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Flavan-3-ol-methylxanthine interactions: Modulation of flavan-3-ol bioavailability in volunteers with a functional colon and an ileostomy.
Ottaviani, JI, Fong, RY, Borges, G, Kimball, J, Ensunsa, JL, Medici, V, Pourshahidi, LK, Kane, E, Ward, K, Durkan, R, et al
Free radical biology & medicine. 2023;:1-8
Abstract
Flavan-3-ols, including the flavan-3-ol monomer (-)-epicatechin, are dietary bioactives known to mediate beneficial cardiovascular effects in humans. Recent studies showed that flavan-3-ols could interact with methylxanthines, evidenced by an increase in flavan-3-ol bioavailability with a concomitant increase in flavan-3-ol intake-mediated vascular effects. This study aimed at elucidating flavan-3-ol-methylxanthine interactions in humans in vivo by evaluating the specific contributions of theobromine and caffeine on flavan-3-ol bioavailability. In ileostomists, the effect of methylxanthines on the efflux of flavan-3-ol metabolites in the small intestine was assessed, a parameter important to an understanding of the pharmacokinetics of flavan-3-ols in humans. In a randomized, controlled, triple cross-over study in volunteers with a functional colon (n = 10), co-ingestion of flavan-3-ols and cocoa methylxanthines, mainly represented by theobromine, increased peak circulatory levels (Cmax) of flavan-3-ols metabolites (+21 ± 8%; p < 0.05). Conversely, caffeine did not mediate a statistically significant effect on flavan-3-ol bioavailability (Cmax = +10 ± 8%, p = n.s.). In a subsequent randomized, controlled, double cross-over study in ileostomists (n = 10), cocoa methylxanthines did not affect circulatory levels of flavan-3-ol metabolites, suggesting potential differences in flavan-3-ol bioavailability compared to volunteers with a functional colon. The main metabolite in ileal fluid was (-)-epicatechin-3'-sulfate, however, no differences in flavan-3-ol metabolites in ileal fluid were observed after flavan-3-ol intake with and without cocoa methylxanthines. Taken together, these results demonstrate a differential effect of caffeine and theobromine in modulating flavan-3-ol bioavailability when these bioactives are co-ingested. These findings should be considered when comparing the effects mediated by the intake of flavan-3-ol-containing foods and beverages and the amount and type of methylxanthines present in the ingested matrixes. Ultimately, these insights will be of value to further optimize current dietary recommendations for flavan-3-ol intake. CLINICAL TRIAL REGISTRATION NUMBER This work was registered at clinicaltrials.gov as NCT03526107 (study part 1, volunteers with functional colon) and NCT03765606 (study part 2, volunteers with an ileostomy).
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Impact of polyphenol oxidase on the bioavailability of flavan-3-ols in fruit smoothies: a controlled, single blinded, cross-over study.
Ottaviani, JI, Ensunsa, JL, Fong, RY, Kimball, J, Medici, V, Kuhnle, GGC, Crozier, A, Schroeter, H, Kwik-Uribe, C
Food & function. 2023;(18):8217-8228
Abstract
Flavan-3-ols are bioactive compounds found in a variety of fruits and vegetables (F&V) that have been linked to positive health benefits. Increasing habitual flavan-3-ol intake is challenged by the generally low consumption of F&V. While smoothies are a commonly endorsed, consumer-accepted means to increase the daily intake of these important foods, fruits used for smoothie preparation can have a high polyphenol oxidase (PPO) activity and thus potentially affect the content and bioavailability of flavan-3-ols. To assess whether or not consuming freshly prepared smoothies made with different PPO-containing fruit impacts the bioavailability of the flavan-3-ols, a controlled, single blinded and cross-over study was conducted in healthy men (n = 8) who consumed a flavan-3-ol-containing banana-based smoothie (high-PPO drink), a flavan-3-ol-containing mixed berry smoothie (low-PPO drink) and flavan-3-ols in a capsule format (control). The peak plasma concentration (Cmax) of flavan-3-ol metabolites after capsule intake was 680 ± 78 nmol L-1, which was similar to the levels detected after the intake of the low PPO drink. In contrast, the intake of the high PPO drink resulted in a Cmax of 96 ± 47 nmol L-1, 84% lower than that obtained after capsule intake. In a subsequent study (n = 11), flavan-3-ols were co-ingested with a high-PPO banana drink but contact prior to intake was prevented. In this context, plasma flavan-3-ol levels were still reduced, suggesting an effect possibly related to post-ingestion PPO activity degrading flavan-3-ols in the stomach. There was a substantial range in the PPO activity detected in 18 different fruits, vegetables and plant-derived dietary products. In conclusion, bioavailability of flavan-3-ols, and most likely other dietary polyphenol bioactives, can be reduced substantially by the co-ingestion of high PPO-containing products, the implications of which are of importance for dietary advice and food preparation both at home and in industrial settings.
