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DENOVO LIPOGENESIS (DNL) DURING FASTING AND ORAL FRUCTOSE IN LEAN AND OBESE HYPERINSULINEMIC SUBJECTS

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... However, those studies included only lean men and an area of uncertainty was whether the carbohydrate intake could produce a higher stimulation of DNL in overweight humans. Furthermore, it was seen that insulin-resistant men showed a modestly increased fractional DNL, but the absolute rate of DNL accounted for only a few extra grams of fat per day (19,34). In the present study, when a stable isotope technique was used it was evident that DNL occurred at NPRQs < 1, even with only a single carbohydrate meal. ...
... The absolute rate of DNL (15) could not be measured because of the lack of a prolonged steady state response, which did not allow measurement of the quantitative role of the higher hepatic DNL found in the overweight men. Nevertheless, these results show that overweight hyperinsulinemic men had a stimulated hepatic DNL, both during fasting and after carbohydrate intake, which is in agreement with data reported previously (34). On the other hand, hyperinsulinemia and the increase in plasma glucose or fatty acids may contribute to the higher triacylglycerol production (35). ...
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Adjustments of carbohydrate intake and oxidation occur in both normal-weight and overweight individuals. Nevertheless, the contribution of carbohydrates to the accumulation of fat through either reduction of fat oxidation or stimulation of fat synthesis in obesity remains poorly investigated. The objective of this study was to assess the postprandial metabolic changes and the fractional hepatic de novo lipogenesis (DNL) induced by a high-carbohydrate, low-fat meal in lean and overweight young men. A high-carbohydrate, low-fat meal was administered to 6 lean and 7 overweight men after a 17.5-h fast. During the fasting and postprandial periods, energy expenditure (EE), macronutrient oxidation, diet-induced thermogenesis, and serum insulin, glucose, triacylglycerol, and fatty acids were measured. To determine DNL, [1-13C]sodium acetate was infused and the mass isotopomer distribution analysis method was applied. After intake of the high-carbohydrate meal, the overweight men had hyperinsulinemia and higher fatty acid and triacylglycerol concentrations than did the lean men. The overweight group showed a greater EE, whereas there was no significant difference in carbohydrate oxidation between the groups. Nevertheless, the overweight men had a marginally higher protein oxidation and a lower lipid oxidation than did the lean men. DNL was significantly higher before and after meal intake in the overweight men and was positively associated with fasting serum glucose and insulin concentrations. Furthermore, postprandial DNL was positively correlated with body fat mass, EE, and triacylglycerol. After a high-carbohydrate, low-fat meal, overweight men had a lower fat oxidation and a higher fractional hepatic fat synthesis than did lean men.
... The effects of dietary fructose on lipid and glucose metabolism have been active areas of research for over 40 y (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). In controlled feeding studies, fructose has been used to elevate daylong serum triacylglycerol (TG) 7 concentrations in healthy (9,11) and diabetic subjects (12), an event that could lead to an accumulation of lipoprotein remnants, which could be atherogenic. ...
... For example, we have recently found a 65% change in the sources of fatty acids used for hepatic VLDL-TG synthesis when research subjects went from fasting to the postprandial state (20,30,31), with significant increases in de novo lipogenesis after meals containing glucose as the CHO source (32). Having been somewhat surprised by the magnitude of the lipogenic effect of glucose-containing liquid meals in our previous work, the question arose as to how these results might be modified by the presence of fructose, a CHO known to stimulate lipogenesis in animals (33) and humans (5,13). We hypothesized that the replacement of even a small amount of the glucose with fructose would increase lipogenic rates. ...
