UNIPROT:P01275 - FACTA Search

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Query: UNIPROT:P01275 (glucagon)
26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein targeting to glycogen (PTG), also known as PPP1R5, is a widely expressed member of a growing family of proteins that target protein phosphatase-1 (PP-1) to glycogen particles. Because PTG also binds to glycogen synthase and phosphorylase kinase, it has been suggested that it serves as a "scaffold" for efficient activation of glycogen synthesis. However, very little is known about the metabolic effects of PTG. In this study, we have used recombinant adenovirus to overexpress PTG in primary rat hepatocytes, a cell type with high glycogenic capacity. We find that overexpression of PTG potently activates glycogen synthesis in cultured hepatocytes. Surprisingly, the glycogenic effect of PTG is observed even in the complete absence of carbohydrates or insulin in the culture medium. Furthermore, glycogenolytic agents such as forskolin or glucagon are largely ineffective at activating glycogen degradation in PTG overexpressing hepatocytes, even though large increases in cAMP levels are demonstrated. These metabolic effects of PTG overexpression are accompanied by a 3.6-fold increase in glycogen synthase activation state and a 40% decrease in glycogen phosphorylase activity. Our results are consistent with a model in which PTG overexpression "locks" the hepatocyte in a glycogenic mode, presumably via its ability to promote interaction of enzymes of glycogen metabolism with PP-1.
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PMID:Overexpression of protein targeting to glycogen (PTG) in rat hepatocytes causes profound activation of glycogen synthesis independent of normal hormone- and substrate-mediated regulatory mechanisms. 975 75

The effects of the adipocyte-derived hormone leptin on glucose metabolism in hepatocytes were investigated. Incubation of hepatocytes from Wistar rats with leptin for 16 h caused a dose-dependent increase in incorporation of [14C]glucose into glycogen, with a maximal effect at 30 nmol/l leptin. This effect of leptin was observed over a range of glucose concentrations (10-25 mmol/l) and was associated with stimulation of net glycogen deposition. It was not counteracted by mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase, indicating that it is not due to increased gluconeogenic flux. Leptin also enhanced the short-term stimulation of glycogen synthesis by insulin. These effects of leptin were associated with inhibition of phosphorylase a, which occurred after 4 h of exposure to leptin. Culture with leptin for 16 h did not affect the activities of glucose-6-phosphatase or glucokinase or the activation state of glycogen synthase. Leptin did not affect glycolysis determined from the detritiation of [3-(3)H]glucose. The inhibitory effects of leptin on phosphorylase a were counteracted by short-term incubation with glucagon but were additive with the inhibitory effects of insulin and also with the inhibition caused by resorcinol (25 pmol/l), which inhibits phosphorylase kinase by a mechanism analogous to the antidiabetic drug proglycosyn. These results show that leptin has additive effects with insulin in inhibiting phosphorylase and stimulating glycogen storage in hepatocytes, indicating that these hormones act by separate but convergent mechanisms. It is concluded that the primary action of leptin in hepatocytes is to enhance glycogen storage. This may be an important compensatory mechanism for the inhibition of insulin secretion.
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PMID:Leptin enhances glycogen storage in hepatocytes by inhibition of phosphorylase and exerts an additive effect with insulin. 989 17

