Alteration of dopamine transport in the striatum and nucleus accumbens of ovariectomized and estrogen-primed rats following N-(p-isothiocyanatophenethyl) spiperone (NIPS) treatment.

The ability of N-(p-isothiocyanatophenethyl) spiperone (NIPS, 10 mg/kg, 24 h), a selective, irreversible alkylating agent of the dopamine D(2) receptor, to alter properties of dopamine uptake and clearance in the striatum and nucleus accumbens of ovariectomized and estrogen-primed (estradiol benzoate, 10 microg, 48 h, 24 h) rats was examined using voltammetry. The effectiveness of NIPS was evaluated independently by measuring agonist mediated potentiation of [35S]-guanosine 5'-(gamma-thiotriphosphate) ([35S]-GTPgammaS) binding and [3H]-dopamine uptake. A decrease in E(max) for ligand potentiated [35S]-GTPgammaS binding and a loss of quinpirole potentiated [3H]-dopamine uptake was observed consistent with a NIPS mediated alkylation and functional down-regulation of the dopamine D(2) receptor. This down-regulation was associated with an attenuation of the dose dependent uptake of dopamine in both the striatum and the accumbens. Co-administration of estrogen and NIPS resulted in a further attenuation of dopamine potentiated [35S]-GTPgammaS binding measured in vitro and dopamine uptake measured in vivo. Analysis of the voltammetric profile revealed that clearance and T(50) times were significantly prolonged in animals treated with estrogen and NIPS compared with those treated with NIPS alone. These data are consistent with both a steroid mediated impairment in dopamine autoreceptor/dopamine transporter coupling and an independent action of estrogen at the level of the dopamine transporter.

Postprandial low-density lipoproteins in type 2 diabetes are oxidized more extensively than fasting diabetes and control samples.

This study examined the kinetics of low-density lipoprotein (LDL) oxidation in the fasting and postprandial states of diabetic and control subjects to determine if LDL oxidation may contribute to accelerated atherosclerosis in diabetes. We compared in vitro oxidation of LDL from 12 control and 13 Type 2 diabetic subjects in the fasting and postprandial states. The extent of oxidation was assessed by length of lag phase, formation of conjugated dienes (CD), lipid peroxides, thiobarbituric acid reactive substances (TBARS), and percentage reduction in free amine groups. Diabetic subjects were significantly older and heavier. Comparisons between control and diabetic subjects in the postprandial state showed that the lag phase was significantly shorter in diabetic subjects than controls (P = 0.005), TBARS were significantly higher (P = 0.006), and levels of CD were higher at 60, 65, and 70 min (P < 0.01). In the fasting state, however, these comparisons were not significant. In diabetic subjects, postprandial samples had a significantly shorter lag phase (P = 0.003), higher TBARS (P = 0.006), and higher levels of CD at 60, 65 (P < 0.001), and 70 min (P = 0.0013) compared to fasting samples. Elevated levels of serum triglycerides in diabetic subjects were negatively correlated to lag phase, in fasting (P = 0.06) and postprandial states (P = 0.002). We conclude that accelerated oxidation of LDL seen in postprandial states in diabetes may be a critical contributor to cardiovascular risks. Elevated levels of serum triglycerides may contribute to the rapid oxidation of LDL seen in diabetic subjects.

Decreased protection by HDL from poorly controlled type 2 diabetic subjects against LDL oxidation may Be due to the abnormal composition of HDL.

High plasma triglyceride concentrations in diabetic subjects increase their risk for developing coronary heart disease. Numerous studies have shown that the high density lipoprotein (HDL) composition is abnormal in type 2 diabetic subjects. One study has shown that HDL (lipoprotein A-I) isolated from subjects with non-insulin-dependent diabetes mellitus exhibits a decreased capacity to induce cholesterol efflux. The current study examined the effect of HDL(2) and HDL(3) subfractions from poorly controlled type 2 diabetic and control subjects on THP-1 macrophage-mediated low density lipoprotein (LDL) oxidation. The composition and protective effects of HDL(2), but not of HDL(3), differed significantly between control and diabetic subjects. HDL(2) from diabetics were triglyceride enriched and cholesterol depleted compared with those from controls. Control HDL(2) inhibited LDL oxidation, as assessed by lipid peroxides and electrophoretic mobility, significantly (P<0.05) more than did diabetic HDL(2) in both the fasting and postprandial state. In addition, HDL(2) from diabetics did not protect against apolipoprotein B-100 fragmentation in LDL. Cross-linking in apolipoprotein A-I, oxidized in the presence of LDL, was extensive in HDL(2) from diabetics compared with that from controls. Serum triglyceride concentrations were negatively correlated with protection by HDL(2) (r=-0.673, P<0.05) in diabetic but not in control subjects. HDL(2)-associated platelet-activating factor acetylhydrolase activity was positively correlated with protection by HDL(2) in control (r=0.872, P<0.002) but not in diabetic subjects. In conclusion, compositional alterations in HDL(2) from poorly controlled type 2 diabetic subjects may reduce its antiatherogenic properties.

