Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of insulin to increase the activity of glycogen synthase (GS) in muscle has been well documented, however, the effect of in vivo insulin to inactivate glycogen phosphorylase (GP) has not been previously shown. To determine the effects of insulin on glycogenolysis in rhesus monkeys, GP and glycogen were determined in muscle samples obtained under basal fasting and insulin-stimulated conditions during a euglycemic hyperinsulinemic clamp in a group of 27 monkeys ranging from normal to overtly diabetic (NIDDM) and compared to GS activity previously examined. The diabetic monkeys had lower basal and insulin-stimulated glycogen concentrations compared to the normal and hyperinsulinemic monkeys (p < 0.05). The response of GP activity ratio (AR) to insulin (delta) was inversely correlated to delta GS fractional velocity (fv) (r = -0.57, p < 0.002) in all of the monkeys. The AR of GP was inversely correlated to the fv of GS measured under insulin-stimulated conditions (r = -0.60, p < 0.05) in the 11 normal monkeys. In the normal group, the range in response of GS to insulin (delta GSfv) was previously shown to be 3-22%, with n = 6 < 11% ('low normals') and n = 5 > 11% ('high normals'). In the present study, the low normals were shown to have (1) higher delta GP independent activity and delta GP total activity compared to the high normals and hyperinsulinemic monkeys (p less than or equal to 0.05), (2) higher insulin-stimulated GP independent activity and GP total activity compared to the other three groups (p < 0.05), (3) higher insulin-stimulated GP activity ratio compared to the high normals and hyperinsulinemic monkeys (p < 0.05), (4) and lower whole-body insulin-mediated glucose disposal rates compared to the high normals (p < 0.05). We conclude that NIDDM is accompanied by low glycogen content in the muscle, and that some clinically normal monkeys have an alteration in insulin action on muscle GS, GP, and whole-body glucose disposal rates that may precede the development of hyperinsulinemia.
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PMID:Glycogen phosphorylase activity and glycogen concentration in muscle of normal to overtly diabetic rhesus monkeys. 864 58

The regulation of glycogen synthase (GS) and glycogen phosphorylase (GP) activity by phosphorylation/ dephosphorylation has been proposed to be via changes in activities of several different protein (serine/threonine) phosphatases and kinases, including protein phosphatase (PP) 1/2A, PP2C, and cAMP-dependent protein kinase (PKA). In order to determine whether PP1/2A, PP2C, and/or PKA activities are related to GS and/or GP activities, these enzymes were measured in freeze-clamped liver biopsies obtained under basal fasting conditions from 16 obese monkeys. Four monkeys were normoglycemic and normoinsulinemic, five were hyperinsulinemic, and seven had type 2 diabetes (NIDDM). Liver glycogen and glucose 6-phosphate (G6P) contents were also determine. Basal enzyme activities and basal substrate concentrations were not significantly different between the three group of obese monkeys; however, there were several significant linear relationships observed when the monkeys were treated as one group. Therefore, multiple regression was used to determine the correlation between key variables. GS fractional activity was correlated to GP fractional activity (p < 0.05) and to PP2C activity (p = 0.005) (adjusted R2, 53%). GP independent activity was correlated to GS independent activity (p < 0.07) and to PKA fractional activity (p = 0.005) (adjusted R2, 64%). PP2C activity was correlated to GS fractional activity (p < 0.0005) and to PP1/2A activity (p < 0.0001) (adjusted R2, 83%). PKA fractional activity was correlated to GP total activity (p < 0.0005) and to age (p = 0.001) (adjusted R2, 82%). G6P content was correlated to glycogen content (p < 0.05) and to PP2C activity (p = 0.0005) (adjusted R2, 73%). In conclusion, PP2C and PKA are involved in the regulation of GS and GP activity in the basal state in liver of obese monkeys with a wide range of glucose tolerance.
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PMID:Relationship of glycogen synthase and glycogen phosphorylase to protein phosphatase 2C and cAMP-dependent protein kinase in liver of obese rhesus monkeys. 944 47

