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In Vivo Insulin Regulation of Skeletal Muscle Glycogen Synthase in Calorie-Restricted and in Ad Libitum–Fed Rhesus Monkeys¹

Obesity and Diabetes Research Center, Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201

²To whom correspondence should be addressed. E-mail: hortmeye{at}umaryland.edu

	ABSTRACT

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Chronic calorie restriction in primates has been shown to have profound and unexpected effects on basal and on in vivo insulin action on skeletal muscle glycogen synthase (GS) activity. The decreased ability of insulin to activate skeletal muscle GS is a hallmark of insulin resistance and type 2 diabetes. The mechanism and role of in vivo insulin regulation of skeletal muscle GS are not fully understood. Two pathways for the activation of GS by insulin have been described by Larner and others: 1) insulin activates glucose transport that results in an increase in glucose-6-phosphate (G6P), thereby activating protein phosphatase-1, which in turn dephosphorylates and activates GS, therefore, pushing substrate into glycogen; and 2) insulin activates GS (perhaps by forming low-molecular-weight mediators which may activate protein phosphatase-1 and 2C) and activated GS subsequently pulls intermediates (e.g., G6P and uridine 5'-diphosphoglucose) into glycogen. To determine whether in vivo insulin regulates glycogen synthesis primarily via a push or pull mechanism and how this mechanism might be affected by long-term calorie restriction, skeletal muscle samples were obtained before and during a euglycemic hyperinsulinemic clamp from 41 rhesus monkeys. The monkeys varied widely in their degree of insulin sensitivity and age and included chronically calorie-restricted (CR) monkeys and ad libitum–fed monkeys. The ad libitum–fed monkeys included spontaneously type 2 diabetic, prediabetic and clinically normal animals. The apparent affinity of GS for the allosteric activator G6P (G6P Ka of GS) was measured and compared with G6P content in the muscle samples. Basal G6P Ka of GS was lower in the CR monkeys compared with the 3 ad libitum–fed groups (P 0.05). Only the normal ad libitum–fed monkeys had a decrease in the G6P Ka of GS with insulin (P < 0.005). The insulin effect (insulin-stimulated minus basal) on the G6P Ka of GS was strongly positively related to the insulin effect on G6P content (r = 0.80, P < 0.0001) across the entire group of monkeys. This finding supports the hypothesis that activation/dephosphorylation of GS by insulin is related to a decrease in G6P content and that paradoxical inactivation/phosphorylation of GS by insulin is related to an increase in G6P content (as demonstrated in 4 of 6 CR monkeys). Therefore, during a euglycemic hyperinsulinemic clamp, insulin regulates skeletal muscle glycogen synthesis primarily via a pull mechanism in both CR and in ad libitum–fed rhesus monkeys.

KEY WORDS: • calorie restriction • insulin • skeletal muscle • glycogen synthase activity

	INTRODUCTION

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Reduced activation of skeletal muscle glycogen synthase (GS)³ and reduced glucose disposal during a euglycemic hyperinsulinemic clamp are hallmarks of type 2 diabetes. Calorie restriction has been shown to decrease fasting plasma glucose and insulin concentrations (8 ,13 ,15) and to improve whole-body insulin-mediated glucose disposal rates in rhesus monkeys (2) . However, improvement in insulin sensitivity by calorie restriction is probably not due to an improvement in insulin activation of skeletal muscle GS (25) or to alterations in basal GLUT4 glucose transporter protein expression (7) .

Evidence that altered insulin activation of GS is not a consequence of hyperglycemia but is involved in insulin resistance preceding the onset of type 2 diabetes includes findings from several studies. In rhesus monkeys, ß-cell hyperresponsiveness to a glucose stimulus, which precedes the onset of type 2 diabetes, was accompanied by reduced insulin activation of skeletal muscle GS during a euglycemic hyperinsulinemic clamp (27) . Insulin-resistant (nondiabetic) humans (5 ,14) and rhesus monkeys (27) have been shown to have lower GS activity (independent and/or fractional activity) during a euglycemic hyperinsulinemic clamp compared with insulin-sensitive subjects. First-degree relatives of patients with type 2 diabetes had significantly lower insulin-stimulated GS-independent activity compared with nondiabetic control subjects (32) . Further, cultured skeletal muscle cells of type 2 diabetic humans had significantly lower basal and insulin-stimulated GS fractional activity compared with nondiabetic control cells (9) . Results from the later two studies suggest that altered regulation of GS by insulin may be genetic in origin. In addition, metformin and diet together did not overcome defective insulin activation of skeletal muscle GS activity in obese type 2 patients (4) .