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The goal of this study was to determine the magnitude by which acute consumption of fructose in a morning bolus would stimulate lipogenesis (measured by infusion of 13C1-acetate and analysis by GC-MS) immediately and after a subsequent meal. Six healthy subjects [4 men and 2 women; aged (mean +/- SD) 28 +/- 8 y; BMI, 24.3 +/- 2.8 kg/m(2); and serum triacylglycerols (TG), 1.03 +/- 0.32 mmol/L] consumed carbohydrate boluses of sugars (85 g each) in a random and blinded order, followed by a standardized lunch 4 h later. Subjects completed a control test of glucose (100:0) and a mixture of 50:50 glucose:fructose and one of 25:75 (wt:wt). Following the morning boluses, serum glucose and insulin after 100:0 were greater than both other treatments (P < 0.05) and this pattern occurred again after lunch. In the morning, fractional lipogenesis was stimulated when subjects ingested fructose and peaked at 15.9 +/- 5.4% after the 50:50 treatment and at 16.9 +/- 5.2% after the 25:75 treatment, values that were greater than after the 100:0 treatment (7.8 +/- 5.7%; P < 0.02). When fructose was consumed, absolute lipogenesis was 2-fold greater than when it was absent (100:0). Postlunch, serum TG were 11-29% greater than 100:0 and TG-rich lipoprotein-TG concentrations were 76-200% greater after 50:50 and 25:75 were consumed (P < 0.05). The data demonstrate that an early stimulation of lipogenesis after fructose, consumed in a mixture of sugars, augments subsequent postprandial lipemia. The postlunch blood TG elevation was only partially due to carry-over from the morning. Acute intake of fructose stimulates lipogenesis and may create a metabolic milieu that enhances subsequent esterification of fatty acids flowing to the liver to elevate TG synthesis postprandially.
... On the other hand, there is growing interest in studying the effects on lipid metabolism and insulin resistance following the ingestion of fructose [11,12]. Stimulation of de novo lipogenesis [13], a defect in the clearance of VLDL (very-low-density lipoprotein) particles [14] or even the esterification of non-oxidized NEFAs (nonesterified fatty acids) in the liver [15] are among the explanations for the hypertriacylglycerolaemia induced by fructose in healthy subjects at rest. Meanwhile, the reduction in insulin sensitivity appears to be dependent on fructose-induced lipid modification [16]. ...
... Moreover, TAG rapidly returned to basal levels 45 min after its peak level (t 75 ) following GluF, discarding the hypothesis of a delay in TAG clearance as one of the possible causes of hypertriacylglycerolaemia, as has been proposed by Chong et al. [15]. Furthermore, the higher level of insulin found with GluF leads us to suggest that the mechanism making the greatest contribution to the increase in TAG was not a reduction in the activation of lipoprotein lipase in adipose tissue and the subsequent delay in lipid clearance [38], but rather de novo lipogenesis, a mechanism widely explained after fructose intake [13,39]. Along these lines, several studies have reported that the fast arrival of fructose at the liver could cause an overload of the pentose phosphate pathway leading to the acute expression of lipogenic genes [40,41], and to the rapid activation of hepatic lipogenesis and the secretion of VLDL via SREBP-1c (sterol-regulatory-elementbinding protein-1c) [42]. ...
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The metabolic response when aerobic exercise is performed after the ingestion of glucose plus fructose is unclear. In the present study, we administered two beverages containing GluF (glucose+fructose) or Glu (glucose alone) in a randomized cross-over design to 20 healthy aerobically trained volunteers to compare the hormonal and lipid responses provoked during aerobic exercise and the recovery phase. After ingesting the beverages and a 15-min resting period, volunteers performed 30 min of moderate aerobic exercise. Urinary and blood samples were taken at baseline (t(-15)), during the exercise (t(0), t(15) and t(30)) and during the recovery phase (t(45), t(75) and t(105)). Plasma insulin concentrations were higher halfway through the exercise period and during acute recuperation (t(15) and t(75); P<0.05) following ingestion of GluF than after Glu alone, without any differences between the effects of either intervention on plasma glucose concentrations. Towards the end of the exercise period, urinary catecholamine concentrations were lower following GluF (t(45); P<0.05). Plasma triacylglycerol (triglyceride) concentrations were higher after the ingestion of GluF compared with Glu (t(15), t(30), t(45) and t(105); P<0.05). Furthermore, with GluF, we observed higher levels of lipoperoxides (t(15), t(30), t(45) and t(105); P<0.05) and oxidized LDL (low-density lipoprotein; t(30); P<0.05) compared with after the ingestion of Glu alone. In conclusion, hormonal and lipid alterations are provoked during aerobic exercise and recovery by the addition of a dose of fructose to the pre-exercise ingestion of glucose.