Type 2 diabetes mellitus is a severe disease with large economic consequences, which is significantly under-diagnosed and incompletely treated in the general population. Control of blood glucose levels is a key objective in treating diabetic patients, who are most often prescribed one or more oral hypoglycaemic agents in addition to diet and exercise modification as well as insulin. In spite of the availability of different classes of hypoglycaemic drugs, treatment regimens are often unable to achieve an intensive degree of glucose control known to most effectively reduce the incidence and severity of diabetic complications. Hepatic glucose output is elevated in type 2 diabetic patients and current evidence indicates that glycogenolysis (release of monomeric glucose from the glycogen polymer storage form) is an important contributor to the abnormally high production of glucose by the liver. Glycogen phosphorylase is the enzyme that catalyses this release and recent advances in new inhibitors of this structurally and kinetically well studied enzyme have enabled work which further delineate the pharmacological and physiological consequences of inhibiting glucose production by this pathway. Most notably, these agents lower glucose in diabetic animal models, both acutely and chronically, appear to affect both gluconeogenic and glycogenolytic pathways and demonstrate potential for a beneficial effect on cardiovascular risk factors. Cumulatively, this information has bolstered interest and promise in glycogen phosphorylase inhibitors (GPIs) as potential new hypoglycaemic agents for treatment of type 2 diabetes mellitus.
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PMID:Glycogen phosphorylase inhibitors for treatment of type 2 diabetes mellitus. 1122 44

Fructose has been shown to have a catalytic effect on glucokinase activity in vitro; however, its effects on hepatic glycogen metabolism in humans is unknown. To address this question, we used (13)C nuclear magnetic resonance (NMR) spectroscopy to noninvasively assess rates of hepatic glycogen synthesis and glycogenolysis under euglycemic (approximately 5 mmol/l) hyperinsulinemic conditions (approximately 400 pmol/l) with and without a low-dose infusion of fructose (approximately 3.5 micromol. kg(-1). min(-1)). Six healthy overnight-fasted subjects were infused for 4 h with somatostatin (0.1 micromol. kg(-1). min(-1)) and insulin (240 pmol. m(-2). min(-1)). During the initial 120 min, [1-(13)C]glucose was infused to assess glycogen synthase flux followed by an approximately 120-min infusion of unlabeled glucose to assess rates of glycogen phosphorylase flux. Acetaminophen was given to assess the percent contribution of the direct and indirect (gluconeogenic) pathways of glycogen synthesis by the (13)C enrichment of plasma UDP-glucuronide and C-1 of glucose. In the control studies, the flux through glycogen synthase and glycogen phosphorylase was 0.31 +/- 0.06 and 0.17 +/- 0.04 mmol/l per min, respectively, and the rate of net hepatic glycogen synthesis was 0.14 +/- 0.05 mmol/l per min. In the fructose studies, the glycogen synthase flux increased 2.5-fold to 0.79 +/- 0.16 mmol/l per min (P = 0.018 vs. control), whereas glycogen phosphorylase flux remained unchanged (0.24 +/- 0.06; P = 0.16 vs. control). The infusion of fructose resulted in a threefold increase in rates of net hepatic glycogen synthesis (0.54 +/- 0.12 mmol/l per min; P = 0.008 vs. control) without affecting the pathways of hepatic glycogen synthesis (direct pathway approximately 60% in both groups). We conclude that during euglycemic hyperinsulinemia, a low-dose fructose infusion causes a threefold increase in net hepatic glycogen synthesis exclusively through stimulation of glycogen synthase flux. Because net hepatic glycogen synthesis has been shown to be diminished in patients with poorly controlled type 1 and type 2 diabetes, stimulation of hepatic glycogen synthesis by this mechanism may be of potential therapeutic value.
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PMID:Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans. 1137 25

A subgroup of patients with type 2 diabetes shows a clustering of abnormalities such as peripheral insulin resistance, hypertension, and microalbuminuria. To evaluate whether these traits reflect intrinsic disorders of cell function rather than in vivo environmental effects, we studied a group of 7 nondiabetic hypertensive subjects with an altered albumin excretion rate (AER) (HyMA+) and 3 groups of patients with type 2 diabetes: 7 with normal blood pressure and normal AER (DH-MA-), 7 with high blood pressure and normal AER (DH+MA-), and 7 with both high blood pressure and altered AER (DH+MA+). Glucose disposal was measured during an hyperinsulinemic clamp (40 mU. m(2)(-1). min(-1)) with primed deuterated [6.6 (2)H(2)] glucose infusion. In the same subjects, a skin biopsy was performed and the following parameters were investigated: glucose transport (as determined by [(3)H]2-deoxyglucose uptake); glycogen synthase activity (as determined by [(14)C] glucose incorporation from UDP-[U-(14)C] glucose into glycogen); glycogen phosphorylase activity (as measured by the incorporation of [U-(14)C]glucose 1-phosphate into glycogen); and total glycogen content. In vivo glucose disposal was significantly reduced in DH+MA- and DH+MA+, with respect to DH-MA-, HyMA+, and controls. Insulin-stimulated glucose transport was similar in the 3 groups of patients with diabetes. A significant reduction of intracellular glycogen content was observed in DH+MA- and DH+MA+ compared with DH-MA- in both basal and insulin-stimulated conditions, probably because of a major impairment of glycogen synthase activity. Glycogen phosphorylase activity did not show differences between the groups. These results suggest that (1) the combination of type 2 diabetes with hypertension and altered AER is associated with impaired insulin sensitivity, and (2) intrinsic, possibly genetic, factors may account for increased peripheral insulin resistance in hypertensive microalbuminuric patients with type 2 diabetes, pointing to the reduction of glycogen synthase activity as a shared common defect.
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PMID:A defect in glycogen synthesis characterizes insulin resistance in hypertensive patients with type 2 diabetes. 1140

