Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the first two thirds of gestation, the concentrations of UDPG, ATP, ADP, and Mg++ in human fetal liver remain constant, whereas the concentration of Pi decreases twofold and the G-6-P and AMP concentrations increase. Incubation of human fetal liver explants with glucagon or insulin did not alter the concentrations of any of these intermediates. ATP, ADP, and Pi are inhibitors of human fetal liver glycogen synthase D-form activity, while G-6-P and AMP and Mg++ are stimulators. Ca++ at concentrations of less than 0.1 mM was found to stimulate glycogen synthase D activity. This effect of Ca++ was also observed in "physiologic" mixtures containing UDPG, G-6-P, ATP, ADP, AMP, Pi, and Mg++ at concentrations found either in liver in utero or in explants. 45Ca++ efflux from perifused (rat) fetal liver explants was stimulated by glucagon. These data provide a picture of the metabolite regulation of human fetal liver glycogen synthase activity in which the D-form may largely control glycogen synthesis in utero and hormonal effects on glycogen synthase may be induced by effects of Ca++ on the D-form.
Diabetes 1975 Dec
PMID:Hormonal regulation of glycogen metabolism in human fetal liver. II. Regulation of glycogen synthase activity. 81 98

Kinetic studies were carried out on liver glycogen synthase and phosphorylase isolated from genetically diabetic db/db mice. Glycogen synthase a and b enzymes from diabetic mice had Vmax values 30% and 20% lower, respectively, than the enzymes from normal mice. Glycogen synthase b from diabetic mice also had a 30% lower I0.5 for Pi and ATP at physiologic concentrations of UDP-glucose (0.25 mM) compared with the normal enzyme. Kinetic studies of phosphorylase a showed that, at low glycogen concentrations (0.25 mg/ml), the Vmax of the diabetic enzyme was twofold greater than that of the normal enzyme. This was probably related to the diabetic phosphorylase a having a lower apparent Km for glycogen. This enzyme also had a slightly higher I0.5 for ATP compared with the enzyme from normal mice. Structural studies of liver glycogen isolated from these diabetic mice showed differences from normal mouse glycogen. Both the alpha- and beta-amylase limits were lower in the diabetic glycogen, and the average chain lengths, exterior chain lengths, and interior chain lengths calculated from these limits were all shorter in the glycogen from diabetic mice. Although both normal and diabetic glycogen absorbed light maximally at 430 nm when complexed with iodine, the absolute absorbance value was significantly lower for the diabetic glycogen. These data suggest an altered branching pattern of liver glycogen from the diabetic mice and it is suggested that this altered structure may ultimately influence the activities of glycogen-metabolizing enzymes. These results provide further characterization of the db/db mouse and show heretofore undescribed changes in phosphorylase a kinetics and glycogen structure that occur in diabetes.
Diabetes 1986 Feb
PMID:Kinetic properties of glycogen synthase and phosphorylase and structural aspects of glycogen in the db/db mouse liver. 308 Mar 50

Severely diabetic (0.15 g/kg streptozocin) rats were transplanted with fetal pancreatic islets under the renal capsule to model peripheral insulin delivery, or into the splenic pulp to model portal delivery. In both groups of transplanted rats, weight gain and blood glucose concentrations were normal. Peripheral insulin delivery abolished the physiologic portal-peripheral insulin concentration gradient but was not associated with peripheral hyperinsulinemia. Incorporation of 3H2O into liver glycogen and the increase in hepatic glycogen concentration after a meal were normal in animals receiving insulin peripherally for 10 wk. Activation of liver glycogen synthase in response to the meal was also normal. Hepatic insulin receptor status in animals with peripheral insulin delivery was identical to that of normal control and splenic pulp islet-transplanted rats. The findings indicate that portal insulin delivery is not a prerequisite for normal hepatic glycogen metabolism in the rat, and that receptor upregulation and increased hepatic extraction of insulin are unlikely to explain the normal hepatic metabolism with peripheral insulin delivery.
Diabetes 1986 Mar
PMID:Hepatic glycogen metabolism and insulin receptor status after long-term peripheral insulin delivery in the islet-transplanted diabetic rat. 308 94

