Fructose has been raised a few times in the last week so I'd thought I'd post this article. As you'll see the HFCS is bad news, and we consume a lot of bad fructose calories. This shouldn't stop you consuming fruit though, it should stop you consuming junk, processed foods!!
Fructose, insulin resistance, and metabolic dyslipidemia
Heather Basciano , Lisa Federico and Khosrow Adeli
Nutrition & Metabolism 2005, 2:5doi:10.1186/1743-7075-2-5
Obesity and type 2 diabetes are occurring at epidemic rates in the United States and many parts of the world. The "obesity epidemic" appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in the amount of dietary fructose consumption from high intake of sucrose and high fructose corn syrup, a common sweetener used in the food industry. A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, perturbs glucose metabolism and glucose uptake pathways, and leads to a significantly enhanced rate of de novo lipogenesis and triglyceride (TG) synthesis, driven by the high flux of glycerol and acyl portions of TG molecules from fructose catabolism. These metabolic disturbances appear to underlie the induction of insulin resistance commonly observed with high fructose feeding in both humans and animal models. Fructose-induced insulin resistant states are commonly characterized by a profound metabolic dyslipidemia, which appears to result from hepatic and intestinal overproduction of atherogenic lipoprotein particles. Thus, emerging evidence from recent epidemiological and biochemical studies clearly suggests that the high dietary intake of fructose has rapidly become an important causative factor in the development of the metabolic syndrome. There is an urgent need for increased public awareness of the risks associated with high fructose consumption and greater efforts should be made to curb the supplementation of packaged foods with high fructose additives. The present review will discuss the trends in fructose consumption, the metabolic consequences of increased fructose intake, and the molecular mechanisms leading to fructose-induced lipogenesis, insulin resistance and metabolic dyslipidemia.
Emerging epidemic of the Metabolic Syndrome
The new millennium has witnessed the emergence of a modern epidemic, the metabolic syndrome, with frightful consequences to the health of humans worldwide. The metabolic syndrome, also referred to as "Diabesity"  describes the increasing incidence of diabetes in combination with obesity as a result of changes in human behaviour, available nutrition, and the adoption of more sedentary lifestyles. Obesity and type 2 diabetes are occurring at epidemic rates in the United States [2-4] and developing countries including China  and India . From 1935 to 1996, the prevalence of diagnosed type 2 diabetes climbed nearly 765% . The global figures are predicted to rise 46% from 150 million cases in 2000 to 221 million in 2010 . This epidemic of type 2 diabetes is complicated by the fact that it is a multi-factorial disease, frequently associated with a cluster of pathologies including obesity, hypertriglyceridemia, impaired glucose tolerance, and insulin resistance, collectively referred to as the metabolic syndrome (formerly known as syndrome X and insulin resistance syndrome). Although there is no universally accepted definition of the metabolic syndrome, most would agree that the syndrome includes a cluster of common pathologies: obesity, insulin resistance, dyslipidemia, and hypertension. It is present in 2550% of the United States population . There has been a heightened awareness of the metabolic syndrome and a subsequent increase in clinical attention directed towards prevention, due to its strong association with premature morbidity and mortality [8,10]. In particular, these risk factors predispose the individual to greater risk for developing cardiovascular disease and Type 2 diabetes. Recently, the National Cholesterol Education Panel (NCEP) has officially described and identified a number of these risk factors for cardiovascular diseases . These include: 1) abdominal obesity, 2) elevated TG levels, 3) low high density lipoprotein (HDL)-cholesterol levels, 4) increased blood pressure, and 5) impaired fasting glucose . There is also now consensus that insulin resistance and obesity are actually part of one common pathologic mechanism of the metabolic syndrome [13,14]. Evidence shows that the metabolic syndrome process begins early in life and persistence from childhood to adolescent/adult life produces type 2 diabetes and cardiovascular disease [15,16]. The symptoms of metabolic syndrome are not necessarily manifestations of age, but develop over a predisposed background established at a young age [17,18]. This is a dangerous predisposition, with trends in modern diet and habit likely influencing health and behaviour in increasingly younger populations.
The main driving forces for the increased prevalence of insulin resistance are modern Westernized diets and patterns of eating associated with the dramatic rises in obesity. Insulin resistance is often linked to the macronutrient content in the diet. In the past, diets high in saturated fats have been shown to induce weight gain, insulin resistance, and hyperlipidemia in humans and animals [19-22]. Recent research suggests that a high intake of refined carbohydrates may also increase the risk of insulin resistance [23-26]. In addition, diets specifically high in fructose have been shown to contribute to a metabolic disturbance in animal models resulting in weight gain, hyperlipidemia , and hypertension .
Nutritional factors influencing the development of the Metabolic Syndrome
Nutrition represents a lifestyle element that can be controlled, and that can directly influence health; therefore preventative nutrition and weight control should become a main focus of consumers and prepared-food providers . The Westernization of diets, with an increase in availability of high calorie foods certainly contributes to the epidemic of metabolic syndrome. In the past, physicians and scientists have made an association between dietary energy from fat and body fat. A large market has developed for the popularity and promotion of low fat diets. Interestingly, however, the decline in dietary fat consumption has not corresponded to a decrease in obesity in fact, the opposite trend has emerged . Certainly, diets high in saturated fats have been shown to induce weight gain, insulin resistance, and hyperlipidemia in humans and animals [19-22,31], but the emphasis on fat reductions has had no significant benefits relative to the obesity epidemic. More importantly, the focus on dietary fat is more likely a distraction to more significant causes of metabolic syndrome . If fat is not the culprit in metabolic disorders, then what is? Increasing evidence now suggests that the rise in consumption of carbohydrates, particularly refined sugars high in fructose, appears to be at least one very important contributing factor.