In humans and in monkeys with varying degrees of insulin sensitivity, in vivo insulin action on skeletal muscle GS was related to whole-body glucose disposal rates (3 ,11 ,27) . It is not clear whether the decline in glucose disposal during a euglycemic hyperinsulinemic clamp in insulin-resistant subjects is due primarily to reduced insulin-stimulated glucose transport/phosphorylation or rather primarily due to decreased insulin-induced activation of GS. This issue is related to the question of whether insulin-mediated glycogen synthesis is controlled mainly by a push or by a pull mechanism (16) . The push hypothesis of glycogen synthesis focuses on the importance of glucose-6-phosphate (G6P) for the activation of GS (18) . The pull hypothesis recognizes the ability of insulin to activate GS in the absence of glucose (17) .

In a previous study, we demonstrated that skeletal muscle G6P content during the maximal insulin stimulation of a euglycemic hyperinsulinemic clamp was significantly higher in prediabetic and in diabetic monkeys compared with normal monkeys (29) . This suggests that insulin-stimulated glucose transport occurred at a greater rate than glycolysis and/or glycogenesis in the insulin-resistant monkeys. In addition, insulin-stimulated skeletal muscle G6P content was inversely related to both whole-body insulin-mediated glucose disposal rate and to insulin-stimulated GS-independent activity (29) . These findings suggest that a reduction in insulin activation of skeletal muscle GS contributes to the insulin resistance of rhesus monkeys to a greater extent than does an alteration of glucose transport/phosphorylation, at least under euglycemic hyperinsulinemic conditions.

Surprisingly, we have observed a decrease in the apparent affinity of skeletal muscle GS for G6P (a paradoxical increase in phosphorylation as shown by an increase in the G6P Ka of GS) during a euglycemic hyperinsulinemic clamp in 4 of 6 chronically calorie-restricted (CR) monkeys (30) and in 7 of 10 very lean (VL) young adult monkeys (28) . The CR monkeys and the VL monkeys had similar fasting plasma insulin concentrations and whole-body insulin-mediated glucose disposal rates compared with normal ad libitum–fed monkeys and are, therefore, not characterized as insulin-resistant. Compared with the normal monkeys, the CR and VL monkeys had fourfold higher basal skeletal muscle GS fractional activity and 70% lower basal G6P Ka of GS (28) . In addition, the CR and VL monkeys had an average increase in skeletal muscle G6P content during the euglycemic hyperinsulinemic clamp, which was significantly different from the average decrease in G6P in the normal monkeys. Similarly, the CR and VL monkeys had an average increase in the G6P Ka of GS during the euglycemic hyperinsulinemic clamp that was significantly different from the average decrease in the G6P Ka of GS in the normal monkeys. We have hypothesized that the CR and VL monkeys with the paradoxical phosphorylation of GS during the euglycemic hyperinsulinemic clamp may be those monkeys that are predisposed to the development of obesity and type 2 diabetes (28) .

To better understand in vivo insulin regulation of skeletal muscle GS in insulin-resistant monkeys as well as in insulin-sensitive monkeys, the G6P Ka of GS was determined in 8 prediabetic and in 8 diabetic monkeys and compared with the previously published G6P Ka of GS in three other groups of monkeys, the CR, the VL and the normal ad libitum–fed monkeys.

	METHODS

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The G6P Ka of GS (G6P Ka of GS) and the maximal activity of GS (Vmax) were measured in basal and insulin-stimulated (euglycemic hyperinsulinemic clamp) skeletal muscle biopsies as previously described (30) . The G6P Ka of GS and Vmax in the eight hyperinsulinemic and in the eight diabetic monkeys is presented here for the first time. The G6P Ka of GS in the 10 VL monkeys (28) , nine normal ad libitum-fed monkeys (28) and in the six CR monkeys (30) have been previously published. The G6P content in the skeletal muscle biopsies of all groups has been previously published (25 ,28 ,29) .