... Several studies in rats confirm that an excess intake of dietary fructose increases lipogenesis, leading to fat buildup, body weight gain, and obesity [50][51][52][53][54] . Other possible mechanisms include a low concentration of the fructose transporter Glucose transporter 5 (GLUT5), which neither stimulates insulin secretion from pancreatic beta cells nor leptin secretion [55][56][57] . ...
... In rats, the in vivo administration of [ 14 C] fructose led to 14 C incorporation in liver lipids [40]. A similar experiment demonstrated the stimulation of hepatic de novo lipogenesis after acute fructose uptake in humans, detecting the inclusion of infused 13 C-labeled acetate into VLDL-palmitate [41]. Further, fructose causes the concomitant inhibition of fatty acid oxidation in the mitochondria of hepatocytes. ...
Article
Fructans are fructose-based oligo-and polysaccharides of natural origin. Fructan and fructose species are sometimes confused by the great public, although they clearly have different biochemical and physiological properties. This review discusses aspects of the use of fructose and fructans in foods in the context of human health, with possible differential effects on cellular autophagy in cells of the human body. Although there are uncertainties on the daily levels of ingested fructose to be considered harmful to human health, there is an emerging consensus on the benefits of the use of fructans in functional foods, sustaining health via direct immunomodulatory and antioxidant effects or through indirect, prebiotic mechanisms.
... Der synes enighed om, at øget de novo lipogenese bevirker øget triglycerid i plasma, specielt palmitatrig triglycerid.Effekt af fruktose og sukrose på de novo lipogenese Sukrose består, som tidligere naevnt, af fruktose og glukose, og det har vaeret undersøgt om sukrose, fruktose eller glukose hver for sig bidrager forskelligt til de novo lipogenese. I korttidsforsøg (< 1 døgn) øger fruktoseindtag hepatisk de novo lipogenese 3-10 gange i forhold til samme maengde glukose(30).I forsøg med 4 døgns kostperioder, er det vist, at hepatisk de novo lipogenese øges 2,5 gange, hvis der overspises(31). De novo lipogenesen øgedes i samme grad, uanset om kostoverskuddet stammede fra glukose eller sukrose, og stigningen var af samme størrelse hos overvaegtige og normalvaegtige personer. ...
... The existence of this pathway was documented by the observation that, in the rat in vivo (17) and in isolated rat hepatocytes (47,214), administration of [ 14 C]fructose led to 14 C incorporation in liver lipids. Stimulation of hepatic de novo lipogenesis can indeed be documented after acute administration of fructose, or of fructose-glucose mixtures, in humans by monitoring incorporation of infused 13 C-labeled acetate into very-low-density lipoprotein (VLDL)-palmitate (165,190). In vitro data indicated that lactate rather than triose-P is the main lipogenic precursor after fructose administration and that activation of pyruvate dehydrogenase by high-fructose diets is a major regulatory step in this process (41,59,162). ...
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While virtually absent in our diet a few hundred years ago, fructose has now become a major constituent of our modern diet. Our main sources of fructose are sucrose from beet or cane, high fructose corn syrup, fruits, and honey. Fructose has the same chemical formula as glucose (C(6)H(12)O(6)), but its metabolism differs markedly from that of glucose due to its almost complete hepatic extraction and rapid hepatic conversion into glucose, glycogen, lactate, and fat. Fructose was initially thought to be advisable for patients with diabetes due to its low glycemic index. However, chronically high consumption of fructose in rodents leads to hepatic and extrahepatic insulin resistance, obesity, type 2 diabetes mellitus, and high blood pressure. The evidence is less compelling in humans, but high fructose intake has indeed been shown to cause dyslipidemia and to impair hepatic insulin sensitivity. Hepatic de novo lipogenesis and lipotoxicity, oxidative stress, and hyperuricemia have all been proposed as mechanisms responsible for these adverse metabolic effects of fructose. Although there is compelling evidence that very high fructose intake can have deleterious metabolic effects in humans as in rodents, the role of fructose in the development of the current epidemic of metabolic disorders remains controversial. Epidemiological studies show growing evidence that consumption of sweetened beverages (containing either sucrose or a mixture of glucose and fructose) is associated with a high energy intake, increased body weight, and the occurrence of metabolic and cardiovascular disorders. There is, however, no unequivocal evidence that fructose intake at moderate doses is directly related with adverse metabolic effects. There has also been much concern that consumption of free fructose, as provided in high fructose corn syrup, may cause more adverse effects than consumption of fructose consumed with sucrose. There is, however, no direct evidence for more serious metabolic consequences of high fructose corn syrup versus sucrose consumption.