Selective effects of different antioxidants on oxidation of lipoproteins from rats.

Lipoprotein oxidation may contribute to development of atherosclerosis, and supplementation with antioxidants may reduce risk for atherosclerotic events. Genistein, a major isoflavone from soy protein, and catechins from green tea have important antioxidant properties. This study compared the effects of various diets containing antioxidant-rich foods or supplements on serum lipids and lipoprotein oxidation of male Sprague-Dawley rats. The control diet used was devoid of vitamin E. Test diets included these ingredients: green tea powder, 20 g/kg; beta-carotene, 250 mg/kg; a low isoflavone soy protein isolate; a genistein-rich soy protein isolate; and vitamin E, 4000 mg/kg. Ten-week-old rats were acclimatized for 1 week on a special custom diet without vitamin E. Following randomization and allocation to different diet groups, rats were fed the test diets for 3 weeks. Blood was drawn by cardiac puncture, and the plasma was separated by centrifugation. The VLDL-LDL fraction was isolated by ultracentrifugation. Oxidation kinetics of the VLDL-LDL fraction were determined by measuring the lag phase and formation of conjugated dienes, lipid peroxides, and TBARS. The vitamin E diet (P < 0.001) and high-genistein diet profoundly decreased all parameters of lipoprotein oxidation. The following alterations were noted with the high-genistein diet compared to the control diet: the lag phase was 49% longer (P=0.002); conjugated diene formation was decreased by 28% (P=0.01); lipid peroxide formation was decreased 31% (P=0.0059); and TBARS production was 35% lower (P=0.019). The low-isoflavone diet increased the lag phase by 43% (P=0.0019) but did not significantly alter other measures of oxidation. Green tea increased only the lag phase by 33% (P=0.012) compared to the control diet. Beta-Carotene had no significant effect on the oxidation of lipoproteins. The effect of genistein-rich soy protein isolates on lipoprotein oxidation in vitro suggests that either soy isoflavones or other antioxidants derived from soy protein, like vitamin E, may be transported in these lipoproteins. The minimal effects of the isoflavone-poor soy protein isolate suggests that either the small amount of isoflavones present have a potent effect or other components of soy protein are exerting these effects. Further studies are required to examine these results.

Periodontal status of diabetic and non-diabetic men: effects of smoking, glycemic control, and socioeconomic factors.

Periodontal disease is more prevalent and more severe in diabetic than in non-diabetic individuals but the magnitude of this increase is still being debated. This prospective, cross-sectional study compared the periodontal status of 118 diabetic men and 115 age-matched non-diabetic men. Plaque and gingival indices, bleeding scores, probing depth, loss of attachment, and number of missing teeth were measured in a blinded manner. Smoking status, glycemic control, socioeconomic status, and previous dental care were also assessed. These parameters were significantly higher in diabetic than non-diabetic men: plaque index, P < 0.0001; gingival index, P < 0.0002; bleeding score, P < 0.0001; probing depth, P = 0.0059; loss of attachment, P < 0.0001; and missing teeth, P < 0.005. These parameters were significantly higher in smokers than non-smokers: gingival index, probing depth, and loss of attachment. The duration of diabetes was not significantly related to the periodontal measures. Glycemic control as assessed by fasting plasma glucose and glycohemoglobin values was not significantly correlated to periodontal status. These studies indicate, for this study group, that diabetes significantly affects all measured parameters of periodontal status.

Oat bran increases serum acetate of hypercholesterolemic men.

Mechanisms for the hypocholesterolemic effects of oat bran remain unclear. Soluble fibers such as oat bran are fermented in the colon to short-chain fatty acids (SCFAs), which may enter the portal vein and attenuate hepatic cholesterol synthesis. To compare effects of oat bran and wheat bran on serum SCFA concentrations, 20 hypercholesterolemic men entered a metabolic ward and received control diets for 1 wk followed by oat-bran or wheat-bran diets for 3 wk. Oat bran decreased serum cholesterol 12.8% (P less than 0.001) whereas wheat bran had no effect. Peripheral serum SCFA concentrations were measured seven times over 14 h at the end of each diet. Serum acetate values from 1200 to 2200 were significantly higher in subjects fed oat-bran vs wheat-bran diets. Peak and incremental peak acetate values were also significantly higher than control values in subjects fed oat bran but not in subjects fed wheat bran. SCFA responses may contribute to the hypocholesterolemic effects of oat bran.

Propionate inhibits hepatocyte lipid synthesis.

