Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. ATP exerts multiple receptor-mediated effects on isolated hepatocytes: glycogenolysis through the activation of glycogen phosphorylase (cAMP-independent, IP3/calcium-mediated), inactivation of glycogen synthase, inhibition of the glucagon effect on cAMP, activation of phospholipase D. The fact that some of these effects can be selectively altered and that they are not, or differently, reproduced by some other analogues of ATP, suggests the presence of more than one receptor. (i) Pertussis toxin abolishes the anti-glucagon effect of ATP without affecting its glycogenolytic effect. (ii) Single cell calcium measurements reveal major differences between ATP and ADP, (iii) 2MeSATP and ADP beta S, in clear contrast to ATP, barely increase the levels of IP3 and their glycogenolytic effects is completely blocked by phorbol ester treatment of hepatocytes. (iv) 2MeSATP differs from ADP beta S since it has no anti-glucagon effect. 2. Effects of UTP on isolated hepatocytes so far do not show any difference with effects of ATP, suggesting interaction with the same receptor(s). 3. It is proposed that liver plasma membranes contain (at least) three different receptors mediating (a) the activation of phospholipase C, (b) the activation of phospholipase D and (c) the inhibition of adenylate cyclase.
 ...
PMID:The complex interaction of ATP and UTP with isolated hepatocytes. How many receptors? 848 12

Casein hydrolysate administration to fasted rats resulted in a biphasic response of glycogen synthase. Fifteen minutes after the protein meal, synthase R (active form) was increased. This was associated with a transient increase in hepatic glucose and glucose-6-phosphate (G6P) concentrations. Both glucose and G6P are known to stimulate synthase phosphatase activity, which would result in activation of synthase. Portal plasma insulin concentration was directly related to the amount of synthase R present. By 1 hour after the meal, synthase R activity was decreased compared with the control activity. Hepatic glycogen concentration was variable during the first 30 minutes after the meal, and then decreased progressively. Portal plasma glucagon concentration and phosphorylase a activity were elevated at all time points. The data suggest that the increased portal plasma glucagon concentration is the major hormonal signal for glycogen metabolism during the second hour following a pure protein meal. However, during the first 30 minutes glycogenolysis is attenuated, perhaps due to the transient increase in insulin and an increased intracellular G6P concentration.
 ...
PMID:The effect of oral casein on hepatic glycogen metabolism in fasted rats. 849 22

The perivenous and periportal zones of the liver acinus differ in enzyme complements and capacities for gluconeogenesis, glycolysis and other metabolic processes. The biochemical factors governing this metabolic zonation are still poorly understood. Glucagon-mediated protein phosphorylation is an important factor in the regulation of hepatic metabolism. Here we show, by comparing the 32P-labelling pattern of isolated periportal and perivenous hepatocytes, that glucagon promotes the phosphorylation of zone-specific peptides as well as three common peptides (glycogen phosphorylase, glycogen synthase and pyruvate kinase) in the two cell types. We propose that the zone-specific phosphorylation of peptides is an important factor governing the shortterm zonation of metabolic processes in the liver.
 ...
PMID:Glucagon stimulates phosphorylation of different peptides in isolated periportal and perivenous hepatocytes. 854 72

Glycogen synthase, the regulatory enzyme of glycogen synthesis undergoes multisite phosphorylation leading to its inactivation. The kinases responsible for this covalent modification (ex. cAMP-dependent protein kinase, protein kinase C and glycogen synthase kinase-3) are controlled by the second messengers generated by different hormones. The isolated hepatocytes has been used as one of the experimental models for studying this complex regulatory process. Inactivation of glycogen synthase by glucagon and vasopressin has been shown to be accompanied with incorporation of phosphate into the enzyme protein. Insulin has been shown to activate glycogen synthase by inhibition of kinases and activation of synthase phosphatase. Glycogen synthase is activated by several gluconeogenic substrates, in addition to glucose. Studies in hepatocytes with activators and inhibitors of protein kinase C show that this enzyme negatively controls glycogen synthase. The differential effects of the phosphatase inhibitors, calyculin A and okadaic acid in liver cells provide supporting evidence that protein phosphatase type-1 plays a major role in the regulation of glycogen synthase. Hepatocytes isolated from diabetic rats of both types (insulin-dependent and non-insulin-dependent) mimic the defective glycogen synthase activation seen in vivo.
 ...
PMID:Regulation of glycogen synthase activation in isolated hepatocytes. 856 54