Basal versus insulin-stimulated means were tested by Student’s t test for paired samples. Group differences were compared by one-way analysis of variance and subsequently by the least significant difference multiple comparison method. Pearson’s correlation coefficient was used to test for significant linear relationships between variables.

	RESULTS

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The basal and insulin-stimulated G6P Ka of GS and Vmax in the five groups of monkeys are shown in Figure 1 . Only the normal ad libitum–fed monkeys had a significant decrease in the G6P Ka of GS with in vivo insulin (P = 0.004). The VL monkeys and the CR monkeys had significantly lower basal G6P Ka of GS compared with the other three ad libitum–fed groups (VL vs. normal, P = 0.004; VL vs. hyperinsulinemic, P = 0.007; VL vs. diabetic, P = 0.02; CR vs. normal, P = 0.01; CR vs. hyperinsulinemic, P = 0.02; CR vs. diabetic, P = 0.05). The hyperinsulinemic monkeys had significantly higher G6P Ka of GS under insulin-stimulated conditions compared with the VL (P = 0.02), normal ad libitum–fed (P = 0.05) and CR monkeys (P = 0.04). Neither the basal nor the insulin-stimulated Vmax of GS was significantly different among the five groups (Fig. 1) .

View larger version (33K): [in this window] [in a new window]   Figure 1. Upper panel: the affinity of GS for the allosteric activator G6P under basal (open bars) and insulin-stimulated (hatched bars) conditions in VL [n = 10 (28) ], normal ad libitum–fed [n = 9 (28) ], hyperinsulinemic (n = 8), type 2 diabetic (n = 8) and CR [n = 6 (30) ] rhesus monkeys. Lower panel: maximal activity of GS under the same conditions and in the same monkeys as above. a = significantly different from insulin-stimulated (P = 0.004); b = significantly different from normal, hyperinsulinemic and diabetic monkeys (P 0.05); c = significantly different from VL, normal and CR monkeys (P 0.05)

View larger version (18K): [in this window] [in a new window]   Figure 2. The relationship between the change (insulin-stimulated minus basal) in the G6P Ka of GS and the change in the G6P content in the muscle.

The +Ka/+G6P monkeys had lower basal G6P Ka of GS compared with the -Ka/-G6P monkeys (P < 0.001) and compared with the -Ka/+G6P monkeys [P < 0.05 (Fig. 3 )]. The -Ka/-G6P monkeys had higher basal muscle G6P content compared with the +Ka/+G6P monkeys (P < 0.0001) and compared with the -Ka/+G6P monkeys [P < 0.01 (Fig. 3) ]. The +Ka/+G6P monkeys had significantly higher basal GS-independent, total and fractional activities compared with the other 2 groups (Fig. 4 ). The +Ka/+G6P monkeys had higher insulin-stimulated G6P Ka of GS (P = 0.06) and higher insulin-stimulated muscle G6P content (P < 0.005) compared with the -Ka/-G6P monkeys (Fig. 5 ). The -Ka/+G6P monkeys had higher body fat content (P < 0.05) and higher fasting plasma glucose values (P < 0.05) compared with the +Ka/+G6P monkeys (Fig. 6 ).

View larger version (31K): [in this window] [in a new window]   Figure 3. Upper panel: the apparent affinity of GS for G6P under basal conditions in three groups of monkeys: -Ka/-G6P, the 14 monkeys with a decrease in the G6P Ka and a decrease in G6P content during insulin stimulation; +Ka/+G6P, the 15 monkeys with an increase in the G6P Ka and an increase in G6P content during insulin stimulation; -Ka/+G6P, the 12 monkeys with a decrease in the G6P Ka and an increase in G6P content during insulin stimulation. Lower panel: the G6P content under basal conditions in the same three groups as above.

