Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Diabetes associated with pancreatic cancer is characterized by profound peripheral insulin resistance. The intracellular mechanism of insulin resistance was investigated in skeletal muscles from N-nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters. Effects of high-fat diet and exercise also were studied. BOP (20 mg/kg body weight) was administrated weekly for 2 weeks. Hyperinsulinemia was found in BOP-treated hamsters at 20 weeks after BOP treatment, suggesting the peripheral insulin resistance is an early feature in pancreatic cancer. Hamsters were killed at 42 weeks, and soleus muscles were taken for the analysis. Skeletal muscle insulin-receptor binding and insulin receptor tyrosine kinase activities were similar between the control and BOP-treated hamsters. However, maximal muscle glycogen synthase activity was significantly reduced in BOP-treated hamsters compared with the control group. Muscle glycogen phosphorylase activity was increased in the BOP-treated group fed with high-fat diet as well as in BOP-treated groups with exercise. These findings indicate that insulin resistance in the hamster pancreatic cancer model is caused by a postreceptor defect, which led to significant decrease of muscle glycogen synthase activity. Whereas a high-fat diet causes more severe insulin resistance in BOP-treated hamsters, high-fat diet and exercising had no significant effects on skeletal muscle insulin-receptor function and glycogen synthase activity. Furthermore, both high-fat diet and exercise enhanced glycogen phosphorylase activity in BOP-treated hamsters.
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PMID:The intracellular mechanism of insulin resistance in the hamster pancreatic ductal adenocarcinoma model. 982 Nov 77

Glucose analogue inhibitors of glycogen phosphorylase, GP, may be of clinical interest in the regulation of glycogen metabolism in diabetes. The receptor geometry of glycogen phosphorylase b, GPb, is available for structure-based design and also for the evaluation of the thermodynamics of ligand-receptor binding. Free energy force field (FEFF) 3D-QSAR analysis was used to construct ligand-receptor binding models. FEFF terms involved in binding are represented by a modified first-generation AMBER force field combined with a hydration shell solvation model. The FEFF terms are then treated as independent variables in the development of 3D-QSAR models by correlating these energy terms with experimental binding energies for a training set of inhibitors. The genetic function approximation, employing both multiple linear regression and partial least squares regression data fitting, was used to develop the FEFF 3D-QSAR models for the binding process and to scale the free energy force field for this particular ligand-receptor system. The significant FEFF energy terms in the resulting 3D-QSAR models include the intramolecular vacuum energy of the unbound ligand, the intermolecular ligand-receptor van der Waals interaction energy, and the van der Waals energy of the bound ligand. Other terms, such as the change in the stretching energy of the receptor on binding, change in the solvation energy of the system on binding, and the change in the solvation energy of the ligand on binding are also found in the set of significant FEFF 3D-QSAR models. Overall, the binding of this class of ligands to GPb is largely characterized by how well the ligand can sterically fit into the active site of the enzyme. The FEFF 3D-QSAR models can be used to estimate the binding free energy of any new analogue in substituted glucose series prior to synthesis and testing.
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PMID:Prediction of ligand-receptor binding thermodynamics by free energy force field three-dimensional quantitative structure-activity relationship analysis: applications to a set of glucose analogue inhibitors of glycogen phosphorylase. 1037 22