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Absorption, distribution, metabolism and excretion of apigenin and its glycosides in healthy male adults.
Borges, G, Fong, RY, Ensunsa, JL, Kimball, J, Medici, V, Ottaviani, JI, Crozier, A
Free radical biology & medicine. 2022;:90-96
Abstract
The bioavailability of apigenin and its O-glycosides in humans was investigated with apigenin-4'-glucuronide (Ap-4'-GlcUA), apigenin-7-glucuronide and apigenin-7-sulfate being identified as in vivo metabolites. Apigenin per se was poorly absorbed with metabolites equivalent to 0.5% of intake excreted in urine 0-24 h post-intake. Consumption of a parsley drink containing apigenin-7-O-(2″-O-apiosyl)glucoside resulted in the peak plasma concentration (Cmax) of Ap-4'-GlcUA occurring after 4 h, indicative of absorption in the lower gastrointestinal tract (GIT). Urinary excretion of the three metabolites corresponded to 11.2% of intake. Ingestion of dried powdered parsley leaves with yogurt extended the Cmax of Ap-4'-GlcUA to 6 h. Consumption of chamomile tea containing apigenin-7'-O-glucoside resulted in a 2 h Cmax of Ap-4'-GlcUA, in keeping with absorption in the upper GIT. Urinary excretion was equivalent to 34% of intake. Intake of the parsley drink provided information on intra- and inter-individual variations in the level of excretion of the apigenin metabolites. CLINICAL TRAIL REGISTRATION NUMBER This trail was registered at clinicaltrials.gov as NCT03526081.
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The Dose-Response Effects of Consuming High Fructose Corn Syrup-Sweetened Beverages on Hepatic Lipid Content and Insulin Sensitivity in Young Adults.
Sigala, DM, Hieronimus, B, Medici, V, Lee, V, Nunez, MV, Bremer, AA, Cox, CL, Price, CA, Benyam, Y, Abdelhafez, Y, et al
Nutrients. 2022;(8)
Abstract
Increased hepatic lipid content and decreased insulin sensitivity have critical roles in the development of cardiometabolic diseases. Therefore, our objective was to investigate the dose-response effects of consuming high fructose corn syrup (HFCS)-sweetened beverages for two weeks on hepatic lipid content and insulin sensitivity in young (18-40 years) adults (BMI 18-35 kg/m2). In a parallel, double-blinded study, participants consumed three beverages/day providing 0% (aspartame: n = 23), 10% (n = 18), 17.5% (n = 16), or 25% (n = 28) daily energy requirements from HFCS. Magnetic resonance imaging for hepatic lipid content and oral glucose tolerance tests (OGTT) were conducted during 3.5-day inpatient visits at baseline and again at the end of a 15-day intervention. During the 12 intervening outpatient days participants consumed their usual diets with their assigned beverages. Significant linear dose-response effects were observed for increases of hepatic lipid content (p = 0.015) and glucose and insulin AUCs during OGTT (both p = 0.0004), and for decreases in the Matsuda (p = 0.0087) and Predicted M (p = 0.0027) indices of insulin sensitivity. These dose-response effects strengthen the mechanistic evidence implicating consumption of HFCS-sweetened beverages as a contributor to the metabolic dysregulation that increases risk for nonalcoholic fatty liver disease and type 2 diabetes.
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Wilson disease and the differential diagnosis of its hepatic manifestations: a narrative review of clinical, laboratory, and liver histological features.