View larger version (31K): [in this window] [in a new window]   Figure 4. GS independent activity (upper panel), total activity (middle panel) and fractional activity (lower panel) under basal conditions in the three groups of monkeys as in Figure 3 .

View larger version (35K): [in this window] [in a new window]   Figure 5. Upper panel: the apparent affinity of GS for G6P under insulin-stimulated conditions in the three groups of monkeys as in Figure 3 . Lower panel: the G6P content under insulin-stimulated conditions in the same 3 groups as above.

View larger version (30K): [in this window] [in a new window]   Figure 6. Upper panel: body fat in the three groups of monkeys as in Figure 3 . Lower panel: fasting plasma glucose in the same three groups as above.

	DISCUSSION

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The proposed roles for insulin regulation of GS include limiting glycogenolysis (31) , controlling the concentration of G6P (34) and actively directing intracellular glucose into glycogen (19) . Metabolic control analysis has been implemented to better understand the contribution of GS activation on controlling the rate of glycogen synthesis (12 ,33 ,34) . Taking into consideration recent work from many laboratories, the consensus is that the control of skeletal muscle glycogen synthesis is shared between GS and glucose transport (12) and that the relative contribution will depend upon the physiological state (33) and on the fiber types of the muscle studied (1) . Therefore, it is likely that defects in insulin signaling, resulting in either or both reduced glucose transport/phosphorylation and GS activation, will contribute to the development of insulin resistance and type 2 diabetes.

One mechanism of insulin activation of skeletal muscle GS is secondary to an increase in G6P (36) . Although G6P has been shown to increase the activity of skeletal muscle protein phosphatase-1 in rats (35) and in humans (20) , an increase in GS fractional activity during a euglycemic hyperinsulinemic clamp was not associated with an increase in G6P content or in an increase in protein phosphatase activity in healthy Southwestern American Indians (20) . We have demonstrated an increase in skeletal muscle GS fractional and independent activity (27) , an increase in skeletal muscle protein phosphatase-1 activity (23) and a decrease in protein kinase A activity (21) during a euglycemic hyperinsulinemic clamp in normal rhesus monkeys. However, these monkeys did not show an increase in skeletal muscle G6P content during the clamp (29) , which would suggest that in vivo insulin is regulating the activity of GS via a mechanism independent of G6P (at least after 100 min of insulin infusion). Furthermore, in the present study, only the normal ad libitum–fed monkeys had a significant decrease in the G6P Ka of GS during the euglycemic hyperinsulinemic clamp. Therefore, it is likely that the activation (dephosphorylation) of skeletal muscle GS is related to an increase in protein phosphatase-1 activity and a decrease in protein kinase A activity during in vivo insulin stimulation.

Insulin may activate GS by increasing the generation/release of low-molecular-weight compounds. Two inositol phosphoglycans were recently shown to dephosphorylate both inhibitor-1 and DARPP-32 by activating protein phosphatase-2C and protein phosphatase-1 (10) , which could potentially lead to the activation of GS. In liver of obese rhesus monkeys, protein phosphatase-2C activity was strongly positively correlated to protein-phosphatase-1 activity and to GS fractional activity and inversely related to G6P content (24) . In addition, in vivo insulin during a euglycemic hyperinsulinemic clamp was shown to increase the activity of liver protein phosphatase-2C and protein phosphatase-1 (22) in the same monkeys in which insulin increased the activity of liver GS and decreased the G6P content (26) . Furthermore, the effect of insulin to decrease liver G6P content was strongly related to the effect of insulin to increase insulin mediator bioactivity (22) . All of this suggests that insulin can activate GS independent of an increase in G6P and that insulin mediators may contribute to the regulation of GS by insulin.

