UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
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The Koletsky (SHROB) strain of rats is spontaneously hypertensive and displays insulin resistance, hyperglucagonemia and hypertriglyceridemia but is normoglycemic under fasting conditions. The aim of this study was to unravel the pattern of expression of genes encoding key regulatory enzymes involved in carbohydrate metabolism in the liver and kidney that may be impacted in this strain. We found that SHROB animals have decreased beta-adrenergic receptor density and, consequently, blunted increases in cAMP levels in response to beta-adrenergic agonists. They also have lower levels of hepatic as well as renal phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) mRNA and protein than their lean littermates. Expression of the genes for glycogen phosphorylase and glycogen synthase was also decreased. Hepatocytes from the SHROB animals exhibited glycogen depletion of only 50% compared to 86% by hepatocytes from lean littermates when challenged with either glucagon or forskolin to stimulate adenylyl cyclase. The expression of C/EBPalpha and C/EBPbeta, two key transcription factors that are essential for the coordinated expression of genes involved in glucose homeostasis, was depressed in livers of the SHROB rats, as were levels of HNF-4alpha, PPARalpha and PGC-1alpha. We conclude that overproduction of glucose is prevented in the SHROB rats by decreased expression of the genes for glycogen phosphorylase and the gluconeogenic enzymes PEPCK and G6Pase, which may prevent progression to diabetes in this model.
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PMID:Metabolic dysregulation in the SHROB rat reflects abnormal expression of transcription factors and enzymes that regulate carbohydrate metabolism. 1768 27

Interest in the kinetics of glycogen phosphorylase has recently been renewed by the hypothesis of a glycogen shunt and by the potential of altering phosphorylase to treat type II diabetes. The wealth of data from studies of this enzyme in vitro and the need for a mathematical representation for use in the study of metabolic control systems make this enzyme an ideal subject for a mathematical model. We applied a two-part approach to the analysis of the kinetics of glycogen phosphorylase b (GPb). First, a continuous state model of enzyme-ligand interactions supported the view that two phosphates and four ATP or AMP molecules can bind to the enzyme, a result that agrees with spectroscopic and crystallographic studies. Second, using minimum error estimates from continuous state model fits to published data (that agreed well with reported error), we used a discrete state model of internal molecular events to show that GPb exists in three discrete states (two of which are inactive) and that state transitions are concerted. The results also show that under certain concentrations of substrate and effector, ATP can activate the enzyme, while under other conditions, it can competetively inhibit or noncompetitively inhibit the enzyme. This result is unexpected but is consistent with spectroscopic, crystallographic, and kinetic experiments and can explain several previously unexplained phenomena regarding GPb activity in vivo and in vitro.
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PMID:Enzyme kinetics of muscle glycogen phosphorylase b. 1791 Apr 19

Type 2 diabetes is an endocrine/metabolic disease characterized by hyperglycemia. It is now well established that insulin resistance and pancreatic beta-cell dysfunction/failure are the two major components of the physiopathology of the disease. Current available therapies do not successfully enable patients with type 2 diabetes to reach glycemic goals. Even with intensive treatment type 2 diabetic patients may face spikes in blood glucose after meals, weight gain, and a loss of effectiveness of their treatments over time. The novel agents recently developed by the Pharmaceutical Industry may either provide an alternative therapeutic strategy or offer useful adjuncts to existing therapies. Glucagon-like peptide 1 (GLP-1), produced in the small intestine and amylin, produced by beta cells in the pancreas, also have glucose lowering effects. Amylin is an hormone secreted after a meal, having a complementary action to insulin. GLP-1, also released in a post-prandial manner, promotes insulin production and secretion, reduces glucagon secretion, delays gastric emptying and induces a feeling of fullness. The most promising effect of GLP-1 is its ability to increase beta-cell mass by stimulating neogenesis and reducing apoptosis in rodents. However the fact that GLP-1 is rapidly degraded by dipeptidylpeptidase IV (DPPIV) in vivo reduces its usefulness. Thus, in order to improve therapeutic efficacy, two approaches have been investigated: the development of GLP-1 analogs resistant to degradation or the development of DPP-IV inhibitors. Synthetic analogs of amylin (pramlintide), GLP-1 (exenatide) and inhibitors of the degradation of GLP-1 (sitagliptin, DPP-IV inhibitor) are now available for clinical use. Promising biological targets being investigated include those leading to insulin sensitization (11beta-HSD-1 inhibitors and antagonists of glucocorticoids receptor), reducing hepatic glucose output (antagonist of glucagon receptor, inhibitors of glycogen phosphorylase and fructose-1,6-biphosphatase) and finally increasing urinary elimination of excess glucose (SGLT inhibitors). A particular role is played by glucokinase activators (GKA) which can both increase insulin secretion and improve hepatic glucose metabolism. In this review, we present a summary of the data available on newly approved treatments (amylin and GLP-1 analogs as well as DPP-IV inhibitors) and give an overview of the targets currently being studied for the treatment of type 2 diabetes with an emphasis on the small molecule drug design.
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PMID:Newly approved and promising antidiabetic agents. 1798 55