Schroeder, SM, Matsukuma, KE, Medici, V
Annals of translational medicine. 2021;(17):1394
Abstract
OBJECTIVE The goal of the present work is to provide an overview of the differential diagnosis of Wilson disease. BACKGROUND Wilson disease is a rare condition due to copper accumulation primarily in the liver and brain. Although there is no definitive cure, current anti-copper treatments are associated with better outcomes if initiated early and if the diagnosis is made promptly. However, diagnostic delays are frequent and often Wilson disease represents a diagnostic challenge. The diagnosis ultimately relies on a combination of clinical, laboratory and genetic findings, and it is crucial that clinicians list Wilson disease in their differential diagnosis, especially in patients presenting with a hepatocellular pattern of liver injury. Some biochemical and liver histological features of Wilson disease overlap with those of more common conditions including nonalcoholic fatty liver disease, alcohol-associated liver disease, and autoimmune hepatitis. In particular, hepatic steatosis, hepatocyte glycogenated nuclei, ballooning degeneration, and Mallory-Denk bodies are often identified in Wilson disease as well as more common liver diseases. In addition, the natural history of liver damage in Wilson disease and the risk of developing liver cancer are largely understudied. METHODS We conducted an enlarged review of published papers on Wilson disease focusing on its diagnosis and distinctive clinical and liver pathology features in relation to common non-cholestatic liver diseases with the final goal in aiding clinicians in the diagnostic process of this rare but treatable condition. CONCLUSIONS Aside from markedly altered copper metabolism, Wilson disease has essentially no pathognomonic features that can distinguish it from more common liver diseases. Clinicians should be aware of this challenge and consider Wilson disease in patients presenting with a hepatocellular pattern of liver injury.
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Consuming Sucrose- or HFCS-sweetened Beverages Increases Hepatic Lipid and Decreases Insulin Sensitivity in Adults.
Sigala, DM, Hieronimus, B, Medici, V, Lee, V, Nunez, MV, Bremer, AA, Cox, CL, Price, CA, Benyam, Y, Chaudhari, AJ, et al
The Journal of clinical endocrinology and metabolism. 2021;(11):3248-3264
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Abstract
CONTEXT Studies in rodents and humans suggest that high-fructose corn syrup (HFCS)-sweetened diets promote greater metabolic dysfunction than sucrose-sweetened diets. OBJECTIVE To compare the effects of consuming sucrose-sweetened beverage (SB), HFCS-SB, or a control beverage sweetened with aspartame on metabolic outcomes in humans. METHODS A parallel, double-blinded, NIH-funded study. Experimental procedures were conducted during 3.5 days of inpatient residence with controlled feeding at a research clinic before (baseline) and after a 12-day outpatient intervention period. Seventy-five adults (18-40 years) were assigned to beverage groups matched for sex, body mass index (18-35 kg/m2), and fasting triglyceride, lipoprotein and insulin concentrations. The intervention was 3 servings/day of sucrose- or HFCS-SB providing 25% of energy requirement or aspartame-SB, consumed for 16 days. Main outcome measures were %hepatic lipid, Matsuda insulin sensitivity index (ISI), and Predicted M ISI. RESULTS Sucrose-SB increased %hepatic lipid (absolute change: 0.6 ± 0.2%) compared with aspartame-SB (-0.2 ± 0.2%, P < 0.05) and compared with baseline (P < 0.001). HFCS-SB increased %hepatic lipid compared with baseline (0.4 ± 0.2%, P < 0.05). Compared with aspartame-SB, Matsuda ISI decreased after consumption of HFCS- (P < 0.01) and sucrose-SB (P < 0.01), and Predicted M ISI decreased after consumption of HFCS-SB (P < 0.05). Sucrose- and HFCS-SB increased plasma concentrations of lipids, lipoproteins, and uric acid compared with aspartame-SB. No outcomes were differentially affected by sucrose- compared with HFCS-SB. Beverage group effects remained significant when analyses were adjusted for changes in body weight. CONCLUSION Consumption of both sucrose- and HFCS-SB induced detrimental changes in hepatic lipid, insulin sensitivity, and circulating lipids, lipoproteins and uric acid in 2 weeks.
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A Pilot Study Comparing the Effects of Consuming 100% Orange Juice or Sucrose-Sweetened Beverage on Risk Factors for Cardiometabolic Disease in Women.