The most compelling evidence that activation (dephosphorylation) of skeletal muscle GS is related to a decrease in G6P is the strong relationship between the change in G6P content and the change in G6P Ka of GS (increase in apparent affinity of GS for G6P) during the euglycemic hyperinsulinemic clamp in monkeys with various degrees of insulin sensitivity and with varying nutritional status, including normal, hyperinsulinemic and diabetic ad libitum–fed monkeys and in CR monkeys. An identical relationship was demonstrated between these two variables in the noninsulin-resistant monkeys (normal ad libitum–fed, VL and CR monkeys) (23) . Therefore, although in vivo insulin affects the phosphorylation state differently in the various groups of monkeys (26 monkeys had a decrease and 15 had an increase in the G6P Ka of GS), the degree to which the enzyme is activated/inactivated (dephosphorylated/phosphorylated) is related to the change in G6P content in both insulin-sensitive and insulin-resistant monkeys. Importantly, 11 of the 15 monkeys showing the paradoxical increase in phosphorylation of GS with insulin stimulation were being maintained in a calorie-limited environment and had relatively low body fat contents. In a previous study, chronically CR monkeys were shown to be under a condition of heightened energy efficiency due to their nutritionally restrained condition (6) .

The monkeys that had an increase in the G6P Ka of GS during the euglycemic hyperinsulinemic clamp were characterized by low basal G6P Ka of GS (high affinity of GS for G6P) and high basal GS activity (independent, total and fractional). They also had the lowest percent body fat and the lowest fasting plasma glucose concentrations. As previously suggested, these monkeys may have a GS molecule that is very sensitive to G6P, which results in a highly dephosphorylated (active) enzyme under basal conditions in order to maintain skeletal muscle glycogen content at a normal value, thus preventing the expression of diabetes (28) . This group included 7 of 10 VL monkeys and 4 of 6 chronically CR monkeys.

In summary, during a euglycemic hyperinsulinemic clamp, dephosphorylation (activation) of skeletal muscle GS is related to a decrease in skeletal muscle G6P content, whereas phosphorylation (inactivation) of GS is related to an increase in G6P content. This result provides strong evidence supporting the hypothesis that in vivo insulin regulates glycogen synthesis primarily via a pull mechanism. In addition, nutritional intervention in the form of calorie restriction results in profound and unexpected effects on both basal GS activity and on insulin regulation of GS activity in skeletal muscle. The high apparent affinity of GS for G6P in the CR monkeys may be related to the anti-diabetic effects of calorie restriction, whereas the paradoxical phosphorylation of GS by insulin in some CR monkeys may be related to a genetic alteration making these animals more susceptible to develop diabetes. These hypotheses warrant further study.

	ACKNOWLEDGMENTS

 
These studies were carried out in collaboration with Barbara C. Hansen and Noni L. Bodkin. I appreciate the excellent technical support of Teerin Meckmongkol for previously unpublished data.

	FOOTNOTES

 
¹ Presented at the symposium "Calorie Restriction: Effects on Body Composition, Insulin Signaling and Aging" as part of the Experimental Biology 2000 meeting held April 15–18, 2000 in San Diego, California. This symposium was sponsored by the American Society for Nutritional Sciences and the American Society for Clinical. The proceedings of this symposium are published as a supplement to The Journal of Nutrition. Guest Editor for this supplement publication was Barbara Hansen, Obesity and Diabetes Research Center, School of Medicine, University of Maryland, Baltimore, Maryland.

³ Abbreviations used: GS, glycogen synthase; G6P, glucose-6-phosphate; CR, calorie-restricted; VL, very lean.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 

1. Azpiazu I., Manchester J., Skurat A. V., Roach P. J., Lawrence J. C. Control of glycogen synthesis is shared between glucose transport and glycogen synthase in skeletal muscle fibers. Am. J. Physiol. Endocinol. Metab. 2000;278:E234-E243[Abstract/Free Full Text]

2. Bodkin N. L., Ortmeyer H. K., Hansen B. C. Long-term dietary restriction in older-aged rhesus monkeys: effects on insulin resistance. J. Gerontol. Biol. Sci. 1995;50A:B142-B147[Abstract]

3. Bogardus C., Lillioja S., Stone K., Mott D. Correlation between muscle glycogen synthase activity and in vivo insulin action in man. J. Clin. Invest. 1984;73:1185-1190

4. Damsbo P., Hermann L. S., Vaag A., Hother-Nielsen O., Beck-Nielsen H. Irreversibility of the defect in glycogen synthase activity in skeletal muscle from obese patients with NIDDM treated with diet and metformin. Diabetes Care 1998;21:1489-1494[Abstract]

