Priming Effect of a Morning Meal on Hepatic Glucose Disposition Later in the Day.

We used hepatic balance and tracer ([3H]glucose) techniques to examine the impact of "breakfast" on hepatic glucose metabolism later in the same day. From 0-240 min, 2 groups of conscious dogs (n = 9 dogs/group) received a duodenal infusion of glucose (GLC) or saline (SAL), then were fasted from 240-360 min. Three dogs from each group were euthanized and tissue collected at 360 min. From 360-600 min, the remaining dogs underwent a hyperinsulinemic (4× basal) hyperglycemic clamp (arterial blood glucose 146 ± 2 mg/dL) with portal GLC infusion. The total GLC infusion rate was 14% greater in dogs infused with GLC than in those receiving SAL (AUC360-600min 2,979 ± 296 vs. 2,597 ± 277 mg/kg, respectively). The rates of hepatic glucose uptake (5.8 ± 0.8 vs. 3.2 ± 0.3 mg ⋅ kg-1 ⋅ min-1) and glycogen storage (4.7 ± 0.6 vs. 2.9 ± 0.3 mg ⋅ kg-1 ⋅ min-1) during the clamp were markedly greater in dogs receiving GLC compared with those receiving SAL. Hepatic glycogen content was ∼50% greater, glycogen synthase activity was ∼50% greater, glycogen phosphorylase activity was ∼50% lower, and the amount of phosphorylated glycogen synthase was 34% lower, indicating activation of the enzyme, in dogs receiving GLC compared with those receiving SAL. Thus, morning GLC primed the liver to extract and store more glucose in the presence of hyperinsulinemic hyperglycemia later in the same day, indicating that breakfast enhances the liver's role in glucose disposal in subsequent same-day meals.

Discovery of the glycogen phosphorylase-modulating activity of a resveratrol glucoside by using a virtual screening protocol optimized for solvation effects.

The identification of natural products that can modulate blood glucose levels is of great interest as it can possibly facilitate the utilization of mild interventions such as herbal medicine or functional foods in the treatment of chronic diseases like diabetes. One of the established drug targets for antihyperglycemic therapy is glycogen phosphorylase. To evaluate the glycogen phosphorylase inhibitory properties of an in-house compound collection consisting to a large extent of natural products, a stepwise virtual and experimental screening protocol was devised and implemented. The fact that the active site of glycogen phosphorylase is highly hydrated emphasized that a methodological aspect needed to be efficiently addressed prior to an in silico evaluation of the compound collection. The effect of water molecules on docking calculations was regarded as a key parameter in terms of virtual screening protocol optimization. Statistical analysis of 125 structures of glycogen phosphorylase and solvent mapping focusing on the active site hydration motif in combination with a retrospective screening revealed the importance of a set of 29 crystallographic water molecules for achieving high enrichment as to the discrimination between active compounds and inactive decoys. The scaling of Van der Waals radii of system atoms had an additional effect on screening performance. Having optimized the in silico protocol, a prospective evaluation of the in-house compound collection derived a set of 18 top-ranked natural products that were subsequently evaluated in vitro for their activity as glycogen phosphorylase inhibitors. Two phenolic glucosides with glycogen phosphorylase-modulating activity were identified, whereas the most potent compound affording mid-micromolar inhibition was a glucosidic derivative of resveratrol, a stilbene well-known for its wide range of biological activities. Results show the possible phytotherapeutic and nutraceutical potential of products common in the Mediterranean countries, such as red wine and Vitis products in general or green raw salads and herbal preparations, where such compounds are abundant.

A new eudesmane sesquiterpene glycosides from Liriope muscari.

A new eudesmane sesquiterpene glycoside, ophiopogonoside B (1), along with five known compounds, ophiopogonoside A (2), ruscogenin-1-O-[ß-D-glucopyranosyl (1 → 2)]-[ß-D-xylopyranosyl (1 → 3)]-ß-D-fucopyranoside (3), palmitic acid (4), palmitic acid glyceride (5), and ß-sitosterol-D-glucopyranoside (6),was isolated from the tuberous roots of Liriope muscari (Decn.) Bailey (Liliaceae). Their structures were confirmed by 1D and 2D NMR spectroscopy. Among them, compounds 1, 2, 4, and 5 were the first reported from the genus Liriope. Ophiopogonoside B (1) showed moderate inhibitory activity to glycogen phosphorylase a.

'The effect of micronutrients on superoxide dismutase in senescent fibroblasts'.

The specific activities of zinc/copper (Zn/Cu)-superoxide dismutase (SOD-1) and manganese (Mn)-superoxide dismutase (SOD-2) were assayed in young passage 5 fibroblasts and in serially subcultured cells that were characterized as senescent at passages 15-35. SOD-1 and SOD-2 activities did not significantly change in senescent and young cells cultured in either routine medium [minimum essential medium 1 (MEM1)], or in Zn, Cu and Mn supplemented medium (MEM2) containing normal human plasma levels of the cations. SOD-1 and SOD-2 activities, however, underwent parallel progressive significant activity increases in senescent passage 20 and 25 cells, which peaked in value in passage 30 and 35 cells subcultured in supplemented medium (MEM3) containing triple human plasma levels of the cations. Concurrently, superoxide radical generation rates underwent progressive significant increases in senescent passage 15-25 cells, which peaked in value in passage 30 and 35 cells subcultured in MEM1 or MEM2. These rates, however, were significantly lowered in senescent cells subcultured in MEM3. We infer that it was only possible to significantly stimulate SOD-1 and SOD-2 activities in senescent MEM3 cultured cells enabling them to combat oxidative stress.