The regulation of liver and skeletal muscle glycogen synthase by plasma insulin and glucose has not been investigated in vivo at physiological blood glucose concentrations. We have, therefore, used the glucose clamp technique to investigate the effects of these variables independently in rats. Short-term streptozocin-(0.15 g/kg) diabetic animals were used in addition to normal rats to avoid endogenous insulin secretion during hyperglycemic clamps. In normal and diabetic animals, 3 h of hyperinsulinemia without change in blood glucose concentrations caused only a small increase in liver glycogen synthase activity (+34%), whereas hyperglycemic clamps at 6.0 and 10.0 mmol/L resulted in marked increases (+268 and +394% of basal, P less than 0.001). Liver glycogen concentrations at the end of the clamps reflected these changes. In skeletal muscle, glycogen synthase was increased by +58% by the euglycemic hyperinsulinemic clamp and was not increased significantly further by hyperglycemia. Similarly, muscle glycogen concentration increased with the 4.0-mmol/L clamp but during the hyperglycemic clamps was only raised more in direct proportion to blood glucose concentrations. The results confirm that blood glucose concentration is the major short-term regulator of glycogen synthase activity in the liver but that insulin is of prime importance in skeletal muscle.
Diabetes 1986 Jun
PMID:In vivo regulation of liver and skeletal muscle glycogen synthase activity by glucose and insulin. 308 63

The effects of epinephrine, vasopressin, and A23187 on glycogen synthase and phosphorylase were examined in isolated rat liver parenchymal cells from fed animals. In normal calcium-containing hepatocytes, epinephrine, vasopressin, and A23187 were more potent at inactivating glycogen synthase, previously activated with 30 mM glucose, than at activating phosphorylase. In calcium-depleted hepatocytes (cells washed and incubated with 1 mM EGTA), the effect of epinephrine on both enzyme activities was impaired, while the effects of vasopressin and A23187 were completely abolished. Insulin was more effective at inhibiting the effects of epinephrine in calcium-depleted cells, but it was without effect on vasopressin and A23187 actions. The ability of epinephrine, vasopressin, and A23187 to elicit calcium efflux from cells was not altered by the presence of 30 mM glucose. These findings are consistent with the idea that the alpha-adrenergic inactivation of liver glycogen synthase may be a result of the increased stimulation of a calcium-dependent protein kinase, possibly phosphorylase b kinase.
Diabetes 1980 Aug
PMID:The role of calcium in alpha-adrenergic inactivation of glycogen synthase in rat hepatocytes and its inhibition by insulin. 677 24

Rat liver glycogen synthase shows almost a 2-fold increase in activity 8 days after onset of alloxan diabetes. Immunological and catalytic criteria indicate that the change in activity is associated with an increase in the amount of enzyme in the diabetic. Apparent rates of degradation were determined for isolated glycogen synthase and phosphorylase from the livers of 2-, 5-, and 8-day diabetic, insulin-treated diabetic and normal rats using the double isotope ([3H]leucine and [14C]leucine) labeling method (Arias, I. M., Doyle, D., and Schimke, R. T. (1969) J. Biol. Chem. 244, 3303-3315). Relative rates of enzyme synthesis and degradation were determined by comparing the 3H incorporation and 3H/14C ratios of the isolated enzymes to the isotope labeling of a liver fraction representing the average of liver proteins. Glycogen synthase showed a gradual increase in the rate of degradation through the course of diabetes with an average relative rate of degradation in the 8-day diabetic 1.8 times greater than the normal. The relative rate of synthesis for glycogen synthase in the diabetic was 2.2- to 2.5-fold greater than the normal. Phosphorylase from 5- and 8-day diabetic rats had relative rates of degradation 4.0-5.3 times greater than enzyme from the normal. In the diabetic, the rate of degradation of phosphorylase was greater than for synthase while the opposite was observed in the normal rat. The relative rate of synthesis for phosphorylase from diabetic rats was approximately 4.5-fold greater than normal. The increased concentration of glycogen synthase in the diabetic liver is because of an increased rate of synthesis and not a decreased rate of enzyme degradation.
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PMID:Effects of alloxan diabetes on the turnover of rat liver glycogen synthase. Comparison with liver phosphorylase. 680 82

