Magnetism tuned by the charge states of defects in bulk C-doped SnO2 materials.

To analyze the controversial conclusions on the magnetism of C-doped SnO2 (SnO2:C) bulk materials between theoretical calculations and experimental observations, we propose the critical role of the charge states of defects in the geometric structures and magnetism, and carry out a series of first principle calculations. By changing the charge states, we can influence Bader charge distributions and atomic orbital occupancies in bulk SnO2:C systems, which consequently conduct magnetism. In all charged SnO2:C supercells, C-2px/py/pz electron occupancies are significantly changed by the charge self-regulation, and thus they make the C-2p orbitals spin polarized, which contribute to the dominant magnetic moment of the system. When the concentration of C dopant in the SnO2 supercell increases, the charge redistribution assigns extra electrons averagely to each dopant, and thus effectively modulates the magnetism. These findings provide an experimentally viable way for controlling the magnetism in these systems.

Co-ordinate regulation of growth factor receptors and lipid phosphate phosphatase-1 controls cell activation by exogenous lysophosphatidate.

The serum-derived lipid growth factors, lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P), activate cells selectively through different members of a family of endothelial differentiation gene (EDG) receptors. Activation of EDG receptors by LPA and S1P provides a variety of signalling cascades depending upon the G-protein coupling of the different EDG receptors. This leads to chemotactic and mitogenic responses, which are important in wound healing. For example, LPA stimulates fibroblast division and S1P stimulates the chemotaxis and division of endothelial cells leading to angiogenesis. Counteracting these effects of LPA and S1P, are the actions of lipid phosphate phosphatases (LPP, or phosphatidate phosphohydrolases, Type 2). The isoform LPP-1 is expressed in the plasma membrane with its active site outside the cell. This enzyme is responsible for 'ecto-phosphatase' activity leading to the degradation of exogenous lipid phosphate mediators, particularly LPA. Expression of LPP-1 decreases cell activation by exogenous LPA. The mechanism for this is controversial and several mechanisms have been proposed. Evidence will be presented that the LPPs cross-talk with EDG and other growth factor receptors, thus, regulating the responses of the cells to lipid phosphate mediators of signal transduction.

Lipid phosphate phosphatase-1 dephosphorylates exogenous lysophosphatidate and thereby attenuates its effects on cell signalling.

The serum-derived phospholipid growth factor, lysophosphatidate (LPA), activates cells through a family of G-protein-coupled EDG receptors. The present article examines the role of lipid phosphate phosphatase-1 (LPP-1, or phosphatidate phosphate 2A) in regulating cell activation by LPA. Overexpressing LPP-1 approximately doubled the rate of dephosphorylation of exogenous LPA by Rat2 fibroblasts. The amount of LPA dephosphorylation was restricted to less than 10% of the total exogenous LPA. Over-expression of LPP-1 attenuated cell activation as indicated by diminished responses including cAMP, Ca2+, activation of phospholipase D and ERK, DNA synthesis and cell division. LPP-1 therefore provides a novel level of regulation for controlling cell signalling by exogenous LPA.

Hyperglycemia contributes to impaired insulin response in GK rat islets.

Insulin secretion and glucose metabolism were compared in pancreatic islets from type 2 diabetic GK rats treated with phlorizin or vehicle. Treatment of control and GK rats with phlorizin for 30 days did not affect body weight, islet glucose utilization, or islet glucose oxidation. In phlorizin-treated GK rats, glucose-induced insulin release was about twofold higher at 11.0 and 16.7 mmol/l glucose compared with vehicle, treated GK rats, whereas phlorizin had no effect on control Wistar rats. However, also in phlorizin-treated GK rats, the amount of insulin released by the islets was significantly less than that from control rats (5.29+/-0.33 vs. 7.50+/-1.31 pmol x min(-1) islet(-1) at 16.7 mmol/l glucose; P<0.001). Islet glucose-6-phosphatase activity was significantly higher in GK rats than in control rats; phlorizin treatment significantly decreased this activity. These findings demonstrate that hyperglycemia per se constitutes an important factor for impaired insulin release in GK rats. Correction of hyperglycemia normalizes islet glucose-6-phosphatase activity, which may be an underlying factor for the partial improvement of glucose-induced insulin release.

Increased glucocorticoid sensitivity in islet beta-cells: effects on glucose 6-phosphatase, glucose cycling and insulin release.

