Silvia Wein

Quercetin enhances adiponectin secretion by a PPAR-γ independent mechanism

To study possible insulin sensitizing, anti-inflammatory and anti-oxidative effects of the flavonol quercetin, rats were fed a high-fat diet (19%, w/w) with (HFQ) or without (HF) 0.03% quercetin or a flavonoid-poor low-fat (5%, w/w) maintenance diet (LF) over 4 weeks. Body weight was measured weekly, and plasma concentrations of adiponectin, leptin, insulin, glucose, triacylglycerols, total cholesterol, as well as of markers of inflammation and oxidative stress were measured (12h fasted) at the end of the feeding period. Adiponectin and peroxisome-proliferator-activated-receptor (PPAR)-gamma mRNA were measured in adipose tissue (WAT) by real-time RT-PCR. PPAR-gamma transactivation was investigated by means of a reporter gene assay. HF feeding resulted in elevated fasted plasma glucose concentrations, while HFQ did not differ from LF feeding. In the HFQ group plasma concentrations and WAT mRNA levels of adiponectin were elevated compared with the HF group, however, PPAR-gamma mRNA concentration in WAT was decreased (HFQ vs. HF). Compared to both other groups quercetin feeding significantly reduced oxidative stress, measured by plasma 8-iso-PGF(2alpha), while body weight gain, body composition and plasma leptin levels were not affected. Neither quercetin nor its metabolites induced PPAR-gamma-mediated transactivation in vitro. Adiponectin stimulating effects of quercetin are PPAR-gamma-independent and prevent impairment of insulin sensitivity without affecting body weight and composition.

Identification of plant extracts with potential antidiabetic properties: Effect on human peroxisome proliferator-activated receptor (PPAR), adipocyte differentiation and insulin-stimulated glucose uptake

Thiazolidinediones (TZDs) are insulin sensitizing drugs used to treat type 2 diabetes. The primary target of the TZDs is the peroxisome proliferator‐activated receptor (PPAR) γ, a key regulator of adipogenesis and glucose homeostasis. Currently prescribed TZDs are full PPARγ agonists, and their use is associated with several side effects. Partial PPARγ agonists appear to be associated with fewer side effects but may still confer the desired insulin sensitizing action. Extracts from common medicinal/food plants were tested in a screening platform comprising a series of bioassays, including tests for PPARγ, α and δ transactivation, adipocyte differentiation and insulin‐stimulated glucose uptake, allowing identification of plants containing potentially interesting PPAR agonists. Twenty‐two plant extracts out of 133 were found to increase insulin‐stimulated glucose uptake and 18 extracts were found to activate PPARγ, 3 to activate PPARα and γ, 6 to activate PPARδ and γ, and 9 to activate PPARγ, α and δ. Among the 24 different plant species tested in the platform, 50% were shown to contain compounds capable of activating PPARγ and stimulating insulin‐dependent glucose uptake with no or little effect on adipocyte differentiation warranting further studies and characterization. Copyright

Medium-chain fatty acids ameliorate insulin resistance caused by high-fat diets in rats.

Background High dietary intake of saturated fat impairs insulin sensitivity and lipid metabolism. The influence of fatty acid chain length, however, is not yet fully understood, but evidence exists for different effects of saturated long‐chain (LC) versus saturated medium‐chain (MC) fatty acids (FA).

Bioavailability of the flavonol quercetin in cows after intraruminal application of quercetin aglycone and rutin.

The bioavailability of quercetin has been intensively investigated in monogastric species, but knowledge about its bioavailability in ruminants does not exist. Thus, the aim of the present study was to determine the bioavailability of quercetin in nonlactating cows equipped with indwelling catheters placed in one jugular vein after intraruminal and additionally after i.v. application, respectively. Quercetin was administered intraruminally in equimolar amounts, either in the aglycone form or as its glucorhamnoside rutin, each at 2 dosages [10 and 50 mg of quercetin/kg of body weight (BW)]. In a second trial, 0.8 mg of quercetin aglycone/kg of BW was applied i.v. Blood samples were drawn 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 h after intraruminal application and every 5 min (first hour), every 10 min(second hour), and at 3 and 6h after i.v. bolus application, respectively. Quercetin and quercetin metabolites with an intact flavonol structure (isorhamnetin, tamarixetin, and kaempferol) in plasma samples were analyzed by HPLC with fluorescence detection. After intraruminal application of quercetin and rutin, respectively, quercetin and its methylated (isorhamnetin, tamarixetin) and dehydroxylated (kaempferol) derivatives were present in plasma mainly as conjugated forms, whereas free quercetin and its derivatives were scarcely detected. For rutin, the relative bioavailability of total flavonols (sum of conjugated and nonconjugated quercetin and its conjugated and nonconjugated derivatives after intake of 50 mg/kg of BW) was 767.3% compared with quercetin aglycone (100%). Absolute bioavailability of total flavonols was only 0.1 and 0.5% after quercetin aglycone and rutin applications, respectively. Our data demonstrate that bioavailability of quercetin from rutin is substantially higher compared with that from quercetin aglycone in cows after intraruminal (or oral) application, unlike in monogastric species.

