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 (C6H12O6), 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.

High-fructose diet stimulates hepatic de novo lipogenesis (DNL) and causes hypertriglyceridemia and insulin resistance in rodents. Fructose-induced insulin resistance may be secondary to alterations of lipid metabolism. In contrast, fish oil supplementation decreases triglycerides and may improve insulin resistance. Therefore, we studied the effect of high-fructose diet and fish oil on DNL and VLDL triglycerides and their impact on insulin resistance. Seven normal men were studied on four occasions: after fish oil (7.2 g/day) for 28 days; a 6-day high-fructose diet (corresponding to an extra 25% of total calories); fish oil plus high-fructose diet; and control conditions. Following each condition, fasting fractional DNL and endogenous glucose production (EGP) were evaluated using [1-13 C]sodium acetate and 6,6-2 H 2 glucose and a two-step hyperinsulinemic-euglycemic clamp was performed to assess insulin sensitivity. High-fructose diet significantly increased fasting glycemia (7 ؎ 2%), triglycerides (79 ؎ 22%), fractional DNL (sixfold), and EGP (14 ؎ 3%, all P < 0.05). It also impaired insulin-induced suppression of adipose tissue lipolysis and EGP (P < 0.05) but had no effect on wholebody insulin-mediated glucose disposal. Fish oil significantly decreased triglycerides (37%, P < 0.05) after high-fructose diet compared with high-fructose diet without fish oil and tended to reduce DNL but had no other significant effect. In conclusion, high-fructose diet induced dyslipidemia and hepatic and adipose tissue insulin resistance. Fish oil reversed dyslipidemia but not insulin resistance. Diabetes

In healthy humans, body fat is a major determinant of the resting rate of muscle sympathetic nerve discharge. Overweight-associated sympathetic activation could represent one potential mechanism contributing to the increased incidence of cardiovascular complications in overweight subjects.

There has been much concern regarding the role of dietary fructose in the development of metabolic diseases. This concern arises from the continuous increase in fructose (and total added caloric sweeteners consumption) in recent decades, and from the increased use of high-fructose corn syrup (HFCS) as a sweetener. A large body of evidence shows that a high-fructose diet leads to the development of obesity, diabetes, and dyslipidemia in rodents. In humans, fructose has long been known to increase plasma triglyceride concentrations. In addition, when ingested in large amounts as part of a hypercaloric diet, it can cause hepatic insulin resistance, increased total and visceral fat mass, and accumulation of ectopic fat in the liver and skeletal muscle. These early effects may be instrumental in causing, in the long run, the development of the metabolic syndrome. There is however only limited evidence that fructose per se, when consumed in moderate amounts, has deleterious effects. Several effects of a high-fructose diet in humans can be observed with high-fat or high-glucose diets as well, suggesting that an excess caloric intake may be the main factor involved in the development of the metabolic syndrome. The major source of fructose in our diet is with sweetened beverages (and with other products in which caloric sweeteners have been added). The progressive replacement of sucrose by HFCS is however unlikely to be directly involved in the epidemy of metabolic disease, because HFCS appears to have basically the same metabolic effects as sucrose. Consumption of sweetened beverages is however clearly associated with excess calorie intake, and an increased risk of diabetes and cardiovascular diseases through an increase in body weight. This has led to the recommendation to limit the daily intake of sugar calories.Pure, white, and deadly: the dark side of sugar was suspected many years ago, when an association between sugar consumption and coronary heart diseases was recognized and emphasized by John Yudkin [1]. Sugar, a natural sweetener obtained from either sugar cane or beets, is a disaccharide composed of one glucose molecule linked through an α1-4 glycoside bond to a fructose molecule. Fructose, besides contributing to half the total content of sugar, can also be found as a hexose in fruits and honey. More recently, sweeteners started to be produced from corn through starch isolation and hydrolysis to glucose, followed by enzymatic isomerization of part of the glucose into fructose [2,3]. The resulting mixture, known as high-fructose corn syrup (HFCS), has several industrial advantages over sugar, the most important being its low price, and has progressively replaced sugar consumption in North America over the past 30 years.Fructose metabolism has been reviewed extensively elsewhere [4][5][6] and will be only briefly outlined here. In the gut, fructose is transported by specific transporters, GLUT5 [7,8]. In some subjects, fructose absorption is quantitatively limited, and some malabsorption occurs when lar...

