Fanny Theytaz

Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans

To assess how intrahepatic fat and insulin resistance relate to daily fructose and energy intake during short‐term overfeeding in healthy subjects.

Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets

BackgroundPCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a circulating protein that promotes hypercholesterolemia by decreasing hepatic LDL receptor protein. Under non interventional conditions, its expression is driven by sterol response element binding protein 2 (SREBP2) and follows a diurnal rhythm synchronous with cholesterol synthesis. Plasma PCSK9 is associated to LDL-C and to a lesser extent plasma triglycerides and insulin resistance. We aimed to verify the effect on plasma PCSK9 concentrations of dietary interventions that affect these parameters.MethodsWe performed nutritional interventions in young healthy male volunteers and offspring of type 2 diabetic (OffT2D) patients that are more prone to develop insulin resistance, including: i) acute post-prandial hyperlipidemic challenge (n=10), ii) 4 days of high-fat (HF) or high-fat/high-protein (HFHP) (n=10), iii) 7 (HFruc1, n=16) or 6 (HFruc2, n=9) days of hypercaloric high-fructose diets. An acute oral fat load was also performed in two patients bearing the R104C-V114A loss-of-function (LOF) PCSK9 mutation. Plasma PCSK9 concentrations were measured by ELISA. For the HFruc1 study, intrahepatocellular (IHCL) and intramyocellular lipids were measured by 1H magnetic resonance spectroscopy. Hepatic and whole-body insulin sensitivity was assessed with a two-step hyperinsulinemic-euglycemic clamp (0.3 and 1.0 mU.kg-1.min-1).FindingsHF and HFHP short-term diets, as well as an acute hyperlipidemic oral load, did not significantly change PCSK9 concentrations. In addition, post-prandial plasma triglyceride excursion was not altered in two carriers of PCSK9 LOF mutation compared with non carriers. In contrast, hypercaloric 7-day HFruc1 diet increased plasma PCSK9 concentrations by 28% (p=0.05) in healthy volunteers and by 34% (p=0.001) in OffT2D patients. In another independent study, 6-day HFruc2 diet increased plasma PCSK9 levels by 93% (p<0.0001) in young healthy male volunteers. Spearman’s correlations revealed that plasma PCSK9 concentrations upon 7-day HFruc1 diet were positively associated with plasma triglycerides (r=0.54, p=0.01) and IHCL (r=0.56, p=0.001), and inversely correlated with hepatic (r=0.54, p=0.014) and whole-body (r=−0.59, p=0.0065) insulin sensitivity.ConclusionsPlasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.

Exercise Prevents Fructose-Induced Hypertriglyceridemia in Healthy Young Subjects

Excess fructose intake causes hypertriglyceridemia and hepatic insulin resistance in sedentary humans. Since exercise improves insulin sensitivity in insulin-resistant patients, we hypothesized that it would also prevent fructose-induced hypertriglyceridemia. This study was therefore designed to evaluate the effects of exercise on circulating lipids in healthy subjects fed a weight-maintenance, high-fructose diet. Eight healthy males were studied on three occasions after 4 days of 1) a diet low in fructose and no exercise (C), 2) a diet with 30% fructose and no exercise (HFr), or 3) a diet with 30% fructose and moderate aerobic exercise (HFrEx). On all three occasions, a 9-h oral [13C]-labeled fructose loading test was performed on the fifth day to measure [13C]palmitate in triglyceride-rich lipoprotein (TRL)-triglycerides (TG). Compared with C, HFr significantly increased fasting glucose, total TG, TRL-TG concentrations, and apolipoprotein (apo)B48 concentrations as well as postfructose glucose, total TG, TRL-TG, and [13C]palmitate in TRL-TG. HFrEx completely normalized fasting and postfructose TG, TRL-TG, and [13C]palmitate concentration in TRL-TG and apoB48 concentrations. In addition, it increased lipid oxidation and plasma nonesterified fatty acid concentrations compared with HFr. These data indicate that exercise prevents the dyslipidemia induced by high fructose intake independently of energy balance.