The effect of the potential antidiabetic drug (-)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarbox ylate (W1807) on the catalytic and structural properties of glycogen phosphorylase a has been studied. Glycogen phosphorylase (GP) is an allosteric enzyme whose activity is primarily controlled by reversible phosphorylation of Ser14 of the dephosphorylated enzyme (GPb, less active, predominantly T-state) to form the phosphorylated enzyme (GPa, more active, predominantly R-state). Upon conversion of GPb to GPa, the N-terminal tail (residues 5-22), which carries the Ser14(P), changes its conformation into a distorted 3(10) helix and its contacts from intrasubunit to intersubunit. This alteration causes a series of tertiary and quaternary conformational changes that lead to activation of the enzyme through opening access to the catalytic site. As part of a screening process to identify compounds that might contribute to the regulation of glycogen metabolism in the noninsulin dependent diabetes diseased state, W1807 has been found as the most potent inhibitor of GPb (Ki = 1.6 nM) that binds at the allosteric site of T-state GPb and produces further conformational changes, characteristic of a T'-like state. Kinetics show W1807 is a potent competitive inhibitor of GPa (-AMP) (Ki = 10.8 nM) and of GPa (+1 mM AMP) (Ki = 19.4 microM) with respect to glucose 1-phosphate and acts in synergism with glucose. To elucidate the structural features that contribute to the binding, the structures of GPa in the T-state conformation in complex with glucose and in complex with both glucose and W1807 have been determined at 100 K to 2.0 A and 2.1 A resolution, and refined to crystallographic R-values of 0.179 (R(free) = 0.230) and 0.189 (R(free) = 0.263), respectively. W1807 binds tightly at the allosteric site and induces substantial conformational changes both in the vicinity of the allosteric site and the subunit interface. A disordering of the N-terminal tail occurs, while the loop of chain containing residues 192-196 and residues 43'-49' shift to accommodate the ligand. Structural comparisons show that the T-state GPa-glucose-W1807 structure is overall more similar to the T-state GPb-W1807 complex structure than to the GPa-glucose complex structure, indicating that W1807 is able to transform GPa to the T'-like state already observed with GPb. The structures provide a rational for the potency of the inhibitor and explain GPa allosteric inhibition of activity upon W1807 binding.
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PMID:Allosteric inhibition of glycogen phosphorylase a by the potential antidiabetic drug 3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarbo xylate. 1054 38

The diabetes that frequently occurs in pancreatic cancer patients is characterized by profound peripheral insulin resistance. The intracellular mechanism of this insulin resistance was investigated in skeletal muscle biopsies from pancreatic cancer patients with or without diabetes and control subjects. Insulin receptor (IR) binding, tyrosine kinase activity, IR messenger RNA (mRNA), IR substrate-1 content, GLUT-4, and GLUT-4 mRNA content were all normal in pancreatic cancer patients. In contrast, multiple defects in glycogen synthesis were found in pancreatic cancer patients, especially in those with diabetes. Glycogen synthase I activity, total activity, and mRNA levels were significantly decreased in pancreatic cancer patients compared with controls. The fractional velocity of glycogen synthase was decreased only in the diabetic pancreatic cancer group. Glycogen phosphorylase a and b activities were increased in diabetic pancreatic cancer patients, but glycogen phosphorylase mRNA levels were not significantly different. The insulin resistance associated with pancreatic cancer is associated with a post-IR defect, which impairs skeletal muscle glycogen synthesis and glycogen storage.
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PMID:The intracellular mechanism of insulin resistance in pancreatic cancer patients. 1072 68

Calorie restriction (CR) has previously been shown to unexpectedly induce a reversal of in vivo insulin action (phosphorylation instead of dephosphorylation) on skeletal muscle glycogen synthase (GS) in four out of six long-term calorie-restricted (CR) monkeys. The purpose of the present study was to determine whether this increase in Ka (concentration of glucose 6-phosphate [G6P] at which GS activity is half-maximal) during insulin is also present in very lean (VL) young adult monkeys maintained on a controlled feeding regimen. Muscle samples from 10 VL monkeys (10 +/- 2% body fat; 7 years old) were obtained before and during a euglycemic hyperinsulinemic clamp and the Ka was determined and compared to the Ka of two other groups of monkeys, one matched in age but fully ad libitum (AL)-fed (n = 9.8 +/- 1 years old, 20 +/- 3% body fat, p = 0.01 vs. VL monkeys), and the other our previously described weight-clamped long-term CR monkeys (n = 6.20 +/- 1 years old, 21 +/- 2% body fat, p = 0.01 vs. VL monkeys). All of the AL monkeys had the expected decrease in Ka with insulin; however, similar to the 4 out of 6 CR monkeys, 7 out of 10 VL monkeys had an increase in Ka with insulin. The 11 monkeys with an increase in Ka (+Ka) (7 VL + 4 CR) were compared to the 14 monkeys with a decrease in Ka with insulin (-Ka) (3 VL + 2 CR + 9 AL). The +Ka monkeys had lower basal Ka (p = 0.0001), higher basal GS fractional activity (p = 0.0003), lower basal G6P content (p = 0.002), lower glycogen phosphorylase fractional activity (p = 0.01), and lower whole-body insulin-mediated glucose disposal rate (p < 0.05) than the -Ka monkeys. We conclude that the condition of steady-state restrained calorie intake (as in the CR monkeys and in the controlled feeding VL monkeys) produces the paradoxical action of in vivo insulin to phosphorylate muscle GS, and raises the possibility that the presence of the unusual response to insulin may serve as a marker in calorie-restrained individuals for the genotype of obesity, insulin resistance and/or Type 2 diabetes.
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PMID:Paradoxical phosphorylation of skeletal muscle glycogen synthase by in vivo insulin in very lean young adult rhesus monkeys. 1084 66