Glucose-6-phosphatase (G6Pase) activity and the rate of glucose cycling are increased in islets from animal models of Type II (non-insulin-dependent) diabetes mellitus. Glucocorticoid treatment further stimulates these processes and inhibits glucose-induced insulin release. To determine whether these effects result from a direct action of glucocorticoids on the beta-cells, we used isolated islets. The islets were from transgenic mice overexpressing the glucocorticoid receptor in their beta-cells to increase the cells' sensitivity to glucocorticoid. Islets from transgenic and non-transgenic control mice utilized and oxidized the same amount of glucose. In contrast, islet G6Pase activity was 70 % higher, glucose cycling was increased threefold and insulin release was 30 % lower in islets from transgenic mice. Hepatic G6Pase activity was the same in transgenic and control mice. Dexamethasone administration increased G6Pase activity and glucose cycling and decreased insulin release in both transgenic and control mouse islets. We conclude that glucocorticoids stimulate islet G6Pase activity and glucose cycling by acting directly on the beta-cell. That activity may be linked to the inhibition of insulin release.

Effects of 3-mercaptopicolinic acid and a derivative of chlorogenic acid (S-3483) on hepatic and islet glucose-6-phosphatase activity.

Glucose-6-phosphatase activity was measured in hepatic microsomes and in pancreatic islets from ob/ob mice. In hepatic microsomes vanadate, phlorizin, 3-mercaptopicolinic acid and a derivative of chlorogenic acid (S-3483) inhibited the translocase activity of the enzyme, vanadate in addition inhibited hydrolase activity. In islets, vanadate inhibited both components of the enzyme, phlorizin inhibited only hydrolase activity while 3-mercaptopicolinic acid and compound S-3483 were without effect. Similarly, when islets were incubated with 3H2O and unlabeled glucose, the incorporation of 3H into medium glucose was inhibited by vanadate and phlorizin, but not by 3-mercaptopicolinic acid and S-3483. These findings suggest that, as with glucokinase, different isoenzymes of glucose-6-phosphatase are present in islets and liver.

Glucose metabolism in Goto-Kakizaki rat islets.

Islets from Goto-Kakizaki (GK) rats from our colony, despite marked impairment of glucose-induced insulin release, used glucose and produced CO2 at a rate 3 times that of islets from control Wistar rats. Almost all glucose used was accounted for in CO2 and lactate production. The percentages of glucose carbon used collected in CO2 and lactate were similar for control and GK islets. GK islets also oxidized 40% more acetate and leucine to CO2 than did control islets. The fraction of carbon leaving the Krebs cycle relative to CO2 production was the same in GK and control islets. The capacities of mitochondria from GK islets to generate ATP from glutamate and malate were similar and that to generate ATP from succinate and rotenone was somewhat less from GK islets. The reason for the enhanced utilization of substrates by islets of the GK rat is not apparent. In conclusion, there is no decrease in islet glucose utilization, glucose oxidation, Krebs cycle function, or the electron transport system evident from these measurements to explain the impaired insulin release in islets from GK rats.

Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids.

Abnormalities contributing to the pathogenesis of non-insulin-dependent diabetes mellitus include impaired beta cell function, peripheral insulin resistance, and increased hepatic glucose production. Glucocorticoids are diabetogenic hormones because they decrease glucose uptake and increase hepatic glucose production. In addition, they may directly inhibit insulin release. To evaluate that possible role of glucocorticoids in beta cell function independent of their other effects, transgenic mice with an increased glucocorticoid sensitivity restricted to their beta cells were generated by overexpressing the glucocorticoid receptor (GR) under the control of the insulin promoter. Intravenous glucose tolerance tests showed that the GR transgenic mice had normal fasting and postabsorptive blood glucose levels but exhibited a reduced glucose tolerance compared with their control littermates. Measurement of plasma insulin levels 5 min after intravenous glucose load demonstrated a dramatic decrease in acute insulin response in the GR transgenic mice. These results show that glucocorticoids directly inhibit insulin release in vivo and identify the pancreatic beta cell as an important target for the diabetogenic action of glucocorticoids.

Inhibitory effects of fatty acids on glucose-regulated B-cell function: association with increased islet triglyceride stores and altered effect of fatty acid oxidation on glucose metabolism.

Long-term exposure to fatty acids (FA) inhibits B-cell function. We tested whether the inhibitory effects are associated with increased islet triglycerides (TG). Rat pancreatic islets were cultured for 48 hours in RPMI 1640 medium with 10% fetal calf serum (FCS) and 11 mmol/L glucose in the presence or absence of the long-chain FA, palmitate. Palmitate (0.125 mmol/L) exposure successively increased islet TG 70% after 6 hours and 200% after 48 hours of culture. The dose-response for palmitate was similar for the increase in TG and inhibition of glucose-induced insulin secretion. Reversal of elevated islet TG in RPMI medium (after 48 hours of palmitate) was 29% after 6 hours and 84% after 24 hours. A more rapid decline of TG was observed in Krebs-Ringer bicarbonate (KRB) medium in the absence of nutrients. This decline was totally prevented by 1 mumol/L of the carnitine palmitoyl transferase-I (CPT-I) inhibitor, etomoxir. Etomoxir enhanced glucose-induced insulin secretion from palmitate-cultured islets; however, this effect was lost when TG were normalized. Under conditions when oxidation of FA from islet TG stores was blocked with etomoxir, we tested the effects of octanoate, the oxidation of which is not blocked by etomoxir. Oxidation of [1-14C]octanoate from islets precultured with palmitate (48 hours) did not differ from that in control islets. Conversely, after palmitate, octanoate inhibited glucose oxidation (14CO2 production from [U-14C]glucose, 613 +/- 41 pmol/10 islets/90 min v 1,129 +/- 87 after control conditions, P < .01). In conclusion, (1) palmitate induces increases in islet TG that are associated with inhibition of B-cell function, and (2) long-term exposure to palmitate also induces an inhibitory effect of FA oxidation on glucose metabolism that is independent of TG.