The development of late onset non-insulin dependent diabetes mellitus (NIDDM) is due to a complicated interplay between genes and environment on one side, and the interaction between metabolic defects in various tissues including the pancreatic beta cell (decreased insulin secretion), skeletal muscle (insulin resistance), liver (increased gluconeogenesis), adipose tissue (increased lipolysis) and possibly gut incretin hormones (defective glucagon like peptide 1 (GLP1) secretion) on the other side. Evidence for a genetic component includes the finding of a variety of metabolic defects in various tissues in non-diabetic subjects with a genetic predisposition to NIDDM, higher concordance rates for abnormal glucose tolerance including NIDDM in monozygotic compared with dizygotic twins, and the more recent demonstration of different NIDDM susceptibility genes at the sites of Insulin Receptor Substrate 1 (IRS1), the beta-3 adrenergic receptor, and the sulfonylurea receptor. However, the latter susceptibility genes only explain a minor proportion of NIDDM in the general population, and the quantitative extent to which genetic versus non-genetic factors contribute to NIDDM is presently unsolved. Environmental components include both an early intrauterine component associated with low birth weight, and later postnatal components including low physical activity, high fat diet, and the subsequent development of obesity and elevated plasma and tissue free fatty acid levels. Our finding of lower birth weights in monozygotic twins compared with their non-diabetic genetically identical co-twins excludes the possibility that the association between NIDDM and low birth weight as demonstrated in several studies may solely be explained by a coincidence between a certain gene causing both a low birth weight and an increased risk of NIDDM. Young first degree relatives of patients with NIDDM are characterized by hyperinsulinaemia and peripheral insulin resistance, which in turn may be explained by a decreased insulin activation of the enzyme glycogen synthase in skeletal muscle. Therefore, a defective skeletal muscle glycogen synthase activation may represent an early phenotypic expression of a genetic defect contributing to an increased risk of later development of NIDDM. However, elderly insulin resistant non-diabetic co-twins (64 years old) of twins with overt NIDDM does not--in contrast to their NIDDM co-twins--have a significantly decreased insulin activation of glycogen synthase in skeletal muscle. This demonstrates that the defective muscle glycogen synthase insulin activation has an apparent non-genetic component, and that this key defect of metabolism can be escaped or postponed even in non-diabetic subjects with a presumably 100% genetic predisposition to NIDDM. The insulin activation of glycogen synthase in skeletal muscle is compensated or apparently normalised in NIDDM patients when studied during their ambient fasting hyperglycaemia and a subsequent isoglycaemic (hyperglycaemic) physiologic insulin infusion. This indicates that the prevailing hyperglycaemia in NIDDM subjects compensates for the defective insulin activation of glycogen synthase present in those subjects when studied during eulycaemia. Our data and those of others also indicates that hyperglycaemia in NIDDM compensates for the defects in insulin secretion, the disproportionately elevated hepatic glucose production, and to some extent for the increased lipid oxidation and the decreased glucose oxidation present in NIDDM patients. Accordingly, NIDDM subjects exhibit all of those defects of metabolism when studied during "experimental decompensation" when the ambient hyperglycaemia is normalized by a prior and later withdrawn intravenous insulin infusion. However, shortly after the withdrawal of the intravenous insulin infusion, the plasma glucose concentration increased spontaneously in the NIDDM patients. (ABSTRACT TRUNCATED)
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PMID:On the pathophysiology of late onset non-insulin dependent diabetes mellitus. Current controversies and new insights. 1042 79

Metformin is regarded as an antihyperglycaemic agent because it lowers blood glucose concentrations in type 2 (non-insulin-dependent) diabetes without causing overt hypoglycaemia. Its clinical efficacy requires the presence of insulin and involves several therapeutic effects. Of these effects, some are mediated via increased insulin action, and some are not directly insulin dependent. Metformin acts on the liver to suppress gluconeogenesis mainly by potentiating the effect of insulin, reducing hepatic extraction of certain substrates (e.g. lactate) and opposing the effects of glucagon. In addition, metformin can reduce the overall rate of glycogenolysis and decrease the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake into skeletal muscle is enhanced by metformin. This has been attributed in part to increased movement of insulin-sensitive glucose transporters into the cell membrane. Metformin also appears to increase the functional properties of insulin- and glucose-sensitive transporters. The increased cellular uptake of glucose is associated with increased glycogen synthase activity and glycogen storage. Other effects involved in the blood glucose-lowering effect of metformin include an insulin-independent suppression of fatty acid oxidation and a reduction in hypertriglyceridaemia. These effects reduce the energy supply for gluconeogenesis and serve to balance the glucose-fatty acid (Randle) cycle. Increased glucose turnover, particularly in the splanchnic bed, may also contribute to the blood glucose-lowering capability of metformin. Metformin improves insulin sensitivity by increasing insulin-mediated insulin receptor tyrosine kinase activity, which activates post-receptor insulin signalling pathways. Some other effects of metformin may result from changes in membrane fluidity in hyperglycaemic states. Metformin therefore improves hepatic and peripheral sensitivity to insulin, with both direct and indirect effects on liver and muscle. It also exerts effects that are independent of insulin but cannot substitute for this hormone. These effects collectively reduce insulin resistance and glucotoxicity in type 2 diabetes.
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PMID:The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. 1057 23

