Alteration of hepatic glycogen synthase phosphatase activity by insulin deficiency

Miller, Thomas B.; Vicalvi, J. J.; Garnache, Alice K.

doi:10.1152/ajpendo.1981.240.5.e539

Cited by 12 publications

(12 citation statements)

References 14 publications

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“…In diabetic animals, total synthase activity has been reported to be increased by a number of laboratories [2][3][4][5][6][7][8], including our own [1]. Bahnak and Gold reported the activity to be greater at 8 days of diabetes than at 3 days, but the differences were not as great as noted in the present study.…”

Section: Discussioncontrasting

confidence: 66%

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Effect of feeding, fasting, and diabetes on liver glycogen synthase activity, protein, and mRNA in rats

Gannon

Nuttall

1997

Diabetologia

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Our laboratory [1], as well as many others [2][3][4][5][6][7][8] , have reported an increase in total synthase activity in liver from diabetic rats. The increase in hepatic synthase activity could be due to an increased mass of the enzyme or to the presence of a more catalytically efficient form(s) of the enzyme. Akatsuka et al. [5] reported changes in the M r of synthase in liver from streptozotocin diabetic rats. They attributed this to an increase in the phosphorylation state of synthase, which in turn resulted in greater total synthase activity. In contrast, in alloxan diabetic rats, Bahnak and Gold [3] reported that the increase in hepatic synthase activity was due to an increased mass of the enzyme. This was associated with an increased synthesis and increased turnover rate. They could not confirm the presence of an altered form of the enzyme [9].The purpose of the present study was to determine whether the increase in total synthase activity observed previously in diabetic rats was associated with an increase in enzyme protein mass and whether the reported increase in enzyme turnover was associated with an increase in mRNA abundance. Therefore, Diabetologia (1997) Summary Hepatic glycogen synthase activity is increased in diabetic animals. However, the relationship between enzymic activity, enzyme protein mass, and mRNA abundance has not been well characterized. In the present study, these relationships were determined in 3-and 8-day diabetic, fed and fasted rats. The results were compared to data obtained in normal fed and fasted animals. In normal rats, total synthase specific activity and protein mass were similar in the fed and fasted state. However, in fed animals, the synthase mRNA abundance was increased 1.7-fold. In 3-day diabetic rats, total synthase specific activity was increased approximately 29 % compared to normal controls. It was unaffected by feeding and fasting and was associated with an approximate 15 % increase in enzyme mass. Synthase mRNA was increased 1.8 and 2.6-fold in fasted and fed animals, respectively. In 8-day diabetic rats, total synthase specific activity was increased more than 2-fold compared to controls. However, the enzyme protein mass was decreased by approximately 20 %. The mRNA abundance in 8-day diabetic fasted rats was only 30 % of controls, while in fed rats it was increased by 40 %. These data indicate that feeding and fasting have a major effect on synthase mRNA abundance which is independent of synthase activity, or protein mass, or both, in normal and diabetic animals. Total synthase specific activity increased with duration of diabetes. This was associated with only a modest change in protein mass. Thus, diabetes induces an increase in synthase catalytic efficacy. The specific activity of phosphorylase is decreased in diabetic rats. [Diabetologia (1997) 40: 758-763]

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Section: Discussioncontrasting

confidence: 66%

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confidence: 88%

Effect of feeding, fasting, and diabetes on liver glycogen synthase activity, protein, and mRNA in rats

Gannon

Nuttall

1997

Diabetologia

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“…Heat-stable inhibitors and targeting subunits have been shown to have a regulatory function on PP-I activity. From studies on experimental diabetes it is not clear whether changes in heat-stable inhibitor activity determine the decreased PP-I activity associated with insulin deficiency (26)(27)(28). The G-subunit is thought to be a specific receptor for PP-I (10) and is a physiological substrate for cAMP-dependent protein kinase.…”

Section: Discussionmentioning

confidence: 99%

Deficiency in phosphorylase phosphatase activity despite elevated protein phosphatase type-1 catalytic subunit in skeletal muscle from insulin-resistant subjects.