... Alloxan is known to cause direct and selective cytotoxicity to the pancreatic -cells by causing cell membrane disruption after its intracellular accumulation (Palmer and Lernmark, 1997), resulting in a decrease in endogenous insulin secretion and release, which leads to decreased glucose utilization by the tissues (Omamoto et al., 1981; Szkudelski, 2001). Prolonged high fructose infusion is known to lead to rapid stimulation of lipogenesis and triglyceride accumulation, which in turn contributes to reduced insulin sensitivity and hepatic insulin resistance or glucose tolerance (Schwarz et al., 1993Schwarz et al., , 1994 Hellerstein et al., 1996) in addition to fructose causing de-expression and inactivity of fructose transporter, GLUT5 (Basciano et al., 2005). Dexamethasone induces insulin-resistance diabetes by causing down-regulation of insulin receptor substrate (IRS)-1 expression (Turnbow et al., 1994Turnbow et al., , 1995) and/or decreasing insulin-stimulated GLUT4 translocation to the cell plasma membrane particularly of skeletal muscles (Garvey et al., 1989; Saad et al., 1993; Weinstein et al., 1998; Sakoda et al., 2000). ...
Article
In African traditional medicine, water decoction made from the dry seeds of Hunteria umbellata (K. Schum) Hallier f. is highly valued in the management of diabetes mellitus. In the present study, the antihyperglycaemic activity of the seed aqueous extract of Hunteria umbellate (K. Schum) Hallier f. (HU) was investigated in alloxan-induced, high fructose- and dexamethasone-induced hyperglycaemic rats. Alloxan-induced, dexamethasone-induced and high fructose-induced hyperglycaemic rats were treated with single, daily oral administration of 1 mg/kg of glibenclamide, 50 mg/kg, 100 mg/kg and 200 mg/kg of HU in Groups III, IV, V and VI, for 14 days, 21 days and 8 weeks, respectively. The effects of these drugs on FBG, free plasma insulin levels, HbA(1c), serum TG and TC, and insulin resistance indices were investigated. Data generated in the current study showed that glibenclamide and graded oral doses of HU caused significant dose related (p < 0.05, < 0.01 and < 0.001) reductions in FBG when compared to the values obtained for the model control (Group II) rats. Similarly, daily oral administration of 66.7 g/kg fructose to rats for 8 weeks was associated with significant (p < 0.001) hyperglycaemia, elevations in plasma HbA(1c), free insulin, fasting insulin resistance indices, serum TG, and cholesterol. However, concomitant oral treatments with 1mg/kg of glibenclamide, 50 mg/kg, 100 mg/kg, and 200 mg/kg of HU extract significantly and dose dependently (p < 0.05, < 0.01 and < 0.001) attenuated development of hyperglycaemia, decreased levels of plasma HbA(1c), free insulin, and serum triglyceride and cholesterol, in the Groups III, IV, V and VI rats, respectively, when compared to fructose-induced hyperglycaemic (Group II) rats. Similar effect was also recorded in the dexamethasone-induced hyperglycaemic rats. Results of this study suggest that the hypoglycaemic and antihyperlipidaemic effects of HU are mediated via enhanced peripheral glucose uptake and improvements in hyperinsulinaemia.
... An increased glycogen synthesis has been shown to participate in the autoregulation of hepatic glucose production in healthy lean subjects[5]and is therefore likely to also function in obese NIDDM subjects. Nonoxidative fructose disposal, which corresponds to glycogen accretion from neoformed glucose[5]and de novo lipogenesis[29]were identical in lean subjects, obese non-diabetic subjects and obese patients with NIDDM. This suggests that stimulation of glycogen synthesis contributed to prevent an increase in EGP after fructose ingestion in all three groups. ...
