport by both translocation and activation of glucose transporters. Douen et al. (39) reported no decrease in the microsomal pool of transporter with exercise whereas Fushiki et al. (40) and Rodnick et al. (15) did report a decrease. The exact reason for the confusion regarding translocation of transporters with acute exercise is not apparent but may reflect problems with the subcellular fractionization techniques. The increase in skeletal muscle glucose transport with acute exercise is similar to the increase seen with maximum insulin stimulation (37, 39). The increases, however, appear to involve different pathways. Although insulin is thought to act via the insulin receptor tyrosine kinase, as discussed earlier, Treadway et al. (42) found no increase in receptor kinase activity after acute exercise. In addition, serum insulin is decreased with exercise (37). Some evidence suggests that calcium may be involved in activating the glucose transport system in muscle with acute exercise. Youn et al. (43)

recently reported that calcium release from the sarcoplasmic reticulum induced by caffeine or N-(6-aminohexyl)-5-chlor1-napthalensulfonamide (W-7) at concentrations below that required to induce muscle contraction increased glucose uptake by isolated epitrochlearis muscle. At higher doses of caffeine or W-7, muscle contraction was induced and glucose uptake was further increased. The response could be blocked by dantrolene or 9-aminoacridine, both inhibitors of sarcoplasmic reticulum calcium release. Further evidence for the involvement of different pathways for insulin and exercise activation of glucose transport comes from studies using hindlimb perfusion or the isolated epitrochlearis muscle. The effects of insulin and exercise have been shown to be additive,especially in the second phase after the initial insulin-independent response (34). Using the epitrochlearis preparation, Constable et al. (44) were able to show an additive effect when the muscles were contracted electrically with insulin present in the bathing solution or when insulin was added after an acute bout of swimming. Sternlicht et al. (37), however, were unable to show an additive effect in rats when insulin was given immediately after a treadmill run and the SL vesicles were isolated 10 mm later. The lack of a response in vivo was attributed to an inhibitory effect of CAMP on the insulin receptor tyrosine kinase. Even though cAMP is well known to accumulate in muscle with exercise, it would be rapidly washed out in the hindlimb or isolated muscle preparation. If insulin is given before the contraction, then an additive effect would be expected. Further evidence for different signaling pathways! transporter pools was recently provided by Horton et al. (45) from studies of the obese, insulin-resistant Zucker rat. They found that with insulin stimulation they could get no increase in glucose transport or translocation of transporters to the SL but that with acute exercise, translocation and transport were both increased. Additional studies by Klip and Marette (ii) using GLUT-4 specific antibodies have also suggested two separate intracellular pools of GLUT-4 transporters, one responsive to insulin and one to exercise.

Exercise

training

Numerous studies with exercise training have demonstrated an increase in whole-body insulin sensitivity. This adaptation has been documented in humans and animals as well as in insulin-resistant states, i.e., the obese Zucker rat, mild streptozotocindiabetes,and diet-induced insulin resistance. Animals with severe streptozotocin-induced diabetes do not appear to show adaptation to training. Some have suggested that the increase in insulin sensitivity with training is due to the effects of the final bout of exercise, i.e., an acute effect. However, training effects have been reported for several days after the final bout of exercise, whereas the acute effect generally lasts for little more than 24 h. Using an isolated SL vesicle preparation, Grimditch et al. (46) found that basal glucose transport was unchanged but that serum insulin levels were reduced by almost 50%. The increase in insulin sensitivity did not result from changes in insulin binding. Neither the number of insulin receptors in the SL preparation nor the binding affinity was changed with training. More recently, Ploug et al. (8) reported that 10 wk of swim training increased maximum insulin-stimulated glucose uptake in fast-twitch red fibers by approximately 33%. Goodyear et al. (25) found a similar increase in the for glucose transport, which resulted from an increase in activation and the amount of GLUT-4 translocated to the SL. GLUT-iand GLUT-4-specific mRNA and protein were in-