Glycogen-targeting subunits of protein phosphatase-1 facilitate interaction of the phosphatase with enzymes of glycogen metabolism. We have shown that overexpression of one member of the family, protein targeting to glycogen (PTG), causes large increases in glycogen storage in isolated hepatocytes or intact rat liver. In the current study, we have compared the metabolic and regulatory properties of PTG (expressed in many tissues), with two other members of the gene family, G(L) (expressed primarily in liver) and G(M)/R(Gl) (expressed primarily in striated muscle). Adenovirus-mediated expression of these proteins in hepatocytes led to the following key observations. 1) G(L) has the highest glycogenic potency among the three forms studied. 2) Glycogen synthase activity ratio is much higher in G(L)-overexpressing cells than in PTG or G(M)/R(Gl)-overexpressing cells. Thus, at moderate levels of G(L) overexpression, glycogen synthase activity is increased by insulin treatment, but at higher levels of G(L) expression, insulin is no longer required to achieve maximal synthase activity. In contrast, cells with high levels of PTG overexpression retain dose-dependent regulation of glycogen synthesis and glycogen synthase enzyme activity by insulin. 3) G(L)- and G(M)/R(Gl)-overexpressing cells exhibit a strong glycogenolytic response to forskolin, whereas PTG-overexpressing cells are less responsive. This difference may be explained in part by a lesser forskolin-induced increase in glycogen phosphorylase activity in PTG-overexpressing cells. Based on these results, we suggest that expression of either G(L) or G(M)/R(Gl) in liver of diabetic animals may represent a strategy for lowering of blood glucose levels in diabetes.
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PMID:Distinctive regulatory and metabolic properties of glycogen-targeting subunits of protein phosphatase-1 (PTG, GL, GM/RGl) expressed in hepatocytes. 1086 64

The effects of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) were investigated on preparations of glycogen phosphorylase (GP) and in C57BL6J (ob/ob) mice by (13)C NMR in vivo. Independent of the phosphorylation state or the mammalian species or tissue from which GP was derived, DAB inhibited GP with K(i)-values of approximately 400 nM. The mode of inhibition was uncompetitive or noncompetitive, with respect to glycogen and P(i), respectively. The effects of glucose and caffeine on the inhibitory effect of DAB were investigated. Taken together, these data suggest that DAB defines a novel mechanism of action. Intraperitoneal treatment with DAB (a total of 105 mg/kg in seven doses) for 210 min inhibited glucagon-stimulated glycogenolysis in obese and lean mice. Thus, liver glycogen levels were 361 +/- 19 and 228 +/- 19 micromol glucosyl units/g with DAB plus glucagon in lean and obese mice, respectively, compared to 115 +/- 24 and 37 +/- 8 micromol glucosyl units/g liver with glucagon only. Moreover, with glucagon only end-point blood glucose levels were at 29 +/- 2 and 17.5 +/- 2 mM in obese and lean mice, respectively, compared to 17.5 +/- 1 and 12 +/- 1 mM with glucagon plus DAB. In conclusion, DAB is a novel and potent inhibitor of GP with an apparently distinct mechanism of action. Further, DAB inhibited the hepatic glycogen breakdown in vivo and displayed an accompanying anti-hyperglycemic effect, which was most pronounced in obese mice. The data suggest that inhibition of GP may offer a therapeutic principle in Type 2 diabetes.
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PMID:Kinetic and functional characterization of 1,4-dideoxy-1, 4-imino-d-arabinitol: a potent inhibitor of glycogen phosphorylase with anti-hyperglyceamic effect in ob/ob mice. 1093 82

