Impaired insulin-like growth factor I-mediated stimulation of glucose incorporation into glycogen in vivo in the ob/ob mouse
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Using 13C nuclear magnetic resonance spectroscopic methods we examined in vivo the synthesis of liver glycogen during the infusion of D-[1-13C]glucose and the turnover of labeled glycogen during subsequent infusion of D-[1-13C]glucose. In fasted rats the processes of glycogen synthesis and degradation were observed to occur simultaneously with the rate of synthesis much greater than degradation leading to net glycogen synthesis. In fed rats, incorporation of infused D-[1-13C]glucose occurred briskly; however, over 2 h there was no net glycogen accumulated. Degradation of labeled glycogen was greater in the fed versus the fasted rats (P less than 0.001), and the lack of net glycogen synthesis in fed rats was due to degradation and synthesis occurring at similar rates throughout the infusion period. There was no indication that suppression of phosphorylase a or subsequent activation of glycogen synthase was involved in modulation of the flux of tracer into liver glycogen. We conclude that in both fed and fasted rats, glycogen synthase and phosphorylase are active simultaneously and the levels of liver glycogen reached during refeeding are determined by the balance between ongoing synthetic and degradative processes.
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Glycogenesis
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In glycogen-containing muscle, glycogenesis appears to be controlled by glucose 6-phosphate (6-P) provision, but after glycogen depletion, an autoinhibitory control of glycogen could be a determinant. We analyzed in cultured human muscle the contribution of glycogen depletion versus glucose 6-P in the control of glycogen recovery. Acute deglycogenation was achieved by engineering cells to overexpress glycogen phosphorylase (GP). Cells treated with AdCMV-MGP adenovirus to express 10 times higher active GP showed unaltered glycogen relative to controls at 25 mM glucose, but responded to 6-h glucose deprivation with more extensive glycogen depletion. Glycogen synthase (GS) activity ratio was double in glucose-deprived AdCMV-MGP cells compared with controls, despite identical glucose 6-P. The GS activation peak (30 min) induced by glucose reincubation dose dependently correlated with glucose 6-P concentration, which reached similar steady-state levels in both cell types. GS activation was significantly blunted in AdCMV-MGP cells, whereas it strongly correlated, with an inverse relationship, with glycogen content. An initial (0-1 h) rapid insulin-independent glycogen resynthesis was observed only in AdCMV-MGP cells, which progressed up to glycogen levels approximately 150 micrograms glucose/mg protein; control cells, which did not deplete glycogen below this concentration, showed a 1-h lag time for recovery. In summary, acute deglycogenation, as achieved by GP overexpression, caused the activation of GS, which inversely correlated with glycogen replenishment independent of glucose 6-P. During glycogen recovery, the activation promoted by acute deglycogenation rendered GS effective for controlling glycogenesis, whereas the transient activation of GS induced by the glucose 6-P rise had no impact on the resynthesis rate. We conclude that the early insulin-independent glycogen resynthesis is dependent on the activation of GS due to GP-mediated exhaustion of glycogen rather than glucose 6-P provision.
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Glucose is stored in mammalian tissues in the form of glycogen. Glycogen levels are markedly reduced in liver or muscle cells of patients with insulin-resistant or insulin-deficient forms of diabetes, suggesting that impaired glycogen synthesis may contribute to development of hyperglycemia. Recently, interest in this area has been further stimulated by new insights into the spatial organization of metabolic enzymes within cells and the importance of such organization in regulation of glycogen metabolism. It is now clear that a four-member family of glycogen targeting subunits of protein phosphatase-1 (PP1) plays a major role in coordinating these events. These proteins target PP1 to the glycogen particle and also bind differentially to glycogen synthase, glycogen phosphorylase, and phosphorylase kinase, thereby serving as molecular scaffolds. Moreover, the various glycogen-targeting subunits have distinct tissue expression patterns and can influence regulation of glycogen metabolism in response to glycogenic and glycogenolytic signals. The purpose of this article is to summarize new insights into the structure, function, regulation, and metabolic effects of the glycogen-targeting subunits of PP1 and to evaluate the possibility that these molecules could serve as therapeutic targets for lowering of blood glucose in diabetes.
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Using 3C nuclear magnetic resonance spectroscopic methods we examined in vivo the synthesis of liver glycogen during the infusion of D-11-13Cjglucose and the turnover of labeled glycogen during subsequent infusion of D-11-13Cjglucose. In fasted rats the processes of glycogen synthesis and degradation were observed to occur simultaneously with the rate of synthesis > degradation leading to net glycogen synthesis. In fed rats, incorporation of infused D-[1-_3Cjglucose occurred briskly; however, over 2 h there was no net glycogen accumulated. Degradation of labeled glycogen was greater in the fed versus the fasted rats (P < 0.001), and the lack of net glycogen synthesis in fed rats was due to degradation and synthesis occurring at similar rates throughout the infusion period. There was no indication that suppression of phosphorylase a or subsequent activation of glycogen synthase was involved in modulation of the flux of tracer into liver glycogen. We conclude that in both fed and fasted rats, glycogen synthase and phosphorylase are active simultaneously and the levels of liver glycogen reached during refeeding are determined by the balance between ongoing synthetic and degrada
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The intravenous administration of glucose to the mouse stimulates 15–20 and up to 40‐fold the conversion of glucose to glycogen in the liver. This effect is observed in the normally fed as well as in the fasted animal and requires 5 min to reach its full development. At that time, the hepatic concentration of glucose 6‐phosphate and of UDPG is markedly lowered whereas the activity of glycogen synthetase, when measured in a concentrated liver homogenate, is greatly increased. The rate of glycogen synthesis is not correlated with the concentration of glucose in the liver but is highly significantly correlated with the activity of liver glycogen synthetase.