Effects of the flavonol quercetin on the bioavailability of simvastatin in pigs.

The influence of the dietary flavonol quercetin on the pharmacokinetics of the HMG-CoA reductase inhibitor simvastatin was investigated in pigs. Simvastatin (0.25mg/kg body weight) was orally administered to six pigs either without or with quercetin (10mg/kg). In addition, simvastatin was administered to three pigs that had received a diet supplemented with the flavonol over a period of 1 week. Daily quercetin intake was 10mg/kg in these animals. Co-ingestion of quercetin with the statin did not alter area under the concentration time curve (AUC(0-->infinity)), time to achieve maximum plasma concentration (t(max)) or half-life (t(1/2)) of simvastatin. However, there was a trend towards a reduction of the maximum plasma concentration (C(max)) of simvastatin when quercetin was administered concomitantly (P=0.06). As compared to controls, AUC(0-->infinity) of simvastatin was significantly decreased after feeding the quercetin-supplemented diet for 1 week. The plasma ratio of simvastatin and its acid metabolite was neither altered by the concomitant quercetin ingestion nor by feeding of the flavonol over a period of 1 week. We conclude that chronic ingestion of high doses of the flavonol quercetin will decrease the bioavailability of simvastatin to a significant extent.

Incorporation of neutral C-terminal residues in 3-amidinophenylalanine-derived matriptase inhibitors

A novel series of matriptase inhibitors based on previously identified tribasic 3-amidinophenylalanine derivatives was prepared. The C-terminal basic group was replaced by neutral residues to reduce the hydrophilicity of the inhibitors. The most potent compound 22 inhibits matriptase with a K(i) value of 0.43 nM, but lacks selectivity towards factor Xa. By combination with neutral N-terminal sulfonyl residues several potent thrombin inhibitors were identified, which had reduced matriptase affinity.

Oral Green Tea Catechins Transiently Lower Plasma Glucose Concentrations in Female db/db Mice

Polyphenols, including green tea catechins, are secondary plant compounds often discussed in the context of health-promoting potential. Evidence for such effects is mainly derived from epidemiological and cell culture studies. The aim of the present study was to investigate antidiabetic, antiadipogenic, and anti-inflammatory effects at nonpharmacological doses in an obese diabetic mouse model that exerts early relevant clinical signs of non-insulin-dependent diabetes mellitus. Female db/db mice received a flavonoid-poor diet either without additive, with rosiglitazone (RSG, 0.02 g/kg diet), or with green tea extract (low-dose green tea extract [LGTE] and high-dose green tea extract [HGTE], 0.1 and 1 g/kg diet). Food and water were freely available. The body weight was monitored weekly. Blood was sampled (12-h fasted) from the tail vein on day 28 and analyzed for glucose, cholesterol, triacylglycerol, nonesterified fatty acids, insulin, adiponectin, and soluble intercellular adhesion molecule-1 (sICAM-1). Blood glucose was also analyzed on day 14. Furthermore, sICAM-1 release was investigated in tumor necrosis factor alpha-stimulated EAhy926 cells. After 14 days, fasting glycemia was improved by RSG or HGTE supplementation compared to controls. However, at the end of the study (day 28), only RSG exhibited glucose-lowering effects and induced plasma adiponectin concentrations, paralleled by higher body weight gain and reduced periuterine fat pads compared to controls. However, only GTE treatment reduced sICAM-1 release in vitro and in vivo. Nonpharmacological HGTE supplementation in db/db mice caused (1) no adiponectin-inducing or antiadipogenic effects, (2) reduced sICAM-1 release, thereby potentially exerting anti-inflammatory effects in the progressive diabetic state, and (3) a transient improvement in glycemia.