There is growing evidence that glycogen targeting subunits of protein phosphatase-1 play a critical role in regulation of glycogen metabolism. In the current study, we have investigated the effects of adenovirus-mediated overexpression of a specific glycogen targeting subunit known as protein targeting to glycogen (PTG) in cultured human muscle cells. PTG was overexpressed both in muscle cells cultured at high glucose (glycogen replete) or in cells incubated for 18 h in the absence of glucose and then incubated in high glucose (glycogen re-synthesizing). In both glycogen replete and glycogen resynthesizing cells, PTG overexpression caused glycogen to be synthesized at a linear rate 1-5 days after viral treatment, while in cells treated with a virus lacking a cDNA insert (control virus), glycogen content reached a plateau at day 1 with no further increase. In the glycogen replete PTG overexpressing cells, glycogen content was 20 times that in controls at day 5. Furthermore, in cells undergoing glycogen resynthesis, PTG overexpression caused a doubling of the initial rate of glycogen synthesis over the first 24 h relative to cells treated with control virus. In both sets of experiments, the effects of PTG on glycogen synthesis were correlated with a 2-3-fold increase in glycogen synthase activity state, with no changes in glycogen phosphorylase activity. The alterations in glycogen synthase activity were not accompanied by changes in the intracellular concentration of glucose 6-phosphate. We conclude that PTG overexpression activates glycogen synthesis in a glucose 6-phosphate-independent manner in human muscle cells while overriding glycogen-mediated inhibition. Our findings suggest that modulation of PTG expression in muscle may be a mechanism for enhancing muscle glucose disposal and improving glucose tolerance in diabetes.
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PMID:Overexpression of protein targeting to glycogen in cultured human muscle cells stimulates glycogen synthesis independent of glycogen and glucose 6-phosphate levels. 1099 19

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.
Diabetes 2000 Dec
PMID:Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1. 1111 96

Tungstate was orally administered to 7.5-week-old male Zucker diabetic fatty (ZDF) rats that already showed moderate hyperglycemia (180 +/- 16 mg/dl). The animals became normoglycemic for approximately 10 days. Then, glycemia started to rise again, although it did not reach the initial values until day 24, when levels stabilized at approximately 200 mg/dl for the duration of the experiment. Untreated ZDF rats showed steadily increased blood glucose levels between 7.5 and 10 weeks of age, when they reached a maximum value of 450 +/- 19 mg/dl, which was maintained throughout the experiment. In addition, tolerance to intraperitoneal glucose load improved in treated diabetic rats. Serum levels of triglycerides were elevated in untreated diabetic rats compared with their lean counterparts (ZLC). In the liver of diabetic animals, glucokinase (GK), glycogen phosphorylase a (GPa), liver-pyruvate kinase (L-PK), and fatty acid synthase (FAS) activities decreased by 81, 30, 54, and 35%, respectively, whereas phosphoenolpyruvate carboxykinase (PEPCK) levels increased by 240%. Intracellular glucose-6-phosphate (G6P) decreased by 40%, whereas glycogen levels remained unaffected. Tungstate treatment of these rats induced a 42% decrease in serum levels of triglycerides and normalized hepatic G6P concentrations, GPa activity, and PEPCK levels. GK activity in treated diabetic rats increased to 50% of the values of untreated ZLC rats. L-PK and FAS activity increased to higher values than those in untreated lean rats (1.7-fold L-PK and 2.4-fold FAS). Hepatic glycogen levels were 55% higher than those in untreated diabetic and healthy rats. Tungstate treatment did not significantly change the phosphotyrosine protein profile of primary cultured hepatocytes from diabetic animals. These data suggest that tungstate administration to ZDF rats causes a considerable reduction of glycemia, mainly through a partial restoration of hepatic glucose metabolism and a decrease in lipotoxicity.
Diabetes 2001 Jan
PMID:Effects of tungstate, a new potential oral antidiabetic agent, in Zucker diabetic fatty rats. 1114 78


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