The specific effect of hyperglycemia on the reported decrease in liver glycogen synthase phosphatase activity was studied in STZ-induced diabetic rats with normal fasting insulinemia. Four groups of animals were investigated: control (nondiabetic), diabetic hyperglycemic (STZ), diabetic normoglycemic (STZ followed by 3-day phloridzin treatment), and a diabetic normoglycemic group injected with glucose to reinstate hyperglycemia. None of the treatments significantly altered fasting plasma insulin and glucagon concentrations. We found that hepatic synthase phosphatase activity decreased in STZ-induced diabetic rats and was further markedly reduced when glycemia was normalized in the diabetic animals. This additional decrease in phosphatase activity was almost fully reversed when hyperglycemia was restored by acute glucose infusion of the normoglycemic diabetic rats. In parallel, the levels of liver G6P and F6P were markedly reduced in the diabetic normoglycemic rats and restored with reinstatement of hyperglycemia. In contrast, liver microsomal glucose-6-phosphatase activity was enhanced and glucokinase activity was lowered in all diabetic groups, regardless of glycemia. Our results indicate that hyperglycemia per se counteracts part of the loss of hepatic synthase phosphatase in diabetic animals and provokes the stable conversion of synthase phosphatase from a less active to a more active form.
Diabetes 1993 Feb
PMID:Opposite effects of hyperglycemia and insulin deficiency on liver glycogen synthase phosphatase activity in the diabetic rat. 838 Oct 96

Genetic factors contribute to the development of NIDDM, and genes involved in regulating pancreatic beta-cell function and insulin's effects on glucose metabolism are good candidates for being NIDDM susceptibility loci. However, testing candidate genes for linkage to NIDDM depends on the identification of highly informative DNA polymorphisms in or near the candidate locus. Here we describe an approach for identifying highly polymorphic markers near candidate genes that utilizes the emerging physical map of the human genome. A sequence-tagged site from the candidate gene is used to screen the Centre d'Etude du Polymorphisme Humain megabase-insert yeast artificial chromosome library, which contains information on the physical localization of >3,000 genetically mapped simple sequence repeat DNA polymorphisms. Thus, identification of a yeast artificial chromosome containing the candidate locus will in many instances also identify a physically linked simple sequence repeat DNA polymorphism that can be used as a marker for the candidate gene in linkage studies. We have used this approach to identify a marker for the islet amyloid polypeptide gene on chromosome 12. The physical mapping of this gene to a yeast artificial chromosome showed that it was in the same yeast artificial chromosome as the gene encoding liver glycogen synthase, another possible NIDDM susceptibility gene. Affected sib pair studies using a simple sequence repeat DNA polymorphism physically linked to the islet amyloid polypeptide and liver glycogen synthase genes showed no evidence for linkage with NIDDM, indicating that they are not major genes contributing to NIDDM susceptibility.
Diabetes 1996 Mar
PMID:An approach for identifying simple sequence repeat DNA polymorphisms near cloned cDNAs and genes. Linkage studies of the islet amyloid polypeptide/amylin and liver glycogen synthase genes and NIDDM. 859 32

The liver responds to an increase in blood glucose levels in the postprandial state by uptake of glucose and conversion to glycogen. Liver glycogen synthase (GYS2), a key enzyme in glycogen synthesis, is controlled by a complex interplay between the allosteric activator glucose-6-phosphate (G6P) and reversible phosphorylation through glycogen synthase kinase-3 and the glycogen-associated form of protein phosphatase 1. Here, we initially performed mutagenesis analysis and identified a key residue (Arg(582)) required for activation of GYS2 by G6P. We then used GYS2 Arg(582)Ala knockin (+/R582A) mice in which G6P-mediated GYS2 activation had been profoundly impaired (60-70%), while sparing regulation through reversible phosphorylation. R582A mutant-expressing hepatocytes showed significantly reduced glycogen synthesis with glucose and insulin or glucokinase activator, which resulted in channeling glucose/G6P toward glycolysis and lipid synthesis. GYS2(+/R582A) mice were modestly glucose intolerant and displayed significantly reduced glycogen accumulation with feeding or glucose load in vivo. These data show that G6P-mediated activation of GYS2 plays a key role in controlling glycogen synthesis and hepatic glucose-G6P flux control and thus whole-body glucose homeostasis.
Diabetes 2013 Dec
PMID:Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis. 2399 Mar 65

Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution to the genome-wide DNA methylation variability in twins. Differences in methylation between monozygotic twin pairs discordant for T2D were subsequently modest. However, 15,627 sites, representing 7,046 genes including PPARG, KCNQ1, TCF7L2, and IRS1, showed differential DNA methylation in adipose tissue from unrelated subjects with T2D compared with control subjects. A total of 1,410 of these sites also showed differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified copy number variants (CNVs) in monozygotic twin pairs discordant for T2D. Taken together, subjects with T2D exhibit multiple transcriptional and epigenetic changes in adipose tissue relevant to the development of the disease.
Diabetes 2014 Sep
PMID:Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. 2514 70


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