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Muscle contraction activates glycogen synthesis, but the mechanism for activation of glycogen synthase after contractile activity is poorly understood. Glycogen concentration is powerful regulator of glycogen synthase and it has been suggested that reduced glycogen content determines activation of glycogen synthase after contractile activity. PURPOSE: The purpose of the present study was to investigate effects of muscle contraction on glycogen synthesis, glycogen synthase activation and glycogen synthase phosphorylation in muscle with different glycogen concentrations. METHODS: We manipulated the muscle glycogen content to low (94.8 ±5.0 mmol-kg−1; 24-hours fasted rats; n=36), normal (203.8±10.2 mmol-kg1; Free access to chow; n=28), and high (459.3±30.9 mmol-kg−1; 24-hours fasted rats were refed for 24 hours to supercompensate glycogen; n=32). After manipulation, muscles were dissected for in vitro studies, mounted on contraction apparatus, and stimulated electrically for 30 min. Subsequently, glycogen synthesis, glycogen synthase activity, and glycogen synthase Ser645, Ser649, Ser653, Ser657 phosphorylation were assessed. RESULTS: Contraction decreased glycogen content by 120.6±4.7 (n=28) and 131.5±8.4 mmol-kg−1 (n=32) in muscles with normal and high glycogen, respectively. In muscles with low glycogen, glycogen breakdown was reduced to 67.4±5.0 mmol-kg−1(p<0.001; n=28). Rate of glycogen synthesis after contraction was inversely correlated to initial glycogen content. Contraction increased GS activity in all groups (p < 0.001). Interestingly, contraction activated glycogen synthase in muscles with high glycogen (p < 0.01) without dephosphorylation of the sites phosphorylated by GSK-3. Contraction dephosphorylated these sites in muscles with low and normal glycogen. When insulin was present after contraction, an additive effect of insulin on glycogen synthesis and glycogen synthase activation. Interestingly, rate of glycogen synthesis reach the same level in muscles with low and normal glycogen when insulin was present after contraction; so did glycogen synthase fractional activity and glycogen synthase Ser645, Ser649, Ser653, Ser657 phosphorylation. CONCLUSION: Contractile activity is a powerful activator of GS and glycogen synthesis even in muscles high glycogen content. In muscles with high glycogen, glycogen synthase fractional activity was increased without dephosphorylation of the sites phosphorylated by GSK-3, indicating that contraction activates glycogen synthase by dephosphorylation of other sites. Supported by the Research Council of Norway and The Novo Nordisk Foundation.
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AbstractGlucose infusion gave no increase of glycogen nor of synthetase I activity in muscle of diabetics at rest, contrary to in normals. After glycogen depletion by exercise, high I activity was seen in both normals and diabetics, and glycogen synthesis was observed during glucose infusion. While glycogen increased, I activity tended to fall. Insulin during infusion apparently affected neither the glycogen synthesis rate nor the I activity in normals, but did increase the I activity and the glycogen synthesis rate in diabetics, most pronouncedly in insulin-dependent patients.Key Words: Diabetes mellitusglycogen synthesisglycogen synthetaseinsulinmuscle exercisemuscle glycogenmuscle metabolism
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Abstract Glycogen synthase, glycogen phosphorylase, glucose‐6‐phosphate dehydrogenase, 6‐phosphogluconate dehydrogenase, and glucose‐6‐phosphatase were determined for the first time in the accessory lobes of Lachi from late embryonic chicks. The activities of these enzymes were compared with those found in other glycogen‐metabolizing tissues, specifically the glycogen body, liver, and skeletal muscle, obtained from the same embryos. The data show that, as in the glycogen body, the accessory lobes of Lachi lack glucose‐6‐phosphatase, but contain relatively high activity levels of glycogen synthase I, total and active glycogen phosphorylase, and the dehydrogenases of glucose‐6‐phosphate and 6‐phosphogluconate. The percent of glycogen synthase I activity in the Lachi lobes is from two‐ to 20‐fold greater than that observed in the glycogen body, liver, or muscle, whereas the percent of glycogen phosphorylase a activity is comparable to that of the liver, but greater than that in the glycogen body or muscle. The activity of each dehydrogenase of the pentose phosphate cycle in the Lachi lobes is similar to that noted in the glycogen body, but is over two‐ or fivefold greater than that activity found in muscle or liver. Our data, together with other recent evidence, suggest that the role of glycogen in these functionally enigmatic tissues may be to support the precocious process of myelin synthesis in the developing bird, as well as possibly to provide alternate sources of energy for the avian central nervous system.
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Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.
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