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Increased endogenous glucose production (EGP) and gluconeogenesis contribute to the pathogenesis of hyperglycaemia in non-insulin-dependent diabetes mellitus (NIDDM). In healthy subjects, however, EGP remains constant during administration of gluconeogenic precursors. This study was performed in order to determine whether administration of fructose increases EGP in obese NIDDM patients and obese non-diabetic subjects. Eight young healthy lean subjects, eight middle-aged obese NIDDM patients and seven middle-aged obese non-diabetic subjects were studied during hourly ingestion of 13C fructose (0.3 g.kg fat free mass-1.h-1) for 3 h. Fructose failed to increase EGP (measured with 6,6 2H glucose) in NIDDM (17.7 +/- 1.9 mumol.kg fat free mass-1.min-1 basal vs 15.9 +/- 0.9 after fructose), in obese non-diabetic subjects (12.1 +/- 0.5 basal vs 13.1 +/- 0.5 after fructose) and in lean healthy subjects (13.3 +/- 0.5 basal vs 13.8 +/- 0.6 after fructose) although 13C glucose synthesis contributed 73.2% of EGP in lean subjects, 62.6% in obese non-diabetic subjects, and 52.8% in obese NIDDM patients. Since glucagon may play an important role in the development of hyperglycaemia in NIDDM, healthy subjects were also studied during 13C fructose ingestion + hyperglucagonaemia (232 +/- 9 ng/l) and during hyperglucagonaemia alone. EGP increased by 19.8% with ingestion of fructose + glucagon (p < 0.05) but remained unchanged during administration of fructose or glucagon alone. The plasma 13C glucose enrichment was identical after fructose ingestion both with and without glucagon, indicating that the contribution of fructose gluconeogenesis to the glucose 6-phosphate pool was identical in these two conditions. We concluded that during fructose administration: 1) gluconeogenesis is increased, but EGP remains constant in NIDDM, obese non-diabetic, and lean individuals; 2) in lean individuals, both an increased glucagonaemia and an enhanced supply of gluconeogenic precursors are required to increase EGP; this increase in EGP occurs without changes in the relative proportion of glucose 6-phosphate production from fructose and from other sources (i.e. glycogenolysis + gluconeogenesis from non-fructose precursors).
... The reasons why simple sugars stimulate fatty acid synthesis more than starch are not completely understood. When sucrose or fructose is ingested, the direct uptake of the fructose molecule and rapid phosphorylation by the liver may explain why fatty acid synthesis is stimulated (Schwarz et al, 1993). ...
Article
Cellular energy metabolism depends on two main energy substrates: glucose and fatty acids. The major determinants of the fuel mix oxidized are glucose availability and insulin secretion that both promote glucose oxidation. Fatty acid oxidation occurs mainly when glucose availability is reduced, for instance during the postabsorptive period, or when energy expenditure is increased, for instance during exercise of long duration. When eucaloric diets with high carbohydrate and low fat content are ingested, de novo lipogenesis is stimulated in adults, but the rate of conversion of glucose to fatty acids is low, which means that carbohydrate intake does not have much influence on fat requirements. The lower limit of fat intake depends on three factors: the fat requirement to meet energy needs, the need for essential fatty acids, and the amount of fat in the diet that is necessary to absorb fat-soluble vitamins. The lower limit of fat intake to meet the energy needs of adults is assumed to be between 10 and 15% of dietary energy, provided that enough carbohydrates are available. For adults, the requirement for essential fatty acids is in the range of 3-5% of dietary energy for linoleic acid, and 0.5-1.0% of dietary energy for linolenic acid. Fat energy should not be below 10% of total energy intake in order to ensure an unrestricted absorption of fat-soluble vitamins, particularly vitamins A and E. The recommendations on upper limits of fat intake for adults must take into account the degree of physical activity. International recommendations indicate that active individuals in energy balance may consume up to 35% of their total energy intake as dietary fat, whereas sedentary individuals should not consume more than 30% of their energy from fat. Saturated fatty acids should not exceed 10% of the energy intake.