Effects of supplementation with essential amino acids on intrahepatic lipid concentrations during fructose overfeeding in humans

BACKGROUND A high dietary protein intake has been shown to blunt the deposition of intrahepatic lipids in high-fat- and high-carbohydrate-fed rodents and humans. OBJECTIVE The aim of this study was to evaluate the effect of essential amino acid supplementation on the increase in hepatic fat content induced by a high-fructose diet in healthy subjects. DESIGN Nine healthy male volunteers were studied on 3 occasions in a randomized, crossover design after 6 d of dietary intervention. Dietary conditions consisted of a weight-maintenance balanced diet (control) or the same balanced diet supplemented with 3 g fructose · kg(-1) · d(-1) and 6.77 g of a mixture of 5 essential amino acids 3 times/d (leucine, isoleucine, valine, lysine, and threonine) (HFrAA) or with 3 g fructose · kg(-1) · d(-1) and a maltodextrin placebo 3 times/d (HFr); there was a washout period of 4 to 10 wk between each condition. For each condition, the intrahepatocellular lipid (IHCL) concentration, VLDL-triglyceride concentration, and VLDL-[(13)C]palmitate production were measured after oral loading with [(13)C]fructose. RESULTS HFr increased the IHCL content (1.27 ± 0.31 compared with 2.74 ± 0.55 vol %; P < 0.05) and VLDL-triglyceride (0.55 ± 0.06 compared with 1.40 ± 0.15 mmol/L; P < 0.05). HFr also enhanced VLDL-[(13)C]palmitate production. HFrAA significantly decreased IHCL compared with HFr (to 2.30 ± 0.43 vol%; P < 0.05) but did not change VLDL-triglyceride concentrations or VLDL-[(13)C]palmitate production. CONCLUSIONS Supplementation with essential amino acids blunts the fructose-induced increase in IHCL but not hypertriglyceridemia. This is not because of inhibition of VLDL-[(13)C]palmitate production. This trial was registered at www.clinicaltrials.gov as NCT01119989.

Metabolic Fate of Fructose Ingested with and without Glucose in a Mixed Meal

Ingestion of pure fructose stimulates de novo lipogenesis and gluconeogenesis. This may however not be relevant to typical nutritional situations, where fructose is invariably ingested with glucose. We therefore assessed the metabolic fate of fructose incorporated in a mixed meal without or with glucose in eight healthy volunteers. Each participant was studied over six hours after the ingestion of liquid meals containing either 13C-labelled fructose, unlabeled glucose, lipids and protein (Fr + G) or 13C-labelled fructose, lipids and protein, but without glucose (Fr), or protein and lipids alone (ProLip). After Fr + G, plasma 13C-glucose production accounted for 19.0% ± 1.5% and 13CO2 production for 32.2% ± 1.3% of 13C-fructose carbons. After Fr, 13C-glucose production (26.5% ± 1.4%) and 13CO2 production (36.6% ± 1.9%) were higher (p < 0.05) than with Fr + G. 13C-lactate concentration and very low density lipoprotein VLDL 13C-palmitate concentrations increased to the same extent with Fr + G and Fr, while chylomicron 13C-palmitate tended to increase more with Fr + G. These data indicate that gluconeogenesis, lactic acid production and both intestinal and hepatic de novo lipogenesis contributed to the disposal of fructose carbons ingested together with a mixed meal. Co-ingestion of glucose decreased fructose oxidation and gluconeogenesis and tended to increase 13C-pamitate concentration in gut-derived chylomicrons, but not in hepatic-borne VLDL-triacylglycerol (TG). This trial was approved by clinicaltrial. gov. Identifier is NCT01792089.