5. Damsbo P., Vaag A., Hother-Nielsen O., Beck-Nielsen H. Reduced glycogen synthase activity in skeletal muscle from obese patients with and without type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1991;34:239-245[Medline]

6. Delany J. P., Hansen B. C., Bodkin N. L., Hannah J., Bray G. A. Long-term calorie restriction reduces energy expenditure in aging monkeys. J. Gerontol. Biol. Sci. 1999;54A:B5-B11[Abstract]

7. Gazdag A. C., Sullivan S., Kemnitz J. W., Cartee G. D. Effect of long-term caloric restriction on GLUT4, phosphatidylinositol- 3 kinase p85 subunit, and insulin receptor substrate-1 protein levels in rhesus monkey skeletal muscle. J. Gerontol. Biol. Sci. 2000;55:B44-B46[Abstract]

8. Hansen B. C., Bodkin N. L. Primary prevention of diabetes mellitus by prevention of obesity in monkeys. Diabetes 1993;42:1809-1814[Abstract]

9. Henry R. R., Ciaraldi T. P., Abrams-Carter L., Mudaliar S., Park K. S., Nikoulina S. E. Glycogen synthase activity is reduced in cultured skeletal muscle cells of non-insulin-dependent diabetes mellitus subjects. J. Clin. Invest. 1996;98:1231-1236[Medline]

10. Huang L. C., Heimark D., Linko J., Nolan R., Larner J. A model phosphatase 2C phosphatase 1 activation cascade via dual control of inhibitor-1 (INH-1) and DARPP-32 dephosphorylation by two inositol glycan putative insulin mediatores from beef liver. Biochem. Biophys. Res. Commun. 1999;255:150-156[Medline]

11. Johnson A. B., Argyraki M., Thow J. C., Jones I. R., Broughton D., Miller M., Taylor R. Impaired activation of skeletal muscle glycogen synthase in non-insulin-dependent diabetes mellitus is unrelated to the degree of obesity. Metabolism 1991;40:252-260[Medline]

12. Jucker B. M., Barucci N., Shulman G. I. Metabolic control analysis of insulin-stimulated glucose disposal in rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 1999;277:E505-E512[Abstract/Free Full Text]

13. Kemnitz J. W., Roecker E. B., Weindruch R., Elson D. F., Baum S. T., Bergman R. N. Dietary restriction increases insulin sensitivity and lowers blood glucose in rhesus monkeys. Am. J. Physiol. 1994;266:E540-E547[Abstract/Free Full Text]

14. Kida Y., Raz I., Maeda R., Nyomba B. L., Stone K., Bogardus C., Summercorn J., Mott D. M. Defective insulin response of phosphorylase phosphatase in insulin-resistant humans. J. Clin. Invest. 1992;89:610-617

15. Lane M. A., Ball S. S., Ingram D. K., Cutler R. G., Engel J., Read V., Roth G. S. Diet restriction in rhesus monkeys lowers fasting and glucose-stimulated glucoregulatory end points. Am. J. Physiol. 1995;268:E941-E948[Abstract/Free Full Text]

16. Lawrence J., Roach P. New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes 1997;46:541-547[Abstract]

17. Lawrence J. C., Guinovart J. J., Larner J. Activation of rat adipocyte glycogen synthase by insulin. J. Biol. Chem. 1977;252:444-450[Abstract/Free Full Text]

18. Lawrence J. C., Larner J. Activation of glycogen synthase in rat adipocytes by insulin and glucose involves increased glucose transport and phosphorylation. J. Biol. Chem. 1978;253:2104-2113[Free Full Text]

19. Manchester J., Skurat A., Roach P., Hauschka S., Lawrence J. C. Increased glycogen accumulation in transgenic mice overexpressing glycogen synthase in skeletal muscle. Proc. Natl. Acad. Sci. USA 1996;93:10707-10711[Abstract/Free Full Text]

20. Okubo M., Bogardus C., Lillioja S., Mott D. M. Glucose-6-phosphate stimulation of human muscle glycogen synthase phosphatase. Metabolism 1988;37:1171-1176[Medline]