We investigated the impact of GLUT2 gene inactivation on the regulation of hepatic glucose metabolism during the fed to fast transition. In control and GLUT2-null mice, fasting was accompanied by a approximately 10-fold increase in plasma glucagon to insulin ratio, a similar activation of liver glycogen phosphorylase and inhibition of glycogen synthase and the same elevation in phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNAs. In GLUT2-null mice, mobilization of glycogen stores was, however, strongly impaired. This was correlated with glucose-6-phosphate (G6P) levels, which remained at the fed values, indicating an important allosteric stimulation of glycogen synthase by G6P. These G6P levels were also accompanied by a paradoxical elevation of the mRNAs for L-pyruvate kinase. Re-expression of GLUT2 in liver corrected the abnormal regulation of glycogen and L-pyruvate kinase gene expression. Interestingly, GLUT2-null livers were hyperplasic, as revealed by a 40% increase in liver mass and 30% increase in liver DNA content. Together, these data indicate that in the absence of GLUT2, the G6P levels cannot decrease during a fasting period. This may be due to neosynthesized glucose entering the cytosol, being unable to diffuse into the extracellular space, and being phosphorylated back to G6P. Because hepatic glucose production is nevertheless quantitatively normal, glucose produced in the endoplasmic reticulum may also be exported out of the cell through an alternative, membrane traffic-based pathway, as previously reported (Guillam, M.-T., Burcelin, R., and Thorens, B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 12317-12321). Therefore, in fasting, GLUT2 is not required for quantitative normal glucose output but is necessary to equilibrate cytosolic glucose with the extracellular space. In the absence of this equilibration, the control of hepatic glucose metabolism by G6P is dominant over that by plasma hormone concentrations.
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PMID:Liver hyperplasia and paradoxical regulation of glycogen metabolism and glucose-sensitive gene expression in GLUT2-null hepatocytes. Further evidence for the existence of a membrane-based glucose release pathway. 1075 92

Glucagon-like peptide-1 (GLP-1) has been shown to have insulin-like effects upon the metabolism of glucose in rat liver, muscle and fat, and on that of lipids in rat and human adipocytes. These actions seem to be exerted through specific receptors which, unlike that of the pancreas, are not - at least in liver and muscle - cAMP-associated. Here we have investigated the effect, its characteristics, and possible second messengers of GLP-1 on the glucose metabolism of human skeletal muscle, in tissue strips and primary cultured myocytes. In muscle strips, GLP-1, like insulin, stimulated glycogen synthesis, glycogen synthase a activity, and glucose oxidation and utilization, and inhibited glycogen phosphorylase a activity, all of this at physiological concentrations of the peptide. In cultured myotubes, GLP-1 exerted, from 10(-13) mol/l, a dose-related increase of the D-[U-(14)C]glucose incorporation into glycogen, with the same potency as insulin, together with an activation of glycogen synthase a; the effect of 10(-11) mol/l GLP-1 on both parameters was additive to that induced by the equimolar amount of insulin. Synthase a was still activated in cells after 2 days of exposure to GLP-1, as compared with myotubes maintained in the absence of peptide. In human muscle cells, exendin-4 and its truncated form 9-39 amide (Ex-9) are both agonists of the GLP-1 effect on glycogen synthesis and synthase a activity; but while neither GLP-1 nor exendin-4 affected the cellular cAMP content after 5-min incubation in the absence of 3-isobutyl-1-methylxantine (IBMX), an increase was detected with Ex-9. GLP-1, exendin-4, Ex-9 and insulin all induced the prompt hydrolysis of glycosylphosphatidylinositols (GPIs). This work shows a potent stimulatory effect of GLP-1 on the glucose metabolism of human skeletal muscle, and supports the long-term therapeutic value of the peptide. Further evidence for a GLP-1 receptor in this tissue, different from that of the pancreas, is also illustrated, suggesting a role for an inositolphosphoglycan (IPG) as at least one of the possible second messengers of the GLP-1 action in human muscle.
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PMID:Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes. 1206 36

Two distinct allosteric inhibitors of glycogen phosphorylase, 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and CP-91149 (an indole-2-carboxamide), were investigated for their effects on the phosphorylation state of the enzyme in hepatocytes in vitro. CP-91149 induced inactivation (dephosphorylation) of phosphorylase in the absence of hormones and partially counteracted the phosphorylation caused by glucagon. Inhibition of glycogenolysis by CP-91149 can be explained by dephosphorylation of phosphorylase a. This was associated with activation of glycogen synthase and stimulation of glycogen synthesis. DAB, in contrast, induced a small degree of phosphorylation of phosphorylase. This was associated with inactivation of glycogen synthase and inhibition of glycogen synthesis. Despite causing phosphorylation (activation) of phosphorylase, DAB is a very potent inhibitor of glycogenolysis in both the absence and presence of glucagon. This is explained by allosteric inhibition of phosphorylase a, which overrides the increase in activation state. In conclusion, two potent phosphorylase inhibitors exert different effects on glycogen metabolism in intact hepatocytes as a result of opposite effects on the phosphorylation state of both phosphorylase and glycogen synthase.
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PMID:Diverse effects of two allosteric inhibitors on the phosphorylation state of glycogen phosphorylase in hepatocytes. 1218 29