Type-2 diabetes is associated with impaired glucose clearance by the liver in the postprandial state, and with elevated glucose production in the post-absorptive state. New targets within the liver are currently being investigated for development of antihyperglycaemic drugs for type-2 diabetes. They include glucokinase, which catalyses the first step in glucose metabolism, the glucagon receptor, and enzymes of gluconeogenesis and/or glycogenolysis such as glucose 6-phosphatase, fructose 1,6-bisphosphatase and glycogen phosphorylase. Preclinical studies with candidate drugs on animal models or cell-based assays suggest that these targets have the potential for pharmacological glycaemic control. Data from clinical studies is awaited. Further work is required for better understanding of the implications of targeting these sites in terms of possible side-effects or tachyphylaxis. The advantage of combined targeting of two or more sites within the liver for minimizing side-effects and tachyphylaxis caused by single-site targeting is discussed.
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PMID:New hepatic targets for glycaemic control in diabetes. 1805 37

In Type 2 diabetes, increased glycogenolysis contributes to the hyperglycaemic state, therefore the inhibition of GP (glycogen phosphorylase), a key glycogenolytic enzyme, is one of the possibilities to lower plasma glucose levels. Following this strategy, a number of GPis (GP inhibitors) have been described. However, certain critical issues are associated with their mode of action, e.g. an impairment of muscle function. The interaction between GP and the liver glycogen targeting subunit (termed G(L)) of PP1 (protein phosphatase 1) has emerged as a new potential anti-diabetic target, as the disruption of this interaction should increase glycogen synthesis, potentially providing an alternative approach to counteract the enhanced glycogenolysis without inhibiting GP activity. We identified an inhibitor of the G(L)-GP interaction (termed G(L)-GPi) and characterized its mechanism of action in comparison with direct GPis. In primary rat hepatocytes, at elevated glucose levels, the G(L)-GPi increased glycogen synthesis similarly to direct GPis. Direct GPis significantly reduced the cellular GP activity, caused a dephosphorylation of the enzyme and decreased the amounts of GP in the glycogen-enriched fraction; the G(L)-GPi did not influence any of these parameters. Both mechanisms increased glycogen accumulation at elevated glucose levels. However, at low glucose levels, only direct GPis led to increased glycogen amounts, whereas the G(L)-GPi allowed the mobilization of glycogen because it did not block the activity of GP. Due to this characteristic, G(L)-GPi in comparison with GPis could offer an advantageous risk/benefit profile circumventing the potential downsides of a complete prevention of glycogen breakdown while retaining glucose-lowering efficacy, suggesting that inhibition of the G(L)-GP interaction may provide an attractive novel approach for rebalancing the disturbed glycogen metabolism in diabetic patients.
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PMID:Inhibition of the interaction between protein phosphatase 1 glycogen-targeting subunit and glycogen phosphorylase increases glycogen synthesis in primary rat hepatocytes. 1829 2

Flavonoids are ubiquitous components in vegetables, fruits, tea, and wine. Therefore, they are often consumed in large quantities in our daily diet. Several flavonoids have been shown to have potential as antidiabetic agents. In the present study, we focused on inhibition of glycogen phosphorylase (GP) by flavonoids. 6-Hydroxyluteolin, hypolaetin, and quercetagetin were identified as good inhibitors of dephosphorylated GP (GPb), with IC 50 values of 11.6, 15.7, and 9.7 microM, respectively. Furthermore, a structure-activity relationship study revealed that the presence of the 3' and 4' OH groups in the B-ring and double bonds between C2 and C3 in flavones and flavonols are important factors for enzyme recognition and binding. Quercetagetin inhibited GPb in a noncompetitive manner, with a K i value of 3.5 microM. Multiple inhibition studies by Dixon plots suggested that quercetagetin binds to the allosteric site. In primary cultured rat hepatocytes, quercetagetin and quercetin suppressed glucagon-stimulated glycogenolysis, with IC 50 values of 66.2 and 68.7 microM, respectively. These results suggested that as a group of novel GP inhibitors, flavonoids have potential to contribute to the protection or improvement of control of diabetes type II.
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PMID:Structure-activity relationships of flavonoids as potential inhibitors of glycogen phosphorylase. 1849 82