Price, CA, Medici, V, Nunez, MV, Lee, V, Sigala, DM, Benyam, Y, Keim, NL, Mason, AE, Chen, SY, Parenti, M, et al
Nutrients. 2021;(3)
Abstract
Overconsumption of sugar-sweetened beverages increases risk factors associated with cardiometabolic disease, in part due to hepatic fructose overload. However, it is not clear whether consumption of beverages containing fructose as naturally occurring sugar produces equivalent metabolic dysregulation as beverages containing added sugars. We compared the effects of consuming naturally-sweetened orange juice (OJ) or sucrose-sweetened beverages (sucrose-SB) for two weeks on risk factors for cardiometabolic disease. Healthy, overweight women (n = 20) were assigned to consume either 3 servings of 100% orange juice or sucrose-SB/day. We conducted 16-hour serial blood collections and 3-h oral glucose tolerance tests during a 30-h inpatient visit at baseline and after the 2-week diet intervention. The 16-h area under the curve (AUC) for uric acid increased in subjects consuming sucrose-SB compared with subjects consuming OJ. Unlike sucrose-SB, OJ did not significantly increase fasting or postprandial lipoproteins. Consumption of both beverages resulted in reductions in the Matsuda insulin sensitivity index (OJ: -0.40 ± 0.18, p = 0.04 within group; sucrose-SB: -1.0 ± 0.38, p = 0.006 within group; p = 0.53 between groups). Findings from this pilot study suggest that consumption of OJ at levels above the current dietary guidelines for sugar intake does not increase plasma uric acid concentrations compared with sucrose-SB, but appears to lead to comparable decreases of insulin sensitivity.
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Synergistic effects of fructose and glucose on lipoprotein risk factors for cardiovascular disease in young adults.
Hieronimus, B, Medici, V, Bremer, AA, Lee, V, Nunez, MV, Sigala, DM, Keim, NL, Havel, PJ, Stanhope, KL
Metabolism: clinical and experimental. 2020;:154356
Abstract
BACKGROUND Fructose consumption increases risk factors for cardiometabolic disease. It is assumed that the effects of free sugars on risk factors are less potent because they contain less fructose. We compared the effects of consuming fructose, glucose or their combination, high fructose corn syrup (HFCS), on cardiometabolic risk factors. METHODS Adults (18-40 years; BMI 18-35 kg/m2) participated in a parallel, double-blinded dietary intervention during which beverages sweetened with aspartame, glucose (25% of energy requirements (ereq)), fructose or HFCS (25% and 17.5% ereq) were consumed for two weeks. Groups were matched for sex, baseline BMI and plasma lipid/lipoprotein concentrations. 24-h serial blood samples were collected at baseline and at the end of intervention. Primary outcomes were 24-h triglyceride AUC, LDL-cholesterol (C), and apolipoprotein (apo)B. Interactions between fructose and glucose were assessed post hoc. FINDINGS 145 subjects (26.0 ± 5.8 years; body mass index 25.0 ± 3.7 kg/m2) completed the study. As expected, the increase of 24-h triglycerides compared with aspartame was highest during fructose consumption (25%: 6.66 mmol/Lx24h 95% CI [1.90 to 11.63], P = 0.0013 versus aspartame), intermediate during HFCS consumption (25%: 4.68 mmol/Lx24h 95% CI [-0.18 to 9.55], P = 0.066 versus aspartame) and lowest during glucose consumption. In contrast, the increase of LDL-C was highest during HFCS consumption (25%: 0.46 mmol/L 95% CI [0.16 to 0.77], P = 0.0002 versus aspartame) and intermediate during fructose consumption (25%: 0.33 mmol/L 95% CI [0.03 to 0.63], P = 0.023 versus aspartame), as was the increase of apoB (HFCS-25%: 0.108 g/L 95%CI [0.032 to 0.184], P = 0.001; fructose 25%: 0.072 g/L 95%CI [-0.004 to 0.148], P = 0.074 versus aspartame). The post hoc analyses showed significant interactive effects of fructose*glucose on LDL-C and apoB (both P < 0.01), but not on 24-h triglyceride (P = 0.340). CONCLUSION A significant interaction between fructose and glucose contributed to increases of lipoprotein risk factors when the two monosaccharides were co-ingested as HFCS. Thus, the effects of HFCS on lipoprotein risks factors are not solely mediated by the fructose content and it cannot be assumed that glucose is a benign component of HFCS. Our findings suggest that HFCS may be as harmful as isocaloric amounts of pure fructose and provide further support for the urgency to implement strategies to limit free sugar consumption.