We report a new case of hereditary hepatic glycogen synthase (GS) deficiency (MIM 240600) in a French Canadian girl referred at 7 years of age for a family history of hyperlipidemia. Her initial evaluation incidentally revealed fasting hypoglycemia and ketonuria after a 10-hr fast with normal growth, development, and physical examination. Additional biochemical findings included fasting hypoalaninemia with elevated plasma branched chain amino acids and postprandial hyperlactatemia. Liver glycogen synthase activity was reduced. Unlike most other reported patients, we observed on three different occasions an increase in fasting plasma glucose levels after glucagon administration during episodes of hypoglycemia. At 13 years of age, her growth and intellect are normal; however, she still has hypoglycemia after 18 hr of fasting. From our patient's course and a review of the literature, we conclude: (A) Usual modes of presentation of GS deficiency are non-specific symptoms after overnight fasting (7/17), incidental findings (3/17), or positive family history (7/17); (B) Most patients maintain normal growth (8/11) and intellectual abilities (12/15); (C) Fasting hypoglycemia (17/17) and reduced liver glycogen content (9/9) are constant features; (D) Biochemical findings also include postprandial hyperlactatemia (13/13), fasting hyperketonemia (12/12), and fasting hypoalaninemia (8/9); (E) Glucagon response following fasting hypoglycemia is usually reduced or absent (7/8) but can be repeatedly present (1/8); (F) Liver steatosis is frequent (6/6). Although rare, GS deficiency results in a characteristic biochemical profile that, if recognized, should lead promptly to its diagnosis.
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PMID:Long-term follow-up of a new case of liver glycogen synthase deficiency. 1279 86

Changes in the glucosylation state of the glycogen primer, glycogenin, or its association with glycogen synthase are potential sites for regulation of glycogen synthesis. In this study we found no evidence for hormonal control of the glucosylation state of glycogenin in hepatocytes. However, using a modified glycogen synthase assay that separates the product into acid-soluble (glycogen) and acid-insoluble (proteoglycogen) fractions we found that insulin and glucagon increase and decrease, respectively, the association of glycogen synthase with an acid-insoluble substrate. The latter fraction had a higher affinity for UDP-glucose and accounted for between 5 and 21% of total activity depending on hormonal conditions. Phosphorylase overexpression mimicked the effect of glucagon. It is concluded that phosphorylase activation or overexpression causes dissociation of glycogen synthase from proteoglycogen causing inhibition of initiation of glycogen synthesis.
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PMID:Phosphorylase regulates the association of glycogen synthase with a proteoglycogen substrate in hepatocytes. 1296 9

Glucagon-like peptide-1 (GLP-1), an incretin with glucose-dependent insulinotropic and insulin-independent antidiabetic properties, has insulin-like effects on glucose metabolism in extrapancreatic tissues participating in overall glucose homeostasis. These effects are exerted through specific receptors not associated with cAMP, an inositol phosphoglycan being a possible second messenger. In rat hepatocytes, activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB), protein kinase C (PKC) and protein phosphatase 1 (PP-1) has been shown to be involved in the GLP-1-induced stimulation of glycogen synthase. We have investigated the role of enzymes known or suggested to mediate the actions of insulin in the GLP-1-induced increase in glycogen synthase a activity in rat skeletal muscle strips. We first explored the effect of GLP-1, compared with that of insulin, on the activation of PI3K, PKB, p70s6 kinase (p70s6k) and p44/42 mitogen-activated protein kinases (MAPKs) and the action of specific inhibitors of these kinases on the insulin- and GLP-1-induced increment in glycogen synthase a activity. The study showed that GLP-1, like insulin, activated PI3K/PKB, p70s6k and p44/42. Wortmannin (a PI3K inhibitor) reduced the stimulatory action of insulin on glycogen synthase a activity and blocked that of GLP-1, rapamycin (a 70s6k inhibitor) did not affect the action of GLP-1 but abolished that of insulin, PD98059 (MAPK inhibitor) was ineffective on insulin but blocked the action of GLP-1, okadaic acid (a PP-2A inhibitor) and tumour necrosis factor-alpha (a PP-1 inhibitor) were both ineffective on GLP-1 but abolished the action of insulin, and Ro 31-8220 (an inhibitor of some PKC isoforms) reduced the effect of GLP-1 while completely preventing that of insulin. It was concluded that activation of PI3K/PKB and MAPKs is required for the GLP-1-induced increment in glycogen synthase a activity, while PKC, although apparently participating, does not seem to play an essential role; unlike in insulin signaling, p70s6k, PP-1 and PP-2A do not seem to be needed in the action of GLP-1 upon glycogen synthase a activity in rat muscle.
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PMID:Cell signalling of glucagon-like peptide-1 action in rat skeletal muscle. 1501 93

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