Fructose-Induced Hyperuricemia Is Associated With a Decreased Renal Uric Acid Excretion in Humans

Ingestion of a high-fructose meal increases blood uric acid (UA) concentration in healthy subjects (1). Furthermore, high-fructose intake over several days is associated with increased fasting UA concentration (1). These effects are generally attributed to an increased UA production, as observed after intravenous fructose administration (2). It has not been assessed, however, whether UA also increases when fructose is administered as several small drinks instead of one single large load or whether a high-fructose diet (HFrD) impairs renal UA clearance (UAC) or fractional excretion (UAFE) as observed in rats (3). We therefore measured blood and urine UA and creatinine concentrations (RX Monza; Randox Laboratories, London, U.K.) and calculated UAC and UAFE in 16 healthy male subjects (mean ± SD age 22.6 ± 2.9, weight 69.7 ± 6.9 kg, BMI 22.1 ± 1.8 kg/m2, mean fat-free mass [FFM] 57.8 ± 5.4 kg) over a 9-h period during which they drank lemon-flavored …

Energy and macronutrient intake after gastric bypass for morbid obesity: a 3-y observational study focused on protein consumption

BACKGROUND The effect of a Roux-en-Y gastric bypass (RYGB) on body weight has been amply documented, but few studies have simultaneously assessed the evolution of energy and macronutrient intakes, energy expenditure, and changes in body composition over time after an RYGB. OBJECTIVE We evaluated energy and macronutrient intakes, body composition, and the basal metabolic rate (BMR) in obese female patients during the initial 3 y after an RYGB. METHODS Sixteen women with a mean ± SEM body mass index (in kg/m(2)) of 44.1 ± 1.6 were included in this prospective observational study. The women were studied on 6 different occasions as follows: before and 1, 3, 6, 12 (n = 16), and 36 (n = 8) mo after surgery. On each occasion, food intake was evaluated from 4- or 7-d dietary records, body composition was assessed with the use of bio-impedancemetry, and energy expenditure was measured with the use of indirect calorimetry. RESULTS Body weight evolution showed the typical pattern reported after an RYGB. Total energy intake was 2072 ± 108 kcal/d at baseline and decreased to 681 ± 58 kcal/d at 1 mo after surgery (P < 0.05 compared with at baseline). Total energy intake progressively increased to reach 1240 ± 87 kcal/d at 12 mo after surgery (P < 0.05 compared with at 1 mo after surgery) and 1448 ± 57 kcal/d at 36 mo after surgery (P < 0.05 compared with at 12 mo after surgery). Protein intake was 87 ± 4 g/d at baseline and ± 2 g/d 1 mo after surgery (P < 0.05 compared with at baseline) and increased progressively thereafter to reach 57 ± 3 g/d at 36 mo after surgery (P < 0.05 compared with at 1 mo after surgery). Carbohydrate and fat intakes over time showed similar patterns. Protein intake from meat and cheese were significantly reduced early at 1 mo after surgery but increased thereafter (P < 0.05). The BMR decreased from 1.12 ± 0.04 kcal/min at baseline to 0.93 ± 0.03, 0.86 ± 0.03, and 0.85 ± 0.04 kcal/min at 3, 12, and 36 mo after surgery, respectively (all P < 0.05 compared with at baseline). CONCLUSIONS Total energy, carbohydrate, fat, and protein intakes decreased markedly during the initial 1-3 mo after an RYGB, whereas the BMR moderately decreased. The reduction in protein intake was particularly severe at 1 mo after surgery, and protein intake increased gradually after 3-6 mo after surgery. This trial was registered at clinicaltrials.gov as NCT01891591.

Effects of roux-en-Y gastric bypass surgery on postprandial fructose metabolism.

Fructose is partly metabolized in small bowel enterocytes, where it can be converted into glucose or fatty acids. It was therefore hypothesized that Roux‐en‐Y gastric bypass (RYGB) may significantly alter fructose metabolism.