Euglycemic hyperinsulinemia evokes both sympathetic activation and vasodilation in skeletal muscle, but the mechanism remains unknown. To determine whether insulin per se or insulin-induced stimulation ofcarbohydrate metabolism is the main excitatory stimulus, we performed, in six healthy lean subjects, simultaneous microneurographic recordings of muscle sympathetic nerve activity, plethysmographic measurements of calf blood flow, and calorimetric determinations of carbohydrate oxidation rate. Measurements were made during 2 h of: (a) insulin/glucose infusion (hyperinsulinemic 16 pmol/kg per min] euglycemic clamp), (b) exogenous glucose infusion at a rate matched to that attained during protocol a, and (c) exogenous fructose infusion at the same rate as for glucose infusion in protocol b. For a comparable rise in carbohydrate oxidation, insulin/glucose infusion that resulted in twofold greater increases in plasma insulin concentrations than did glucose infusion alone, evoked twofold greater increases in both muscle sympathetic nerve activity and calf blood flow. Fructose infusion, which increased carbohydrate oxidation comparably, but had only a minor effect on insulinemia, did not stimulate either muscle sympathetic nerve activity or calf blood flow. These observations suggest that in humans hyperinsulinemia per se, rather than insulin-induced stimulation of carbohydrate metabolism, is the main mechanism that triggers both sympathetic activation and vasodilation in skeletal muscle. (J. Clin. Invest. 1993. 92:147-154.) Key words: energy expenditure * fructose infusion * glucose infusion * microneurography -hyperinsulinemic euglycemic clamp

The sympathetic nervous system is an important regulatory mechanism of both metabolic and cardiovascular function, and altered sympathetic activity may play a role in the etiology and/or complications of obesity. In lean subjects, insulin evokes sympathetic activation and vasodilation in skeletal muscle. In obese subjects such vasodilation is impaired and, in turn, may contribute to insulin resistance. To examine the relationship between sympathetic and vasodilatory responses in skeletal muscle to hyperinsulinemia, we simultaneously measured muscle sympathetic nerve activity (MSNA) and calf blood flow at basal and during a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp in eight lean and eight obese subjects. The major findings of this study are twofold: obese subjects had a 2.2 times higher fasting rate of MSNA, and euglycemic hyperinsulinemia, which more than doubled MSNA and increased calf blood flow by roughly 30% in lean subjects, had only a minor vasodilatory and sympathoexcitatory effect in obese subjects. In contrast, two non-insulin-sympathetic stimuli evoked comparably large increases in MSNA in lean and obese subjects. We conclude that insulin resistance in obese subjects is associated with increased fasting MSNA and a specific impairment of sympathetic neural responsiveness to physiological hyperinsulinemia in skeletal muscle tissue. (J. Clin. Invest. 1994. 93:2365-2371.) Key words: microneurographyhyperinsulinemic euglycemic clamp -insulin resistance * energy expenditure * muscle blood flow

The mechanisms involved in body weight regulation in humans include genetic, physiological, and behavioral factors. Stability of body weight and body composition requires that energy intake matches energy expenditure and that nutrient balance is achieved. Human obesity is usually associated with high rates of energy expenditure. In adult individuals, protein and carbohydrate stores vary relatively little, whereas adipose tissue mass may change markedly. A feedback regulatory loop with three distinct steps has been recently identified in rodents: 1) a sensor that monitors the size of adipose tissue mass is represented by the amount of leptin synthesized by adipose cells (a protein encoded by the ob gene) which determines the plasma leptin levels; 2) hypothalamic centers, with specific leptin receptors, which receive and integrate the intensity of the signal; and 3) effector systems that influence the two determinants of energy balance, i.e., energy intake and energy expenditure. With the exception of a few very rare cases, the majority of obese human subjects have high plasma leptin levels that are related to the size of their adipose tissue mass. However, the expected regulatory responses (reduction in food intake and increase in energy expenditure) are not observed in obese individuals. Thus obese humans are resistant to the effect of endogenous leptin, despite unaltered hypothalamic leptin receptors. Whether defects in the leptin signaling cascade play a role in the development of human obesity is a field of great actual interest that needs further research. Present evidences suggest that genetic and environmental factors influence eating behavior of people prone to obesity and that diets that are high in fat or energy dense undermine body weight regulation by promoting an overconsumption of energy relative to need.

A 7-d high-fructose diet increased ectopic lipid deposition in liver and muscle and fasting VLDL-triacylglycerols and decreased hepatic insulin sensitivity. Fructose-induced alterations in VLDL-triacylglycerols appeared to be of greater magnitude in the OffT2D group, which suggests that these individuals may be more prone to developing dyslipidemia when challenged by high fructose intakes. This trial was registered at clinicaltrials.gov as NCT00523562.