Conversion of glucose into glycogen is a major pathway that contributes to the removal of glucose from the portal vein by the liver in the postprandial state. It is regulated in part by the increase in blood-glucose concentration in the portal vein, which activates glucokinase, the first enzyme in the pathway, causing an increase in the concentration of glucose 6-P (glucose 6-phosphate), which modulates the phosphorylation state of downstream enzymes by acting synergistically with other allosteric effectors. Glucokinase is regulated by a hierarchy of transcriptional and post-transcriptional mechanisms that are only partially understood. In the fasted state, glucokinase is in part sequestered in the nucleus in an inactive state, complexed to a specific regulatory protein, GKRP (glucokinase regulatory protein). This reserve pool is rapidly mobilized to the cytoplasm in the postprandial state in response to an elevated concentration of glucose. The translocation of glucokinase between the nucleus and cytoplasm is modulated by various metabolic and hormonal conditions. The elevated glucose 6-P concentration, consequent to glucokinase activation, has a synergistic effect with glucose in promoting dephosphorylation (inactivation) of glycogen phosphorylase and inducing dephosphorylation (activation) of glycogen synthase. The latter involves both a direct ligand-induced conformational change and depletion of the phosphorylated form of glycogen phosphorylase, which is a potent allosteric inhibitor of glycogen synthase phosphatase activity associated with the glycogen-targeting protein, GL [hepatic glycogen-targeting subunit of PP-1 (protein phosphatase-1) encoded by PPP1R3B]. Defects in both the activation of glucokinase and in the dephosphorylation of glycogen phosphorylase are potential contributing factors to the dysregulation of hepatic glucose metabolism in Type 2 diabetes.
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PMID:Glucokinase and molecular aspects of liver glycogen metabolism. 1865 36

The Spontaneously Diabetic Torii (SDT) rat has recently been established as a new model of non-obese type 2 diabetes. In this study, we examined changes in hepatic glucose metabolism in prediabetic and diabetic SDT rats compared with age-matched control rats. The prediabetic state was confirmed at 16 weeks of age, and the diabetic state was confirmed at 24 and 32 weeks of age. Decreases in glucokinase mRNA levels and activity were observed in the prediabetic state. In this state, glycogen synthase activity and glycogen content were also decreased in the SDT rat. In addition to the above changes, glycogen phosphorylase mRNA and activity were decreased and gluconeogenetic enzyme mRNA levels were significantly increased in the diabetic state. These results indicate there is a great potential that abnormalities in hepatic glucose metabolism play a role in the progression to onset of diabetes. We suggest that the SDT rat is a valuable diabetic model for investigations into mechanisms or causes of progression to diabetes.
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PMID:Characterization of hepatic glucose metabolism disorder with the progress of diabetes in male Spontaneously Diabetic Torii rats. 1905 44

Resveratrol, a ubiquitous stress-induced phytoalexin, has demonstrated a wide variety of biological activities which make it a good candidate for the treatment of diabetes mellitus. The present study was aimed to evaluate its therapeutic potential by assaying the activities of key enzymes of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats. The daily oral treatment of resveratrol (5 mg/kg body weight) to diabetic rats for 30 days demonstrated a significant (p<0.05) decline in blood glucose and glycosylated hemoglobin levels and a significant (p<0.05) increase in plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver and kidney tissues of diabetic rats were significantly (p<0.05) reverted to near normal levels by the administration of resveratrol. Further, resveratrol administration to diabetic rats improved hepatic glycogen content suggesting the antihyperglycemic potential of resveratrol in diabetic rats. The obtained results were compared with glyclazide, a standard oral hypoglycemic drug. Thus, the modulatory effects of resveratrol on attenuating these enzymes activities afford a promise for widespread use for treatment of diabetes in the future.
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PMID:Modulatory effects of resveratrol on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats. 1905 88

Type 2 diabetes is characterised by elevated blood glucose concentrations, which potentially could be normalised by stimulation of hepatic glycogen synthesis. Under glycogenolytic conditions, the interaction of hepatic glycogen-associated protein phosphatase-1 (PP1-G(L)) with glycogen phosphorylase a is believed to inhibit the dephosphorylation and activation of glycogen synthase (GS) by the PP1-G(L) complex, suppressing glycogen synthesis. Consequently, the interaction of G(L) with phosphorylase a has emerged as an attractive anti-diabetic target, pharmacological disruption of which could provide a novel mechanism to lower blood glucose levels by increasing hepatic glycogen synthesis. Here we report for the first time the in vivo consequences of disrupting the G(L)-phosphorylase a interaction, using a mouse model containing a Tyr284Phe substitution in the phosphorylase a-binding region of the G(L) protein. The resulting G(L)(Y284F/Y284F) mice display hepatic PP1-G(L) activity that is no longer sensitive to allosteric inhibition by phosphorylase a, resulting in increased GS activity under glycogenolytic conditions, demonstrating that regulation of G(L) by phosphorylase a operates in vivo. G(L)(Y284F/Y284F) and G(L)(Y284F/+) mice display improved glucose tolerance compared with G(L)(+/+) littermates, without significant accumulation of hepatic glycogen. The data provide the first in vivo evidence in support of targeting the G(L)-phosphorylase a interaction for treatment of hyperglycaemia. During prolonged fasting the G(L)(Y284F/Y284F) mice lose more body weight and display decreased blood glucose levels in comparison with their G(L)(+/+) littermates. These results suggest that, during periods of food deprivation, the phosphorylase a regulation of G(L) may prevent futile glucose-glycogen cycling, preserving energy and thus providing a selective biological advantage that may explain the observed conservation of the allosteric regulation of PP1-G(L) by phosphorylase a in mammals.
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PMID:Disruption of the allosteric phosphorylase a regulation of the hepatic glycogen-targeted protein phosphatase 1 improves glucose tolerance in vivo. 1927 33

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