Caffeic acid attenuates malathion induced metabolic disruption in rat liver, involvement of acetylcholinesterase activity.

It has been confirmed that organophosphorus compounds OP altered glucose homeostasis. Considerable experimental and clinical evidences have contributed the beneficial effects of polyphenol molecules on metabolic homeostasis. However, up to date limited studies have been performed on this topic. The aim of this study was to evaluate whether caffeic acid, an active phenolic component was able to reduce metabolic disruption induced by malathion administration. Malathion at 100mg/kg was administered to rats alone or in combination with caffeic acid at100 mg/kg. Malathion decreases hepatic GP activity and increases HK activity accompanied with a rise in the hepatic glycogen rate. Moreover, coadministration of malathion with caffeic acid resulted in restoration of malathion-induced GP inhibition and HK1 increase. These results may be due to the significant increase recorded in acetylcholinesterase (AchE) activity in vivo after coadministration of malathion and caffeic acid. Indeed, malathion is known to inhibit AChE activity leads to subsequent activation of cholinergic receptor that increased in part, catecholamine and glucocorticoids secretion; provoked glycogenolysis and gluconeogenesis activation. Thus, we can suggest that increase's (AchE) activity seems to be responsible for caffeic acid restoration on malathion-induced metabolic disruptions. Recent studies support the hypothesis that oxons bind to a secondary site on acetylcholinesterase, leading to activation/inhibition of the catalytic site. Thus, caffeic acid or its derivates may be leading to activation of the catalytic site within the second site interaction.

Idazoxan activates rat forebrain glycogen phosphorylase in vivo: a histochemical study.

In vitro experiments show norepinephrine activates glycogen phosphorylase and glycogenolysis in forebrain glia. The present study used idazoxan (5 mg/kg) to elevate NE in vivo and examined patterns of active (aGP) and total (tGP) glycogen phosphorylase reactivity in selected neocortical, hippocampal, diencephalic, and striatal sites using a histochemical method. In somatosensory neocortex, aGP reactivity was highest in Layer 4 with consistent reactivity in the barrel fields in vehicle-treated brains. In the hippocampus, the stratum lacunosum moleculare was highly reactive, while cell layers were least reactive. The dentate gyrus and CA3 were more reactive for aGP than CA1. In the diencephalon, the medial habenula was most reactive followed by the reticular nucleus of the thalamus. In the striatum, globus pallidus was most reactive. Reactivity patterns for tGP were similar to those for aGP, but more intense. The neocortex had the highest overall reactivity for tGP. An estimate of the percentage of aGP relative to tGP suggested the regions sampled had similar levels of median basal activation (approximately 65%). Idazoxan increased aGP reactivity in all regions of the neocortex assessed (layers 3-6 of primary and secondary somatosensory cortex and the barrel fields). The neuropil layers, but not the cell layers, of hippocampus were more reactive following idazoxan treatment. Idazoxan also increased aGP reactivity in the laterodorsal, paraventricular, and reticular nuclei of the thalamus. The largest idazoxan-induced changes, as an estimated percentage of tGP, occurred in the hippocampus (approximately 16% for stratum lacunosum moleculare and for CA1 stratum oriens). Increases ranged from approximately 3 to 6% in neocortex and were less than 3% in the diencephalic and striatal areas. These effects of idazoxan are consistent with a role for norepinephrine in activating forebrain glycogenolyis in vivo and supporting increased brain metabolism. They contrast with earlier evidence showing that idazoxan reduces 2-deoxyglucose uptake in these brain areas. Idazoxan, and norepinephrine, may preferentially recruit glycolytic over oxidative metabolism in the rat forebrain.

Glycogen synthesis correlates with androgen-dependent growth arrest in prostate cancer.

BACKGROUND: Androgen withdrawal in normal prostate or androgen-dependent prostate cancer is associated with the downregulation of several glycolytic enzymes and with reduced glucose uptake. Although glycogen metabolism is known to regulate the intracellular glucose level its involvement in androgen response has not been studied. METHODS: We investigated the effects of androgen on glycogen phosphorylase (GP), glycogen synthase (GS) and on glycogen accumulation in the androgen-receptor (AR) reconstituted PC3 cell line containing either an empty vector (PC3-AR-V) or vector with HPV-E7 (PC3-AR-E7) and the LNCaP cell line. RESULTS: Androgen addition in PC3 cells expressing the AR mimics androgen ablation in androgen-dependent prostate cells. Incubation of PC3-AR-V or PC3-AR-E7 cells with the androgen R1881 induced G1 cell cycle arrest within 24 hours and resulted in a gradual cell number reduction over 5 days thereafter, which was accompanied by a 2 to 5 fold increase in glycogen content. 24 hours after androgen-treatment the level of Glucose-6-P (G-6-P) had increased threefold and after 48 hours the GS and GP activities increased twofold. Under this condition inhibition of glycogenolysis with the selective GP inhibitor CP-91149 enhanced the increase in glycogen content and further reduced the cell number. The androgen-dependent LNCaP cells that endogenously express AR responded to androgen withdrawal with growth arrest and increased glycogen content. CP-91149 further increased glycogen content and caused a reduction of cell number. CONCLUSION: Increased glycogenesis is part of the androgen receptor-mediated cellular response and blockage of glycogenolysis by the GP inhibitor CP-91149 further increased glycogenesis. The combined use of a GP inhibitor with hormone therapy may increase the efficacy of hormone treatment by decreasing the survival of prostate cancer cells and thereby reducing the chance of cancer recurrence.