The purpose of the present study was to evaluate the role of muscle glycogen synthase activity in the reduction of glucose uptake during hypoglycaemia. Six healthy young men were examined twice; during 120 min of hyperinsulinaemic (1.5 mU.kg-1. min-1) euglycaemia followed by: 1)240 min of graded hypoglycaemia (plasma glucose nadir 2.8 mmol/l) or 2) 240 min of euglycaemia. At 350-360 min a muscle biopsy was taken and indirect calorimetry was performed at 210-240 and 330-350 min. Hypoglycaemia was associated with markedly increased levels of adrenaline, growth hormone and glucagon and also with less hyperinsulinaemia. During hypoglycaemia the fractional velocity for glycogen synthase was markedly reduced; from 29.8 +/- 2.3 to 6.4 +/- 0.9%, p < 0.05. Total glucose disposal was decreased during hypoglycaemia (5.58 +/- 0.55 vs 11.01 +/- 0.75 mg.kg-1. min-1 (euglycaemia); p < 0.05); this was primarily due to a reduction of non-oxidative glucose disposal (2.43 +/- 0.41 vs 7.15 +/- 0.7 mg.kg-1 .min-1 (euglycaemia); p < 0.05), whereas oxidative glucose disposal was only suppressed to a minor degree. In conclusion hypoglycaemia virtually abolishes the effect of insulin on muscle glycogen synthase activity. This is in keeping with the finding of a marked reduction of non-oxidative glucose metabolism.
 ...
PMID:Inhibition of muscle glycogen synthase activity and non-oxidative glucose disposal during hypoglycaemia in normal man. 863 76

Insulin resistance is a characteristic feature in recipients of a pancreas transplant, but the relative contribution of the liver and peripheral tissues to this abnormality within a spanning range of insulin concentrations is unknown. To assess the impact of insulin action on glucose metabolism after pancreas transplantation, a euglycemic-hyperinsulinemic clamp with sequential insulin infusions (5, 40, and 200 mU.m-2.min-1 for 120 min each), combined with isotopic determinations of the rates of hepatic glucose production and extrahepatic glucose uptake, indirect calorimetry, and measurements of glycogen synthase and hexokinase activities in vastus lateralis muscle, were performed in six pancreas-kidney transplant recipients (Px group) and compared with those performed in six nondiabetic kidney transplant recipients with similar immunosuppression (Kx group) and six nondiabetic control subjects. The overall effects of insulin on whole-body glucose metabolism, determined as the glucose infusion rates versus the corresponding steady-state serum insulin concentrations, demonstrated a rightward shift in the dose-response curves of the transplanted groups compared with those of normal subjects. The dose-response curve for glucose disposal rates (Rd) was shifted to the right in the Px and Kx groups, and the maximal glucose disposal rate was reduced by 40% in the Px group (11.7 +/- 1.1 mg.kg-1 fat-free mass.min-1) and 30% in the Kx group (13.9 +/- 1.2 mg.kg-1 fat-free mass.min-1) compared with that in control subjects (19.1 +/- 2.2 mg.kg-1 fat-free mass.min-1) (P < 0.05). The dose-response curve for suppression of hepatic glucose output rates was similar at increasing hepatic sinusoidal insulin concentrations. Glucose oxidation rates were similar in all groups, whereas nonoxidative glucose rates were reduced by 50% in the Px group and by 30% in the Kx group compared with those in the control group (P < 0.05). In the Px group, an impaired activation of the fractional velocity and absent decrease in the half-maximal stimulation of muscle glycogen synthase occurred during the insulin infusion. However, this finding could only explain in part the degree of impairment in nonoxidative glucose metabolism. No differences were found in total hexokinase activity in muscle between normal subjects and the transplant groups at basal insulinemia or after insulin stimulation. During hyperinsulinemia, glucagon and nonesterified fatty acids were not suppressed as much in the transplanted groups as they were in normal control subjects (P < 0.05). In conclusion, pancreas transplantation causes impaired peripheral action of insulin as compared with that in normal subjects and kidney transplant recipients. The main course of insulin resistance in the two transplant groups is explained by the immunosuppressive treatment, but the augmented insulin resistance in pancreas transplant recipients could partly be explained by the chronic peripheral hyperinsulinemia. The principal site of insulin resistance was a reduced insulin-stimulated nonoxidative glucose metabolism of peripheral tissues, which resulted in decreased capacity to store glucose as glycogen. The impaired peripheral insulin action could only partly be explained by a reduced activation of the glycogen synthase enzyme in skeletal muscle.
 ...
PMID:Impaired insulin-stimulated nonoxidative glucose metabolism in pancreas-kidney transplant recipients. Dose-response effects of insulin on glucose turnover. 877 33