Two substituted ureas of beta-D-glucose, N-acetyl-N'-beta-D-glucopyranosyl urea (Acurea) and N-benzoyl-N'-beta-D-glucopyranosyl urea (Bzurea), have been identified as inhibitors of glycogen phosphorylase, a potential target for therapeutic intervention in type 2 diabetes. To elucidate the structural basis of inhibition, we determined the structure of muscle glycogen phosphorylase b (GPb) complexed with the two compounds at 2.0 A and 1.8 A resolution, respectively. The structure of the GPb-Acurea complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change in the tertiary structure. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the GPb-glucose complex, while the acetyl urea moiety is in a favourable electrostatic environment and makes additional polar contacts with the protein. The structure of the GPb-Bzurea complex shows that Bzurea binds tightly at the catalytic site and induces substantial conformational changes in the vicinity of the catalytic site. In particular, the loop of the polypeptide chain containing residues 282-287 shifts 1.3-3.7 A (Calpha atoms) to accommodate Bzurea. Bzurea can also occupy the new allosteric site, some 33 A from the catalytic site, which is currently the target for the design of antidiabetic drugs.
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PMID:Binding of N-acetyl-N '-beta-D-glucopyranosyl urea and N-benzoyl-N '-beta-D-glucopyranosyl urea to glycogen phosphorylase b: kinetic and crystallographic studies. 1189 39

The effect of inhibition of glycogen phosphorylase by 1,4-dideoxy-1,4-imino-d-arabinitol on rates of gluconeogenesis, gluconeogenic deposition into glycogen, and glycogen recycling was investigated in primary cultured hepatocytes, in perfused rat liver, and in fed or fasted rats in vivo clamped at high physiological levels of plasma lactate. 1,4-Dideoxy-1,4-imino-d-arabinitol did not alter the synthesis of glycerol-derived glucose in hepatocytes or lactate-derived glucose in perfused liver or fed or fasted rats in vivo. Thus, 1,4-dideoxy-1,4-imino-d-arabinitol inhibited hepatic glucose output in the perfused rat liver (0.77 +/- 0.19 versus 0.33 +/- 0.09, p < 0.05), whereas the rate of lactate-derived gluconeogenesis was unaltered (0.22 +/- 0.09 versus 0.18 +/- 0.08, p = not significant) (1,4-dideoxy-1,4-imino-d-arabinitol versus vehicle, micromol/min * g). Overall, the data suggest that 1,4-dideoxy-1,4-imino-d-arabinitol inhibited glycogen breakdown with no direct or indirect effects on the rates of gluconeogenesis. Total end point glycogen content (micromol of glycosyl units/g of wet liver) were similar in fed (235 +/- 19 versus 217 +/- 22, p = not significant) or fasted rats (10 +/- 2 versus 7 +/- 2, p = not significant) with or without 1,4-dideoxy-1,4-imino-d-arabinitol, respectively. The data demonstrate no glycogen cycling under the investigated conditions and no effect of 1,4-dideoxy-1,4-imino-d-arabinitol on gluconeogenic deposition into glycogen. Taken together, these data also suggest that inhibition of glycogen phosphorylase may prove beneficial in the treatment of type 2 diabetes.
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PMID:Evidence against glycogen cycling of gluconeogenic substrates in various liver preparations. 1204 3

The regulation of the hepatic glucose output through glycogenolysis is an important target for type 2 diabetes therapy. Glycogenolysis is catalyzed in liver, muscle and brain by tissue specific isoforms of glycogen phosphorylase (GP). Because of its central role in glycogen metabolism, GP has been exploited as a model for structure-assisted design of potent inhibitors, which may be relevant to the control of blood glucose concentrations in type 2 diabetes. Several regulatory binding sites have been identified in GP, such as the catalytic, the allosteric, and the inhibitor binding sites. Protein crystallography has contributed significant structural information on the specificity and interactions that distinguish the binding sites, and also revealed a new unexpected binding site (new allosteric site). In this review, the kinetic, crystallographic binding, and physiological studies of a number of compounds, inhibitors of GP, are described, and the essential inhibitory and binding properties of specific compounds are analyzed in an effort to provide rationalizations for the affinities of these compounds and to exploit the molecular interactions that might give rise to a better inhibitor. These studies have given new insights into fundamental structural aspects of the enzyme enhancing our understanding of how the enzyme recognizes and specifically binds ligands, that could be of potential therapeutic value in the treatment of type 2 diabetes.
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PMID:Glycogen phosphorylase as a molecular target for type 2 diabetes therapy. 1247 Feb 12