... Obese, hyperinsulinemic humans exhibit a de novo lipogenesis contribution of ≤ 3-fold higher, but this still represents < 10% of VLDL triacylglycerol (125). Oral administration of fructose (at 10 mg·kg lean body mass Ϫ1 ·min Ϫ1 ) for 6 h in subjects who fasted overnight increased the fractional de novo lipogenesis contribution substantially (to > 30%), whereas isoenergetic glucose administration failed to increase de novo lipogenesis above 2-4% (127). In this study, absolute de novo lipogenesis flux was still quantitatively minor, however, representing < 5% of the total hepatic fructose disposal rate, and serum triacylglycerol concentrations did not change acutely. ...
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Current trends in health promotion emphasize the importance of reducing dietary fat intake. However, as dietary fat is reduced, the dietary carbohydrate content typically rises and the desired reduction in plasma cholesterol concentrations is frequently accompanied by an elevation of plasma triacylglycerol. We review the phenomenon of carbohydrate-induced hypertriacylglycerolemia, the health effects of which are among the most controversial and important issues in public health nutrition today. We first focus on how seminal observations made in the late 1950s and early 1960s became the basis for subsequent important research questions and areas of scientific study. The second focus of this paper is on the current knowledge of biological mechanisms that contribute to carbohydrate-induced hypertriacylglycerolemia. The clinical rationale behind mechanistic studies is this: if carbohydrate-induced hypertriacylglycerolemia shares a metabolic basis with endogenous hypertriacylglycerolemia (that observed in subjects consuming high-fat diets), then a similar atherogenic risk may be more likely than if the underlying metabolic mechanisms differ. The third focus of the paper is on both the positive metabolic changes that occur when high-carbohydrate diets are consumed and the potentially negative health effects of such diets. The review concludes with a summary of some important research questions that remain to be addressed. These issues include the level of dietary carbohydrate that induces carbohydrate-induced hypertriacylglycerolemia, whether the phenomenon is transient or can be avoided, whether de novo lipogenesis contributes to the phenomenon, and what magnitude of triacylglycerol elevation represents an increase in disease risk.
... Fructose, in particular, has been identified as a monosaccharide with an especially potent effect on de novo lipogenesis (10,11). Most previous studies have examined the effect of diet composition or energy levels on de novo lipogenesis in lean subjects; however, there is some evidence that de novo lipogenesis is greater in hyperinsulinemic obese subjects (11,12). An experimental feature shared by many of these previous studies was that the response time to the dietary manipulation was short, generally ≤ 6 h duration (10,11). ...
Article
The results of previous studies suggest that de novo lipogenesis may play an important role in the etiology of obesity, particularly during overconsumption of different carbohydrates. We hypothesized that de novo lipogenesis would increase during overfeeding, would vary depending on the type of carbohydrate consumed, and would be greater in obese than in lean women. De novo lipogenesis was measured during 96 h of overfeeding by 50% with either sucrose or glucose and during an energy balance treatment (control) in 8 lean and 5 obese women. De novo lipogenesis was determined by measuring the amount of deuterium incorporation into plasma triacylglycerols. Fat and carbohydrate balance were measured simultaneously by continuous whole-body calorimetry. De novo lipogenesis did not differ significantly between lean and obese subjects, except with the control treatment, for which de novo lipogenesis was greater in the obese subjects. De novo lipogenesis was 2- to 3-fold higher after overfeeding by 50% than after the control treatment in all subjects. The type of carbohydrate overfeeding (sucrose or glucose) had no significant effect on de novo lipogenesis in either subject group. Estimated amounts of absolute VLDL production ranged from a minimum of 2 g/d (control) to a maximum of 10 g/d after overfeeding. This compares with a mean fat balance of approximately 275 g after 96 h of overfeeding. Individual subjects showed characteristic amounts of de novo lipogenesis, suggesting constitutive (possibly genetic) differences. De novo lipogenesis increases after overfeeding with glucose and sucrose to the same extent in lean and obese women but does not contribute greatly to total fat balance.
... Higher fractional DNL values in the HPTG and diabetic HPTG groups in this study are compatible with previous reports in which DNL was increased in obesity and in insulin-resistant states (25,59,60). Higher DNL in the HPTG and diabetic HPTG groups may be explained by high levels of insulin (61). ...