Oat bran lowers serum cholesterol in animals and humans. Propionate, a short-chain fatty acid produced by colonic bacterial fermentation of soluble fiber, is a potential mediator of this action. We tested the effect of propionate on hepatocyte lipid synthesis in rats using [1-14C]acetate, 3H2O, and [2-14C]mevalonate as precursors. Propionate produced a statistically significant inhibition of cholesterol biosynthesis from [1-14C]acetate at a concentration of 1.0 mM and from 3H2O and [2-14C]mevalonate at concentrations of 2.5 mM. Propionate also produced a significant inhibition of fatty acid biosynthesis at concentrations of 2.5 mM using [1-14C]acetate as a precursor. The demonstration of propionate-mediated inhibition of cholesterol and fatty acid biosynthesis at these concentrations suggests that propionate may inhibit cholesterol and fatty acid biosynthesis in vivo and may mediate in part the hypolipidemic effects of soluble dietary fiber. Further studies are needed to clarify this action of propionate and to establish the exact mechanisms by which the inhibition occurs.

Dietary fiber content of a simulated American diet and selected research diets.

Few studies accurately report total-dietary-fiber (TDF) content of current and alternative diets. In this study we analyzed and calculated TDF content of a simulated American diet with household Nationwide Food Consumption Survey data. We also analyzed the fiber content of four research diets: control; bean; high fiber, maintenance (HFM); and high carbohydrate, high fiber (HCF). Analyzed and calculated fiber values for the simulated diet were similar. The simulated, control, bean, HFM, and HCF diets provided 5.6, 8.1, 12.2, 17.4, and 22.8 g TDF/1000 kcal, respectively. Soluble-fiber content ranged from 1.7 g/1000 kcal for the simulated diet to 6.1 g/1000 kcal for the HCF diet. Cereal products contributed the most to total fiber content of the simulated diet, followed in order by vegetables, legumes, fruits, and miscellaneous foods. Fiber content of the simulated diet was below recommended levels. The HFM diet is suggested for individuals desiring to increase their dietary fiber intake.

A comparison of the lipid-lowering and intestinal morphological effects of cholestyramine, chitosan, and oat gum in rats.

Cholestyramine, chitosan, and oat gum are lipid-lowering compounds. Cholestyramine use in humans may contribute to colonic adenocarcinoma; chitosan and oat gum are being studied in the rat to determine their potential for human use. To compare these compounds, we fed three groups of 10 male Sprague-Dawley rats one of the substances at 5% of diet with 1% cholesterol and 0.2% cholic acid; two other groups were fed cellulose with and without 1% cholesterol and 0.2% cholic acid. All groups had similar food intake and weight gains. Cholesterol feeding increased total liver lipids almost 3-fold and liver cholesterol concentration almost 10-fold. Cholestyramine, oat gum, and chitosan all significantly lowered liver cholesterol with cholestyramine feeding yielding levels identical to the noncholesterol-fed basal group. Chitosan and oat gum lowered liver cholesterol moderately. Cholestyramine and chitosan both significantly lowered serum cholesterol compared to the cellulose group. Oat gum was less effective. Hemoglobin and serum iron were similar in all groups except the oat gum group, which had decreased serum iron. Histological examination of small and large bowel with morphometry revealed statistically significant increases in both proximal and distal small bowel and distal large bowel mucosal thickness in the cholestyramine-fed group. No changes were noted in the proximal large bowel. Neither chitosan nor oat gum produced mucosal change other than an increase in the distal small bowel with the oat gum diet. Chitosan may have lipid-lowering effects similar to those of cholestyramine without the deleterious changes in intestinal mucosa.

Dietary fiber content of selected foods.

Dietary fiber measurements are essential to assessment of the potential therapeutic and preventive effects of fiber intake. Ideally, dietary fiber analyses should measure all components--soluble polysaccharides, noncellulosic polysaccharides, cellulose, and lignin--and the constituent sugars of the soluble and noncellulosic polysaccharides. We modified existing techniques to measure reproducibly the total dietary fiber, polysaccharide, and lignin components and the sugar constituents of selected foods. Soluble-fiber content as percentage of total dietary fiber for groups of foods averaged 32% for cereal products, 32% for vegetables, 25% for dried beans, and 38% for fruits. Lignin content, estimated gravimetrically, was approximately 1.4 g/100 g dry wt for 24 foods. Detailed fiber measurements are critical for evaluating the potential health benefits of dietary fiber intake.

Short-chain fatty acid fermentation products of plant fiber affect glucose metabolism of isolated rat hepatocytes.

Short-chain fatty acids (SCFA) produced during fermentation of plant fibers and absorbed from the colon may affect hepatic glucose metabolism. We examined the effects of different fatty acids on rates of glucose production and glycolysis in isolated rat hepatocytes. Acetate, butyrate, and long-chain fatty acids significantly increased glucose production from lactate. However, propionate and valerate significantly decreased glucose production from lactate. Whereas 5 mM butyrate increased the incorporation of [14C]lactate into [14C]glucose by 80%, 5 mM propionate produced a 67% decrease. Glycolysis was significantly decreased by acetate, butyrate, and long-chain fatty acids. However, propionate and valerate significantly increased glycolysis. Thus propionate, which inhibits hepatic acetate metabolism, acts to increase glucose use and decrease glucose production. Plant fibers may influence hepatic glucose metabolism via their SCFA metabolites.