Diabetes is among the largest contributors to global mortality through its long term complications. The worldwide epidemic of type 2 diabetes has been stimulating the quest for new concepts and targets for the treatment of this incurable disease. A new target is glycogen phosphorylase (GP), the main regulatory enzyme in the liver responsible for the control of blood glucose levels. One of several approaches to influence the action of GP is the use of glucose derivatives as active site inhibitors. This field of research commenced 10-15 years ago and, due to joint efforts in computer aided molecular design, organic synthesis, protein crystallography, and biological assays, resulted in glucopyranosylidene-spiro-hydantoin 16 (K(i) = 3-4 micro M) as the most efficient glucose analog inhibitor of GP of that time. The present paper surveys the recent developments of this field achieved mainly in the last five years: the synthesis and evaluation of glucopyranosylidene-spiro-thiohydantoin 18 (K(i) = 5 micro M) which has proven equipotent with 16, and is available in gram amounts; furanosylidene- and xylopyranosylidene-spiro-(thio)hydantoins whose ineffectiveness (K(i) > 10 mM) confirmed the high specificity of the catalytic site of GP towards the D-glucopyranosyl unit; "open" hydantoins like methyl N-(1-carboxamido-D-glucopyranosyl)carbamate 37 (K(i) = 16 micro M) and N-acyl-N'-(beta-D-glucopyranosyl)ureas among them the to date best glucose analog inhibitor N-(2-naphthoyl)-N'-(beta-D-glucopyranosyl)urea (35, K(i) = 0.4 micro M) which can also bind to the so-called new allosteric site of GP; C-(beta-D-glucopyranosyl)heterocycles (tetrazole, 1,3,4-oxadiazoles, benzimidazole (K(i) = 11 micro M), and benzothiazole). Iminosugars like isofagomine (45, IC(50) = 0.7 micro M), noeuromycin (53, IC(50) = 4 micro M), and azafagomine (54, IC(50) = 13.5 micro M) also bind strongly to the active site of GP, however, substitution on the nitrogens makes the binding weaker. The natural product five-membered iminosugar DAB (56) exhibited IC(50) approximately 0.4-0.5 micro M. Azoloperhydropyridines which can be regarded iminosugar-annelated heterocycles show moderate inhibition of GP: nojiritetrazole 12 (K(i) = 53 micro M) is the best inhibitor and fewer nitrogens in the five-membered ring weakens the binding. Physiological investigations have been carried out with N-acetyl-beta-D-glucopyranosylamine 6, spiro-thiohydantoin 18, isofagomine 45, and DAB 56 to underline the potential use of these compounds in the treatment of type 2 diabetes. Computational methods suggest to synthesize further anomerically bifunctional glucose derivatives which may be good inhibitors of GP.
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PMID:Glucose analog inhibitors of glycogen phosphorylases as potential antidiabetic agents: recent developments. 1276 45

The discovery of antidiabetic agents that inhibit hepatic glucose production is a popular and potentially fruitful research area for the pharmaceutical research community. Metformin, a marketed agent with this mechanism of action, is widely used for the treatment of type 2 diabetes, however, more efficacious agents are sought. A number of promising proteins are being targeted for modulation by new compounds, including the glucagon receptor, glycogen phosphorylase, glucocorticoid receptor, 11 beta-hydroxysteroid dehydrogenase-1, fructose-1,6-bisphosphatase, carnitine palmitoyltransferase-1, glycogen synthase kinase-3, glucose-6-phosphate T1 translocase and the A2B receptor. Compounds designed to work against these targets are at the early clinical or preclinical phase of study. Glucagon receptor antagonists, glycogen phosphorylase inhibitors, 11 beta-hydroxysteroid dehydrogenase-1 inhibitors, carnitine palmitoyltransferase-1 inhibitors and fructose-1,6-bisphosphatase inhibitors are, or have been, clinically evaluated. Preclinical studies against the other targets have yielded compounds that demonstrate efficacy in diabetic animal models and clinical activity will continue.
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PMID:Pharmacological regulation of hepatic glucose production. 1280 81


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