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Effects of Consuming Sugar-Sweetened Beverages for 2 Weeks on 24-h Circulating Leptin Profiles, Ad Libitum Food Intake and Body Weight in Young Adults.
Sigala, DM, Widaman, AM, Hieronimus, B, Nunez, MV, Lee, V, Benyam, Y, Bremer, AA, Medici, V, Havel, PJ, Stanhope, KL, et al
Nutrients. 2020;(12)
Abstract
Sugar-sweetened beverage (sugar-SB) consumption is associated with body weight gain. We investigated whether the changes of (Δ) circulating leptin contribute to weight gain and ad libitum food intake in young adults consuming sugar-SB for two weeks. In a parallel, double-blinded, intervention study, participants (n = 131; BMI 18-35 kg/m2; 18-40 years) consumed three beverages/day containing aspartame or 25% energy requirement as glucose, fructose, high fructose corn syrup (HFCS) or sucrose (n = 23-28/group). Body weight, ad libitum food intake and 24-h leptin area under the curve (AUC) were assessed at Week 0 and at the end of Week 2. The Δbody weight was not different among groups (p = 0.092), but the increases in subjects consuming HFCS- (p = 0.0008) and glucose-SB (p = 0.018) were significant compared with Week 0. Subjects consuming sucrose- (+14%, p < 0.0015), fructose- (+9%, p = 0.015) and HFCS-SB (+8%, p = 0.017) increased energy intake during the ad libitum food intake trial compared with subjects consuming aspartame-SB (-4%, p = 0.0037, effect of SB). Fructose-SB decreased (-14 ng/mL × 24 h, p = 0.0006) and sucrose-SB increased (+25 ng/mL × 24 h, p = 0.025 vs. Week 0; p = 0.0008 vs. fructose-SB) 24-h leptin AUC. The Δad libitum food intake and Δbody weight were not influenced by circulating leptin in young adults consuming sugar-SB for 2 weeks. Studies are needed to determine the mechanisms mediating increased energy intake in subjects consuming sugar-SB.
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Nutritional Ketosis for Weight Management and Reversal of Metabolic Syndrome.
Gershuni, VM, Yan, SL, Medici, V
Current nutrition reports. 2018;7(3):97-106
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Plain language summary
The five main components of Metabolic Syndrome — obesity, fasting blood sugar, high triglycerides (TGs), low HDL cholesterol, and hypertension — are all improved by carbohydrate restriction which reduces insulin secretion. Ketones are water-soluble molecules produced by the liver from fatty acids when blood glucose and liver glycogen stores are depleted, for example through fasting, low carbohydrate intake or intense exercise. Nutritional ketosis through a very low carbohydrate ketogenic diet (VLCKD) results in lower insulin levels which can lead to a shift in metabolism towards the use of fat stores for energy. A “well-formulated” ketogenic diet is described as composed of 5–10% carbohydrates (<20–50g/day), adequate protein (1–1.5g/kg/day), and fat until satiated, with blood ketone levels of 0.5 to 3 mg/dL. Nutritional ketosis is different from diabetic ketoacidosis which can affect type 1 diabetics and which is a medical emergency. A number of meta-analyses of randomised controlled trials have shown that VLCKD are better than low fat diets with respects to weight loss, lipid profiles, glucose metabolism, blood pressure and inflammatory markers. The authors review the literature and mechanisms of action.
Abstract
PURPOSE OF REVIEW The goal of this paper is to review current literature on nutritional ketosis within the context of weight management and metabolic syndrome, namely, insulin resistance, lipid profile, cardiovascular disease risk, and development of non-alcoholic fatty liver disease. We provide background on the mechanism of ketogenesis and describe nutritional ketosis. RECENT FINDINGS Nutritional ketosis has been found to improve metabolic and inflammatory markers, including lipids, HbA1c, high-sensitivity CRP, fasting insulin and glucose levels, and aid in weight management. We discuss these findings and elaborate on potential mechanisms of ketones for promoting weight loss, decreasing hunger, and increasing satiety. Humans have evolved with the capacity for metabolic flexibility and the ability to use ketones for fuel. During states of low dietary carbohydrate intake, insulin levels remain low and ketogenesis takes place. These conditions promote breakdown of excess fat stores, sparing of lean muscle, and improvement in insulin sensitivity.