Liver and skeletal muscle glycogen metabolism were investigated in rats 1 and 4 weeks after bile duct ligation (BDL) and in pair-fed, sham-operated control rats. Livers were subjected to morphometric analysis to express glycogen content and enzyme activities per mL hepatocytes. One week after BDL, the hepatic glycogen content was 28.8 +/- 13.8 versus 38.6 +/- 16.4 mg/mL hepatocyte in BDL and control rats, respectively. Total activity of glycogen synthase (50.2 +/- 7.0 vs. 63.5 +/- 9.4 mU/mL hepatocytes) and glycogen phosphorylase (59.4 +/- 12.9 vs. 90.8 +/- 18.9 U/mL) were significantly reduced in BDL whereas the active fraction of glycogen synthase (27 +/- 6 vs. 38 +/- 5%) but not of glycogen phosphorylase was reduced. The skeletal muscle glycogen content was not different between BDL and control rats. Four weeks after BDL, hepatic glycogen content was further reduced (20.5 +/- 14.2 vs. 52.9 +/- 6.4 mg/mL). Total activity of glycogen synthase (38.8 +/- 12.1 vs. 60.1 +/- 4.6 mU/mL hepatocytes) and glycogen phosphorylase (127 +/- 19 vs. 178 +/- 33 U/mL hepatocytes) were both reduced in BDL rats as were their corresponding active fractions (30 +/- 18 vs. 66 +/- 8% and 58 +/- 10 vs. 76 +/- 10). At this time point, the glycogen content in soleus muscle was decreased by 64% in BDL. The glucagon plasma concentration was increased in BDL rats at both time points. There were positive correlations between the volume fraction and both hepatic glycogen content and total activity of hepatic glycogen synthase. Plasma glucagon and the active fraction of hepatic glycogen synthase were negatively correlated. The current studies show a progressive decrease in the hepatic and skeletal muscle glycogen content in BDL rats. The observed decrease in the activities of glycogen synthase and phosphorylase suggest that reduced glycogen synthesis is the major mechanism leading to the reduction in the hepatic glycogen content in BDL rats.
 ...
PMID:Progressive decrease in tissue glycogen content in rats with long-term cholestasis. 885 95

This study examined whether physiological changes in glucagon alter net hepatic glucose uptake (NHGU) or glycogen synthesis under conditions of hyperglycemia, hyperinsulinemia, and portal vein glucose concentrations exceeding those in the arterial circulation. Somatostatin was infused into 42-h-fasted dogs, insulin and glucagon were replaced intraportally at basal rates, and peripheral infusion of glucose maintained the hepatic glucose load twofold basal for 90 min (period 1). In period 2 (240 min) the insulin infusion was increased fourfold, glucose was infused intraportally, the hepatic glucose load was twofold basal, and glucagon was infused to create levels 150% basal (HiGGN, n = 6) or 40% basal (LoGGN, n = 6). NHGU rates (mg.kg-1.min-1) were low during period 1 (-0.9 +/- 0.7 in LoGGN and -0.2 +/- 0.4 in HiGGN, not significant) but increased during period 2 (-4.1 +/- 0.6 in LoGGN and -1.9 +/- 0.2 in HiGGN, P < 0.05). Endogenous glucose production (Endo Ra) declined during period 2 in LoGGN (P < 0.01 vs. basal) but did not change in HiGGN. Tracer-determined hepatic glucose uptake did not differ between groups. The poststudy increment in liver glycogen synthase I (12.5 +/- 3 vs. 6.5 +/- 2% of total) was greater in LoGGN (P < 0.05), as was net glycogen synthesis (27 +/- 8 vs. 13 +/- 3 mg/g liver, P = 0.06). An elevation in glucagon reduced NHGU (because of failure to suppress Endo Ra) and glycogen synthase activation and tended to reduce glycogen deposition.
 ...
PMID:Physiological changes in circulating glucagon alter hepatic glucose disposition during portal glucose delivery. 931 37