4fl V.I c. 1QQ Thc. FASFR In,irn,t RARNARD AND YOUNCREN www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on November 13, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber

creased in the trained muscles and were thought to be responsible for the increase in maximum insulin-stimulated glucose uptake. Rodnick et al. (47) reported an increase in the GLUT-4 concentration of plantaris, a mixed muscle, and no change in the slow-twitch oxidative soleus muscle after 6 wk of voluntary treadmill running. Wake et a!. (48) also found an increase in the GLUT-4 mRNA in plantaris and both the red and white portions of the quadriceps. These results in rats indicate that training does result in adaptations not seen with a single bout of exercise. Recent studies in humans by Houmard et al. (49) have confirmed that with acute exercise GLUT-4 content of muscle is unchanged but is almost doubled after exercise training. However, the significance of the increase in GLUT-4 with training has not been established. In the untrained state, maximum insulin stimulation results in only a 50% depletion of the microsomal GLUT-4 pool. Thus, one must question whether the increase in GLUT-4 with training has any effect on the welldocumented increase in insulin sensitivity or whether some other rate-limiting step is changed. The GLUT-4 content of different muscles with different types of fiber has been reported to correlate with maximum glucose uptake achieved by electrical stimulation or insulin plus stimulation, but not with insulin alone (50). Two groups have studied the receptor tyrosine kinase activity after training. Santos et a!. (51) reported a decrease in insulin-stimulated kinase activity in one muscle and no change in the other when activity was expressed per unit of insulin binding. Dohm et al. (52) also reported a decrease in insulin-stimulated kinase activity with training. Physical

inactivity

Studies with bed rest, hindlimb casting, or denervation all indicate that physical inactivity increases insulin resistance. Fushiki et al. (53) found that 2 wk of inactivity created by placing rats in mild restraining cages decreased insulin sensitivity at high concentrations of insulin during euglycemic clamp tests. In addition, they found a significant reduction in cytochalasin-B binding in the plasma and microsomal membrane fractions isolated after maximum insulin stimulation. Henriksen et al. (54) found that after 3 days of denervation of the soleus muscle, insulin-stimulated glucose uptake was severely depressed, as was the concentration of GLUT-4. Hindlimb suspension had just the opposite effect. In summary, physical activity can have a significant effect on the glucose transport system. Acute exercise can increase glucose transport to the same level as a maximum dose of insulin. Although GLUT-4 is translocated to the SL, the mechanism responsible for the translocation is different from the insulin mechanism. This acute effect lasts for a few hours and is followed by a phase of increased insulin sensitivity that may last for up to a day; the mechanisms responsible are unknown. Regular exercise training also increases insulin sensitivity for several days after the final bout of exercise. There is no change in the number of insulin receptors, but the pool of GLUT-4 transporters is increased. Physical inactivity has been shown to produce insulin resistance and a decrease in GLUT-4.

DIET The quality and quantity of food consumed both have portant effect on insulin resistance. Diets high in refined sugar (sucrose or fructose) have been shown duce insulin resistance. The combination of fat and sugar seems to produce the worst effect (55). Grimditch

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(55, 56) compared a high-fat (40% kcal), sucrose (40% kcal) diet with a low-fat (6% kcal), starch (68% kcal) diet. After 10 wk there was no significant difference in body weight or fat between the two groups, but the i.v. glucose tolerance test demonstrated insulin resistance. Using their isolated SL vesicle preparation they found that basal glucose transport was unchanged; however, insulin levels were increased by 100% in the group on a high-fat diet. Maximum insulinstimulated glucose transport was significantly reduced in the high-fat group. The number of insulin receptors in the SL preparation was unaffected by the diet but the affinity of the high-affinity portion of the Scatchard curve was reduced in the high-fat group. Boyd et a!. (57) also found a similar adverse effect of the high-fat, sucrose diet on muscle glucose transport. They studied insulin receptor tyrosine kinase activity in vivo by injecting insulin IP and then isolating the receptors. No difference was found between the two diets. In addition to the effect of food quality on insulin resistance, the quantity of food consumed can also have an impact. Excess consumption of calories from even a low-fat, complex carbohydrate diet can lead to muscle insulin resistance. This is demonstrated clearly in the hyperphagic, obese (fa!fa) Zucker rat. In this model of insulin resistance, skeletal muscle insulin receptors as well as the receptor tyrosine kinase have been reported to be decreased, with no change in the GLUT-4 content of muscle (58, 59). Similar defects in the insulin receptor have been reported for obese humans (60, 61). Caloric restriction in the fatty Zucker rat normalizes serum insulin, indicating a major reduction in insulin resistance (62). Weight loss in morbidly obese humans has been shown to restore insulin responsiveness in skeletal muscle (63). In summary, diets high in simple sugars (fructose or sucrose), especially when combined with high levels of fat, can cause insulin resistance. The mechanisms responsible, however, are not known. In view of the importance of diet in the treatment of diabetes and other forms of insulin resistance, more work obviously is needed in this area.