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Newly synthesized triglyceride (TG) may exit the liver immediately as VLDL-TG or be stored and secreted after a delay. We quantified the contributions from plasma NEFA, diet, and de novo lipogenesis (DNL) to VLDL-TG via immediate and delayed pathways in five lean, normolipidemic subjects; six obese, hypertriglyceridemic (HPTG) nondiabetics; and six obese, HPTG diabetics. Intravenous [(2)H(31)]palmitate and [1-(13)C(1)] acetate and oral [(2)H(35)]stearate were administered for 30 h preceding an overnight fast. [1,2,3,4-(13)C(4)]palmitate was infused during the subsequent 12 h fast. Contributions from plasma NEFA via the immediate pathway were 64 +/- 15, 33 +/- 6, and 58 +/- 2% in control, HPTG, and diabetic HPTG, respectively. Delayed pool fractional contributions were as follows: dietary FA, 2.0 +/- 0.9, 2.5 +/- 1, and 12 +/- 2%; DNL, 3 +/- 0.3, 14 +/- 3, and 13 +/- 4%; delayed NEFA, 15 +/- 4, 20 +/- 4, and 30 +/- 3%. VLDL-TG production rates and absolute input rates from the delayed pool were significantly higher in HPTG and diabetic HPTG than in controls. In conclusion, we provide direct kinetic evidence for a hepatic TG storage pool in humans and document its metabolic sources. The turnover time and sources of this pool differ in diabetic HPTG and nondiabetic HPTG, with potential therapeutic implications.
... However, DNL and plasma TAG concentrations were not found to be different between the two types of carbohydrate overfeeding. Schwarz et al. (1993) have demonstrated that oral administration of fructose for 6 h (at 10 mg/kg lean body mass per min) increases fractional DNL substantially (to > 30%) compared with an isoenergetic load of glucose, which fails to increase DNL (2-4 %). This finding is consistent with preliminary data from the acute metabolic study comparing fructose and glucose described earlier (p. ...
Article
The elevation of blood lipid concentrations in response to the consumption of low-fat high-carbohydrate diets is known as carbohydrate-induced hypertriacylglycerolaemia (HPTG). An understanding of the mechanisms involved in the interaction between carbohydrates and plasma lipids may help determine whether carbohydrate-induced HPTG would increase cardiovascular risk. There is growing evidence to suggest that the sugar component of the diet may be largely responsible, rather than the total carbohydrate. In most studies designed to investigate the mechanisms of carbohydrate-induced HPTG, the amounts and types of sugars and starches used in the diets are not specified. Findings have been mixed and inconsistent. It is proposed that the elucidation of mechanisms from current studies could have been confounded by the different ways in which sugars are metabolized in the body. At present, there are few studies that have evaluated the independent effects of dietary sugars. Interest has been focused on de novo lipogenesis (DNL), as it has recently been found to be positively correlated with increases in fasting TAG levels produced on high-carbohydrate diets, indicating that DNL may contribute to carbohydrate-induced HPTG. DNL has been found to be determined by starch:sugar in a high-carbohydrate diet and affected by different types of sugars. The presence of DNL in adipose tissue is supported by emerging gene-expression studies in human subjects. In the wake of rising intakes of sugars, further research is needed to investigate the mechanisms associated with different sugars, so that appropriate therapeutic strategies can be adopted.
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Fructose intake and the prevalence of obesity have both increased over the past two to three decades. Compared with glucose, the hepatic metabolism of fructose favors lipogenesis, which may contribute to hyperlipidemia and obesity. Fructose does not increase insulin and leptin or suppress ghrelin, which suggests an endocrine mechanism by which it induces a positive energy balance. This review examines the available data on the effects of dietary fructose on energy homeostasis and lipid/carbohydrate metabolism. Recent publications, studies in human subjects, and areas in which additional research is needed are emphasized.