Glucagon-like peptide 1(7-36)amide (GLP-1) is currently under investigation as a possible tool in the treatment of non-insulin-dependent diabetes mellitus. In addition to enhancing nutrient-stimulated insulin release, the peptide also favors glycogen synthesis and glucose use in liver, muscle, and adipose tissue. GLP-1 also activates glycogen synthase a in hepatocytes from both normal and diabetic rats. In the present study, the kinetic aspects of such an activation were investigated in hepatocytes from normal rats and from animals rendered diabetic induced by injection of streptozotocin, either in the adult age (insulin-dependent diabetes mellitus model) or in days 1 or 5 after birth (non-insulin-dependent diabetes mellitus models). GLP-1 increased, in a dose-dependent manner, glycogen synthase a activity in the hepatocytes from all groups studied. The activation of the enzyme reached a steady state within 1 min exposure to GLP-1, which, at 10(-12) M, caused a half-maximal activation. When comparing fed vs. overnight-starved normal rats, a somewhat lower basal activity of glycogen synthase a in fasted animals (P < 0.05) coincided with a greater relative increment in reaction velocity in response to GLP-1. The basal activity of glycogen synthase a and the relative extent of its inhibition by glucagon or activation by insulin and GLP-1 were modulated by the extracellular concentration of D-glucose. The activation of glycogen synthase a by either insulin or GLP-1 resulted not solely in an increase in maximal velocity but also in a decrease in affinity of the enzyme for uridine diphosphate-glucose; in diabetic animals, the capacity of insulin or GLP-1 to increase the maximal velocity and Michaelis-Menten constant were less marked than in normal rats. In conclusion, this study indicates that the GLP-1-induced activation of glycogen synthase a displays attributes of rapidity, sensitivity, and nutritional dependency that are well suited for both participation in the physiological regulation of enzyme activity and therapeutic purpose.
 ...
PMID:Effects of glucagon-like peptide 1 on the kinetics of glycogen synthase a in hepatocytes from normal and diabetic rats. 960 88

Insulin resistance is present in nearly all patients with cirrhosis, but its etiology remains unknown. Chronic hyperinsulinemia has been suspected as a potential candidate, and we therefore tested the hypothesis that, in cirrhosis, prolonged reduction of the hyperinsulinemia restores insulin sensitivity. Whole-body insulin sensitivity (euglycemic insulin-clamp technique), glucose turnover (6,6-2H2-glucose isotope dilution), glucose oxidation (indirect calorimetry), non-oxidative glucose disposal, and fractional glycogen synthase activity in muscle (biopsies) were measured in eight clinically stable patients with cirrhosis before and at the end of a 4-day continuous subcutaneous infusion of the somatostatin-analogue octreotide (200 microg/24 h) designed to continuously reduce plasma insulin levels. Baseline data were compared with results obtained in healthy individuals matched for sex, age, and weight (n = 8). During the baseline (pre-octreotide) study, patients demonstrated a significant decrease in insulin-mediated glucose uptake compared with controls (5.75 +/- 0.21 vs. 7.98 +/- 0.84 mg/kg/min; P < .03), which was entirely accounted for by an impairment in non-oxidative glucose disposal (P < .04). Four-day infusion of octreotide to cirrhotic patients: 1) reduced postabsorptive and meal-stimulated plasma insulin levels by approximately 35% to 45% without significantly affecting glucose tolerance; 2) did not significantly alter plasma free fatty acids (FFA), growth hormone, and glucagon levels in the postabsorptive state and during the meal test; 3) normalized insulin-mediated whole-body glucose disposal (7.63 +/- 0.72 mg/kg/min post-octreotide; P = not significant vs. control). Restoration of insulin-mediated glucose utilization was entirely caused by normalization of non-oxidative glucose disposal; 4) was associated with a considerably more pronounced stimulation by insulin of the fractional glycogen synthase in muscle compared with pre-octreotide results (increment above baseline pre: 0.035 +/- 0.010 vs. post: 0.060 +/- 0.023 nmol/min/mg protein; P < .04). Fractional glycogen activity significantly correlated with non-oxidative glucose disposal during insulin infusion (r = .69; P < .03). Prolonged reduction of hyperinsulinemia for 96 hours in cirrhotic patients normalizes insulin-mediated glucose uptake and glycogen synthesis in muscle. We conclude that chronic hyperinsulinemia causes insulin resistance in cirrhosis.
 ...
PMID:Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity. 965 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>