DIABETES Insulin-dependent

diabetes

mellitus

Numerous studies with rats in which insulin deficiency was induced by streptozotocin have demonstrated severe insulin resistance in skeletal muscle. Glucose transport in isolated SL vesicles was reduced under basal and insulin-stimulated conditions (64). The reduction in glucose transport was due to fewer glucose transporters in the SL membrane under both conditions. Daily insulin injections corrected the transport under basal conditions but did not completely normalize the insulin-stimulated glucose transport. The response during insulin deficiency has been attributed to a decrease in GLUT-4 mRNA and protein (65, 66). However, Richardson et al. (67) and Kahn et a!. (7) both reported that decreased glucose transport preceded the reduction in GLUT-4 transporters, which indicates that some other important mechanisms are involved. The number of insulin receptors has been reported to increase during insulin deficiency, whereas the receptor tyrosine kinase activity per unit of insulin binding is severely depressed (68). Insulin injections twice a day in the diabetic rats normalized the number of receptors as well as the tyrosine kinase activity (69). Unfortunately, little information is available on patients with insulin-dependent diabetes mellitus (IDDM). Bak et a!. (69) obtained muscle biopsies from seven patients with IDDM and found that

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S. W., and Wardzala, L. J. (1980) Potential mechanism of action on glucose transport in the isolated rat adipose cell. j Biol. Chem. 255, 4758-4762 2. Suzuki, K., and Kono, T. (1980) Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. Proc. NatI. Acad. Sd. USA 77, 2542-2545 3. Klip, A., and Douen, A. G. (1989) Role of kinases in insulin stimulation of glucose transport. j Membr. Biol. 111, 1-23 4. Rosen, 0. M. (1989) Structure and function of insulin receptors. Diabetes 38, 1508-1511 5. James, D. E., Brown, R., Navarro, J., and Pilch, P. F. (1988) Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein. Nature (London) 333, 183-185 6. Bell, G. I., Kayano, T., Buse, J. B., Burant, C. F., Takeda, J, Lin, D., Fukumoto, S., and Seino, S. (1990) Molecular biology of mammalian glucose transporters. Diabetes Care 13, 198-208 7. Kahn, B. B., Rossetti, L., Lodish, H. F., and Charron, M. J. (1991) Decreased in vivo glucose uptake but normal expression of GLUT-i and GLUT-4 in skeletal muscle of diabetic rats. j Gun. Invest. 87, 2197-2206 8. Ploug, T, Stallknecht, B. M., Pedersen, 0., Kahn, B. B., Ohkuwa, T, Vinten, J., and Galbo, H. (1990) Effect of endurance training on glucose transport capacity and glucose transporter expression in rat skeletal muscle. Am. j Physiol. 259, E778-E786 9. Rodnick, K. J., Henriksen, E. J., James, D. E., and Holloszy, J. 0. (1992) Exercise training, glucose transporters and glucose transport in rat skeletal muscles. Am. j PhysioL 262, C9-C14 10. Kern, M., Wells, J. A., Stephens, J. M., Elton, C. W, Friedman, J. E., Tapscott, E. B., Pekala, P. H., and Dohm, G. L. (1990) Insulin responsiveness in skeletal muscle is determined by glucose transporter (Glut-4) protein level. Biochem. J. 270, 397-400 ii. Klip, A., and Marette, A. (1992) Acute and chronic signals controlling glucose transport in skeletal muscle. j Cell. Biochem. 48, 1. Cushman,