Nyomba

Brautigan²,

Schlender³

et al. 1991

J. Clin. Invest.

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Glycogen synthase is activated by protein phosphatase type-i (PP-1). The spontaneous PP-1 activity accounts for only a small fraction of total PP-1 activity, which can be exposed by trypsin digestion of inhibitor proteins in the presence of Mn2+. We determined total PP-1 activity in muscle biopsies from insulin-sensitive and -resistant nondiabetic Pima Indians. Inhibitor-2 sensitive PP-1 represented 90% oftotal phosphatase activity. Spontaneous and total PP-1 activities were reduced in insulin resistant subjects (P < 0.05-0.01), suggesting that the reduced PP-1 activity is not the result of inhibition by trypsinlabile phosphatase regulatory subunits. This difference was further investigated by Western blots using two different antibodies. An antibody raised against the rabbit muscle PP-I catalytic subunit was used to analyze muscle extracts concentrated by DEAE-Sepharose adsorption. An antibody raised against a peptide derived from the COOH-terminal end ofthe PP-1 catalytic subunit was used to analyze crude muscle extracts. Both antibodies recognized a PP-1 catalytic subunit of -33 kD, which unexpectedly was more abundant in insulin-resistant subjects (P < 0.05-0.01). The increase in the tissue PP-1 protein content may be a response to compensate for the impairment in the enzyme activity. (J. Clin. Invest. 1991Invest. . 88:1540Invest. -1545

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“…After feeding, diabetic animals fail to synthesize liver glycogen from glucose and gluconeogenic precursors [3, 4, 5, 6, 7, 8, 9, 10], mainly because of defective activation of glycogen synthase. The impact of diabetes on glycogen metabolism in the kidney has received less attention.…”

Section: Introductionmentioning

confidence: 99%

Influence of Long-Term Diabetes on Renal Glycogen Metabolism in the Rat

Nannipieri

Lanfranchi

Santerini

et al. 2001

Nephron

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Background/Aims: The effects of acute insulin deficiency on the kidney have been investigated in animal models of experimental diabetes; however, the impact of long-term diabetes has not been determined. Methods: We measured renal glycogen contents in streptozotocin (STZ)-diabetic rats 3 weeks (n = 12) or 9 months (n = 12) after the induction of diabetes, and in 2 groups of control rats of similar age (n = 16 and n = 12, respectively), in the fed state and after a 24-hour fast. Results: Diabetic rats had high glucose levels, low insulin but normal glucagon concentrations in portal blood. In the fasting state, kidney glycogen content was very low in both young control and young diabetic rats (54 ± 15 and 189 ± 26 µg/g, respectively, mean ± SD); in contrast, glycogen levels were markedly elevated in rats with long-standing diabetes as compared to old nondiabetic animals (2,628 ± 1,023 ± and 1,968 ± 989 µg/g of diabetic rat, fasting and fed, respectively, p < 0.001 vs. 0 ± 0 and 4 ± 6 µg/g of control rats). On electron microscopy, large glycogen clusters were localized to the renal tubules. Kidney phosphorylase activity was higher, and synthase activity lower in diabetic than control rats (p < 0.05 for both), whereas kidney glycogen was strongly related to plasma glucose levels, suggesting that the enzyme changes were secondary to glycogen accumulation itself. Renal hexosephosphates and fructose-2,6-bisphosphate contents were both increased in long-term diabetic rats (p < 0.05), implying enhanced fluxes through both glycolysis and gluconeogenesis. Conclusion: In chronic, untreated diabetes glycogen accumulates in the renal tubules; prolonged hyperglycemia is the sole driving force for this phenomenon.

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Alteration of hepatic glycogen synthase phosphatase activity by insulin deficiency

Cited by 12 publications

References 14 publications

Effect of feeding, fasting, and diabetes on liver glycogen synthase activity, protein, and mRNA in rats

Effect of feeding, fasting, and diabetes on liver glycogen synthase activity, protein, and mRNA in rats

Deficiency in phosphorylase phosphatase activity despite elevated protein phosphatase type-1 catalytic subunit in skeletal muscle from insulin-resistant subjects.

Influence of Long-Term Diabetes on Renal Glycogen Metabolism in the Rat

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