Dietary flavonoids do not affect vitamin E status in growing rats

This study aimed at investigating potential effects of the flavonoids genistein, quercetin and catechin and the role of co-ingested dietary fat on vitamin E concentrations in rats. In experiment 1, genistein, quercetin and catechin were fed to rats, incorporated into semisynthetic diets at concentrations of 2 g/kg, either as individual compounds or in combination to investigate their individual and possible synergistic actions towards alpha-tocopherol in plasma and selected tissues. For experiments 2 and 3, quercetin was selected as a representative model flavonoid to study the effects of the quantity (5% vs. 10%) and type of dietary fat (coconut fat plus corn oil vs. rapeseed oil; experiment 2) and the role of cholesterol (experiment 3) on potential flavonoid-vitamin E interactions. The concentrations of alpha-tocopherol and gamma-tocopherol in the plasma, liver, lung and cortex of flavonoid-fed rats were not significantly different from the concentrations measured in control rats in all three experiments. However, increasing the amount of coconut fat plus corn oil from 5 to 10% resulted in lower alpha-tocopherol concentrations in plasma and tissue. The alpha-tocopherol concentrations in the rats fed rapeseed oil were significantly higher than in rats fed coconut fat plus corn oil. The addition of 0.2% cholesterol to the diet did not influence the tocopherol concentrations in plasma and tissue in both quercetin-supplemented and control rats. Additionally, the mRNA levels of alpha-TTP, CYP3A4, CYP4F and Mdr2, which are integral proteins involved in vitamin E homeostasis were measured. Only genistein reduced the Mdr2 mRNA level, but none of the other transcripts. All other flavonoids were without effect. In conclusion, co-ingested dietary fat appears to influence vitamin E concentrations in rats, but does not seem to be an important determinant of flavonoid-vitamin E interactions.

Concomitant Intake of Quercetin with a Grain-Based Diet Acutely Lowers Postprandial Plasma Glucose and Lipid Concentrations in Pigs

Treatment goals of diabetes mellitus type 2 (DMT2) include glycemic control and reduction of nonglycemic risk factors, for example, dyslipidemia. Quercetin, a plant-derived polyphenol, often discussed for possible antidiabetic effects, was investigated for acute postprandial glucose- and lipid-lowering effects in healthy growing pigs. Male pigs (n = 16, body weight = BW 25–30 kg) were fed flavonoid-poor grain-based meals without (GBM) or with quercetin (GBMQ). In a first experiment, postprandial plasma concentrations of glucose, nonesterified fatty acids (NEFA), and triacylglycerols were analyzed in 8 pigs receiving 500 g of either GBM or GBMQ (10 mg/kg BW) in a cross-over design. Blood samples were collected before, and up to 5 h every 30 min, as well as 6 and 8 h after the feeding. In the second experiment, 2 h after ingestions of 1000 g of either GBM or GBMQ (50 mg/kg BW) animals were sacrificed; gastric content was collected and analyzed for dry matter content. Quercetin ingestion reduced postprandial glucose, NEFA, and TG concentration, but two hours after ingestion of the meal no effect on gastric emptying was observed. Our results point to inhibitory effects of quercetin on nutrient absorption, which appear not to be attributable to delayed gastric emptying.

Effect of quercetin on the toxicokinetics of ochratoxin A in rats

Previous studies indicate that the intestinal absorption of the nephrotoxic mycotoxin ochratoxin A (OTA) occurs mainly through passive diffusion of the undissociated form. However, several in vitro studies have shown that OTA is partly re-secreted into the intestinal lumen by the multi-drug resistance associated protein (MRP2) and breast cancer resistance protein (BRCP). In vitro studies using Caco-2 cells have shown that some polyphenols (quercetin, genistein, resveratrol) may impair OTA efflux through competitive inhibition of MRP2, possibly resulting in an increased systemic availability of OTA. Among the tested polyphenols, quercetin showed the highest potential as efflux pump inhibitor; therefore, the aim of the present in vivo study was to investigate possible effects of quercetin on the toxicokinetics of OTA in rats. Eighteen growing male F344 Fisher rats (body weight: 200 g) were allocated to two dietary treatments consisting of (1) a commercial, flavonoid-free balanced diet containing 10 mg OTA/kg derived from inoculated wheat and (2) the same diet supplemented with 100 mg quercetin/kg. The animals were fed restrictively (~0.7 of ad libitum intake, 13 g/d) to avoid differences in OTA intake. Animals were kept in metabolism cages to facilitate total urine and faeces collection. After 6 days on trial, rats were euthanised and blood, liver, kidney, muscle and brain samples were taken from each animal. Faeces, urine and tissue samples were analysed for OTA and its main metabolite ochratoxin α by high-performance liquid chromatography using fluorescence detection. Quercetin supplementation had no effect (P > 0.05) on feed consumption, OTA-intake, water intake and body weight gain. Faecal and urinary excretion of OTA and ochratoxin α and concentrations of OTA in all tissues were not affected by quercetin supplementation. Based on the total excretion and tissue concentrations of OTA, it is concluded that the polyphenol quercetin has no impact on the toxicokinetics of OTA in vivo.