Non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes and has received the most attention. Skeletal muscle insulin resistance has been well documented in NIDDM but it is only one factor in the disease (16). Using an isolated SL vesicle preparation, Scheck et a!. (70) found no difference in basal glucose transport in lean patients and lean controls. The NIDDM patients, however, had serum insulin levels three times as high as the controls. Dohm et al. (60) had previously reported similar results with isolated muscle strips. They found no difference in basal transport between nonobese controls, obese individuals, and obese NIDDM patients. Insulin-stimulated glucose uptake in the controls increased by almost threefold, but only a small effect was seen in the obese and no response was detected in the NIDDM patients. Several groups, as reviewed by Haring and ObermaierKusser (71), have reported a reduction in insulin receptor tyrosine kinase activity in NIDDM patients similar to the reductions seen in obese individuals. A recent study by McGuire et a!. (72) has suggested that a lack of insulin suppression of protein tyrosine phosphatase activity may play a key role in the reduced tyrosine kinase activity reported for insulin-resistant muscle. The number of insulin receptors has been reported to be decreased in NIDDM (70). However, the microsomal pool of transportersor muscle GLUT-4 protein content has been reported to be unchanged (70, 73, 74) or only slightly decreased (75). The defects responsible for the insulin resistance apparently are reversible, as diet and exercise have been shown to control NIDDM (76). Freidenberg et a!. (77) have reported reversibility of the kinase defect in fat cells from NIDDM patients after weight loss, and Friedman et a!. (63) reported restoration of insulin responsiveness in skeletal muscle after weight loss. In summary, skeletal muscle insulin resistance is one of the main characteristics of diabetes mellitus. In IDDM basal and insulin-stimulated glucose transport are both reduced, as demonstrated in the streptozotocin-induced diabetic model. A reduction in both tyrosine kinase activity and the intracellular pool of GLUT-4 transporters has been reported. However, other mechanisms may also be involved in the insulin resistance seen in the streptozotocin model. The number of insulin-receptors is increased in the strep model, but in the insulin-treated patient with IDDM the number of receptors is reduced. The number of receptors is also reduced in the patient with NIDDM. Tyrosine kinase activity is reduced, possibly due to increased tyrosine phosphatase activity. The intracellular pool of GLUT-4 transporters is unchanged or only slightly reduced in NIDDM. Although much progress has been made in understanding the regulation of glucose transport in skeletal muscle, there are still many important unanswered questions. In view of the fact that insulin resistance is an important health factor in our society, the importance of understanding glucose transport in skeletal muscle should not be underestimated. Supported 7592.

REFERENCES

AGO

TI,.

ccco

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18.

A. G., Rastogi, S., Cartee, G. D., Holloszy, J. 0., Ramlal, T, Bilan, P. J., Vranic, M., and Klip, A. (1990) Exercise induces recruitment of the “insulin-responsive glucose transporter”j Biol. Chem. 265, 13427-13430 Goodyear, L. J., Hirshxnan, M. F., Smith, R. J., and Horton, E. 5. (1991) Glucose transporter number, activity, and isoform content in plasma membranes of red and white skeletal muscle. Am. J. P/ysiol. 261, E556-E561 Klip A., and P#{226}quet,M. R. (1990) Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care 13, 228-243 Rodnick, K. J., Slot, J. W., Studelska, D. R., Hanpeter, D. E., Robinson, L. J, Geuze, H. J., and James, D. E. (1992) Immunocytochemical and biochemical studies of GLUT 4 in rat skeletal muscle. j Biol. Chem. 267, 6278-6285 DeFronzo, R. A., (1987) The triumvirate: 3-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 57, 667-687 Richter, E. A., Garetto, L. P., Goodman, M. N., and Ruderman, N. B. (1984) Enhanced muscle glucose metabolism after exercise: modulation by local factors. Am. j Physiol. 246, E476-E484 Azhar, S., Butte, J. C., Santos, R. F., Mondon, C. E., and

Reaven, G. M. (1991) Characterization of insulin receptor kinase activity and autophosphorylation in different skeletal muscle types. Am. j Physiol. 260, El-El 19. Klip, A. (1987) Hexase transport across skeletal muscle sarcolemma. In Sarcolemmal Biochemistry, Vol. 2 (Kidwai, A. M., ed)

pp. 129-153, CRC, Boca Raton, Florida 20. Friedman, J. E., Dudek, R. W., Whitehead, D. S., Downes, D. L., Frisell, W. R., Caro, J. F., and Dohm, G. L. (1991) Immunoloca!ization of glucose transporter GLUT 4 within human skeletal muscle. Diabetes 40, 150-154

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