21. Ortmeyer H. K. Insulin decreases skeletal muscle cAMP-dependent protein kinase (PKA) activity in normal monkeys and increases PKA activity in insulin-resistant monkeys. J. Basic Clin. Physiol. Pharmacol. 1998;8:223-235

22. Ortmeyer H. K. Insulin increases liver protein phosphatase-1 and protein phosphatase-2C activities in lean, young adult rhesus monkeys. Horm. Metab. Res. 1998;30:705-710[Medline]

23. Ortmeyer H. K. Insulin resistance in skeletal muscle: a role for impaired insulin activation of glycogen synthase. Zierath J. eds. Frontiers in Animal Diabetes Research: Muscle Metabolism 2000 Overseas Publishers Association Lausanne, Switzerland in press

24. Ortmeyer H. K. Relationship of glycogen synthase and glycogen phosphorylase to protein phosphatase 2C and cAMP-dependent protein kinase in liver of obese rhesus monkeys. Obes. Res. 1997;5:613-621[Medline]

25. Ortmeyer H. K., Bodkin N. L., Hansen B. C. Chronic caloric restriction alters glycogen metabolism in rhesus monkeys. Obes. Res. 1994;2:549-555

26. Ortmeyer H. K., Bodkin N. L., Hansen B. C. Insulin regulates liver glycogen synthase and glycogen phosphorylase activity reciprocally in rhesus monkeys. Am. J. Physiol. Endocrinol. Metab. 1997;272:E133-E138[Abstract/Free Full Text]

27. Ortmeyer H. K., Bodkin N. L., Hansen B. C. Insulin-mediated glycogen synthase activity in muscle of spontaneously insulin-resistant and diabetic rhesus monkeys. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 1993;265:R552-R558[Abstract/Free Full Text]

28. Ortmeyer H. K., Bodkin N. L., Hansen B. C. Paradoxical phosphorylation of skeletal muscle glycogen synthase by in vivo insulin in very lean young adult rhesus monkeys. Ann. N. Y. Acad. Sci. 1999;892:247-260[Medline]

29. Ortmeyer H. K., Bodkin N. L., Hansen B. C. Relationship of skeletal muscle glucose-6-phosphate to glucose disposal rate and glycogen synthase activity in insulin-resistant and non-insulin-dependent diabetic rhesus monkeys. Diabetologia 1994;37:127-133[Medline]

30. Ortmeyer H. K., Huang L., Larner J., Hansen B. C. Insulin unexpectedly increases the glucose 6-phosphate Ka of skeletal muscle glycogen synthase in calorie-restricted monkeys. J. Basic Clin. Physiol. Pharmacol. 1998;9:309-323[Medline]

31. Rossetti L., Hu M. Skeletal muscle glycogenolysis is more sensitive to insulin than is glucose transport/phosphorylation: relation to the insulin-mediated inhibition of hepatic glucose production. J. Clin. Invest. 1993;92:2963-2974

32. Schalin-Jäntti C., Härkönen M., Groop L. C. Impaired activation of glycogen synthase in people at increased risk for developing NIDDM. Diabetes 1992;41:598-604[Abstract]

33. Schulz A. R. Control analysis of muscle glycogen metabolism. Arch. Biochem. Biophys. 1998;353:172-180[Medline]

34. Shulman R. G., Rothman D. L. Enzymatic phosphorylation of muscle glycogen synthase: a mechanism for maintenance of metabolic homeostasis. Proc. Natl. Acad. Sci. 1996;93:7491-7495[Abstract/Free Full Text]

35. Villar-Palasi C. Effect of glucose phosphorylation on the activation by insulin of skeletal muscle glycogen synthase. Biochim. Biophys. Acta. 1995;1244:203-208[Medline]

36. Villar-Palasi C., Guinovart J. J. The role of glucose 6-phosphate in the control of glycogen synthase. FASEB J 1997;11:544-558[Abstract]

37. Villar-Palasi C., Larner J. Insulin-mediated effect on the activity of UDPG-glycogen transglucosylase of muscle. Biochim. Biophys. Acta 1960;39:171-173[Medline]

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