Quantifying the carboxylation of pyruvate in pancreatic islets.

Pyruvate has been estimated to enter the citric acid cycle in islets by carboxylation to the same extent or more than by decarboxylation. Those estimates were made assuming the dimethyl esters of [1,4-14C]succinate and [2-3-14C]succinate, incubated with islets at a concentration of 10 mM, gave the same ratio of 14CO2 yields as if [1-14C]acetate and [2-14C]acetate had been incubated. The labeled succinates, at 10 mM, but not 1 mM, are now shown to give ratios higher than the labeled acetates at those concentrations and therefore higher estimates when related to yields from [2-14C]glucose and [6-14C]glucose. Using the labeled acetate ratios in paired incubations, the rate of pyruvate carboxylation is still estimated to be about two-thirds the rate of pyruvate decarboxylation. Participation of the malic enzyme-catalyzed reaction explains the greater ratio of yields of 14CO2 from the succinates at 10 mM than 1 mM and increases in those ratios on glucose addition and can account for the removal from the citric acid cycle of oxaloacetate carbon formed in the carboxylation.

Deficiency of pyruvate dehydrogenase activity in pancreatic islets of diabetic GK rats.

We investigated the role of islet pyruvate dehydrogenase (PDH) enzyme activity and fatty acid oxidation in the impaired insulin secretion in spontaneously diabetic GK rats. Blood glucose levels were elevated in 2- to 3-month-old GK rats (8.7 +/- 0.5 vs. 6.5 +/- 0.3 mM in control Wistar rats; P < 0.01), whereas serum insulin levels were comparable to those in control rats. Insulin and DNA contents were similar in freshly isolated islets from GK and control rats, whereas insulin responses to 27 mM glucose from GK islets were reduced by 52%. The effect of acetate or pyruvate on insulin responses evoked by succinate monomethylester (SAM) were compared to indirectly assess deficient generation of acetyl-coenzyme A from pyruvate. Acetate potentiated SAM-induced insulin secretion similarly in GK and control islets, whereas 10 mM pyruvate (which supplies acetyl-coenzyme A through PDH enzyme activity) failed to normally potentiate insulin secretion in GK islets (92% of SAM-induced response in GK vs. 154% in control islets). The PDH activity (active form) was decreased in GK islets by 35% (P < 0.001). The proportion of active form PDH to total PDH activity was reduced in GK islets (56% vs. 71% in control islets; P < 0.01). The activity of PDH kinase (which inactivates PDH by phosphorylation) was increased in GK islets, the rate of ATP-dependent inactivation of PDH was -0.29 +/- 0.02 vs. -0.19 +/- 0.02/min in control islets (P < 0.05). Culturing GK islets for 48 h at 5.5 mM glucose failed to correct the impaired insulin response to glucose and the decreased PDH activity. Serum FFA levels and islet triglyceride contents did not differ between GK and control rats. Etomoxir (1.0 and 10 microM), a carnitine palmitoyl transferase I inhibitor, failed to enhance glucose-induced insulin release in GK islets. The following conclusions were reached: 1) a kinase-mediated decrease in PDH activity in islets of GK rats may in part account for the decreased ratio of oxidized to utilized glucose and impaired insulin release in these islets; and 2) impaired insulin release in the GK rats is not linked to an inhibitory influence of islet fatty acid oxidation.

Prevalence of Toxoplasma gondii infection in man and animals in Guangdong, Peoples Republic of China.

Tissue and serum samples from animals and man in Guangdong Province of the Peoples Republic of China were examined for Toxoplasma gondii infection. Tissues from 519 swine, 576 rodents, 84 people, one cat and two dogs were bioassayed in mice. T. gondii was isolated from 13 pools of swine tissues, but not from any other hosts. Serum samples from animals and man were examined at 1:64 dilution in the indirect hemagglutination test. Antibodies to T. gondii were found in 10.4% of 816 pigs, 0.9% of 955 rodents, 0.7% of 3085 people, 4.4% of 90 cattle, 8.3% of 12 rabbits and 2.1% of 47 cats. None were found in 83 buffaloes.