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Treatment of type 2 diabetes mellitus (T2DM) patients with pioglitazone results in a more favorable lipid profile, and perhaps more favorable cardiac outcomes, than treatment with rosiglitazone. Pioglitazone treatment increases VLDL-triacylglycerol clearance, but the role of de novo lipogenesis (DNL) has not been explored, and no direct comparison has been made between the thiazolidinediones (TZDs). Twelve subjects with T2DM and hypertriacylglyceridemia were randomized to either rosiglitazone or pioglitazone treatment. Stable isotope infusion studies were performed at baseline and after 20 weeks of treatment. Both treatments reduced glucose and HbA(1c) concentrations equally. Pioglitazone treatment resulted in a 40% reduction in hepatic DNL (P < 0.01) and in a 25% reduction in hepatic glucose production (P < 0.05), while rosiglitazone did not significantly change either parameter, although comparisons of changes between treatments were not significantly different. These pilot results indicate that pioglitazone reduces hepatic DNL while rosiglitazone does not. Larger follow-up studies are required to confirm differential effects of these agents definitively. The reduction in DNL may underlie altered assembly or atherogenicity of lipoprotein particles and may reflect PPARalpha or other non-PPARgamma actions on the liver by pioglitazone. These differences might help explain previously reported differences in lipid profiles and cardiovascular disease outcomes for rosiglitazone and pioglitazone.
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Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar is implicated in dyslipidemia, fatty liver, and insulin resistance. The aim of the study was to develop a simple outpatient tolerance test for lipogenic sensitivity to dietary sugar. In inpatients given repeated doses of fructose, protocol 1 compared the acute increase in DNL determined from the percentage of palmitate ("new palmitate") and the percentage of isotopically labeled palmitate ("%DNL") in very low-density lipoprotein triglyceride (TG). Protocol 2 compared the increase in new palmitate in outpatients given three different sugar beverages in a randomized crossover design. There were 15 lean and overweight volunteers in protocol 1 and 15 overweight volunteers in protocol 2. In protocol 1, subjects received 1.4 g/kg fructose in divided oral doses over 6 h; in protocol 2, subjects received 0.5 g/kg fructose, 0.5 g/kg fructose plus 0.5 g/kg glucose, or 1 g/kg fructose plus 1 g/kg glucose each as a single oral bolus. We measured the increase in DNL by two methods. After repeated doses of fructose, new palmitate was significantly correlated with the increase in %DNL (Δ, r = 0.814; P < 0.001) and with fasting insulin levels (area under the curve, r = 0.754; P = 0.001). After a single sugar dose, new palmitate showed a dose effect and was greater after fructose plus glucose. Very low-density lipoprotein TG and total TG significantly increased in both protocols. A single oral bolus of fructose and glucose rapidly increases serum TG and TG palmitate in overweight subjects. A dual sugar challenge test could prove useful to identify individuals at risk for carbohydrate-induced dyslipidemia and other adverse effects of increased DNL.
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Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.
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We have reported that, compared with glucose-sweetened beverages, consuming fructose-sweetened beverages with meals results in lower 24-h circulating glucose, insulin, and leptin concentrations and elevated triacylglycerol (TG). However, pure fructose and glucose are not commonly used as sweeteners. High-fructose corn syrup (HFCS) has replaced sucrose as the predominant sweetener in beverages in the United States. We compared the metabolic/endocrine effects of HFCS with sucrose and, in a subset of subjects, with pure fructose and glucose. Thirty-four men and women consumed 3 isocaloric meals with either sucrose- or HFCS-sweetened beverages, and blood samples were collected over 24 h. Eight of the male subjects were also studied when fructose- or glucose-sweetened beverages were consumed. In 34 subjects, 24-h glucose, insulin, leptin, ghrelin, and TG profiles were similar between days that sucrose or HFCS was consumed. Postprandial TG excursions after HFCS or sucrose were larger in men than in women. In the men in whom the effects of 4 sweeteners were compared, the 24-h glucose and insulin responses induced by HFCS and sucrose were intermediate between the lower responses during consumption of fructose and the higher responses during glucose. Unexpectedly, postprandial TG profiles after HFCS or sucrose were not intermediate but comparably high as after pure fructose. Sucrose and HFCS do not have substantially different short-term endocrine/metabolic effects. In male subjects, short-term consumption of sucrose and HFCS resulted in postprandial TG responses comparable to those induced by fructose.
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