Carbohydrates and the link to the Metabolic Syndrome
The general increases in consumption of calories, and specifically of refined carbohydrates and fructose, is clear and correlates positively with an alarming increases in metabolic syndrome. Can these seemingly harmless nutrients actually be directly associated with metabolic syndrome? Recent studies appear to support this link. In a 2004 study, Gross et al examined nutrient consumption in the United States between 1909 and 1997, and discovered there was a significant correlation in the prevalence of diabetes with fat, carbohydrate, corn syrup, and total energy intakes. Most striking was the fact that when total energy intake was accounted for, corn syrup was positively associated with type 2 diabetes, while protein and fat were not . High fructose corn syrups (HFCS) are quite commonly found in soft drinks and juice beverages, and are incorporated into many convenient pre-packaged foods, such as breakfast cereals and baked goods. Fructose consumption has thus largely increased over the past few decades most likely as a result of this increased use of HFCS, which contains between 5590% fructose. The use of HFCS has increased an alarming 1000% between 1970 and 1990 . In 1970, individual consumption of fructose was only 0.5 lb/year. However, in 1997, this figure rose to an alarming 62.4 lb/year . The type of common, general use sweeteners represent as large an impact as the dramatic increase in the use of these caloric sweeteners. Between 1909 and 1997, sweetener use increased by 86%; and specifically, corn syrup sweeteners now represent over 20% of total daily carbohydrate intake, at an increase of 2100% .
These documented trends have inspired a number of consumption studies and recommendations towards HFCS intake. In 1992, the USDA recommended that only 40 g of extra sugars should be added to a standard 2000 calorie a day diet . The amount of HFCS found in only one 12-oz soft drink equals this total proportion of daily intake. HFCS consumption trends are further exacerbated by the fact that soft drink and fruit juice consumption itself has increased dramatically, adding even more extraneous calories and fructose to the diet. From 1965 to 1996, a food consumption study involving 11 to 18 year olds revealed that total energy and fat intakes were decreasing. There were significant decreases in milk consumption but large increases in the consumption of soft drinks and non-citrus juices . Increasingly, children seem to be choosing mass-produced, 'tasty' artificial juices and sodas over healthier alternatives. In a recent letter to the editor, Jacobson  illustrates some important factors that contribute to increased consumption of soft drinks, and the link to obesity; a) Society is constantly bombarded by huge million-dollar advertising campaigns for soft drinks, offered extra-extra-large serving sizes with free refills, and surrounded by ubiquitous access to soft drink vending machines even in schools, and b) children's standard drinks to accompany meals, and especially fast food, have become soft drinks. The increased use of HFCS in soft drinks and food products are thus exacerbated by increased exposure, and consumption of these products. HFCS are the main caloric sweeteners utilized in soft drinks in the United States, with fructose representing over 40% of sweeteners added to prepared foods and beverages . In a study of females aged 12 to 19 years milk intake decreased by 36%, whereas sodas and fruit drink consumption increased to nearly double from the 1970s to the mid 1990s. From 1994 to 1996, it was found that even though intake of soda, juices, tea, and alcoholic beverages remained constant, the steady decrease of milk intake continued . This becomes a major problem, because while these high-calorie beverages are being consumed, calories from the rest of the diet are not subsequently reduced. The reality is that people do not eliminate or reduce their food portions because they drank a can of soda that day. Data indicate that energy from beverages generally does not displace or decrease energy from other foods consumed, leading to energy imbalances . The main diet issues involve a general lack of education and/or understanding of the implications with recent consumption patterns. Despite education programs to prevent obesity and diabetes worldwide, there has been little focus on the reduction of fructose and HFCS in beverages.
Fructose is readily absorbed and rapidly metabolized by human liver. For thousands of years humans consumed fructose amounting to 1620 grams per day, largely from fresh fruits. Westernization of diets has resulted in significant increases in added fructose, leading to typical daily consumptions amounting to 85100 grams of fructose per day. The exposure of the liver to such large quantities of fructose leads to rapid stimulation of lipogenesis and TG accumulation, which in turn contributes to reduced insulin sensitivity and hepatic insulin resistance/glucose intolerance. These negative effects of fructose are the reason that fructose metabolism has gained recent research attention. Interestingly, small catalytic quantities of fructose can have positive effects, and actually decrease the glycemic response to glucose loads, and improve glucose tolerance. These effects are also observed without any changes in insulin responses and non-esterified fatty acid (NEFA) and TG levels [40,41]. In 1976, sugar substitutes such as fructose had been found to offer the 'advantage' of a 'better' utilization in conditions of limited insulin production. Fructose had a smaller influence on serum insulin concentrations than glucose, and no influence on plasma glucose levels. At that time, this evidence was considered to support fructose as a positive treatment for diabetic control . In 1986 HFCS were even proposed as a low-cost substitute for fructose in diabetic management. Based on these early observations, nutritive sweeteners were considered safe by the Food and Drug Administration, although, it has now been found that intakes above 25% of total energy consumed will cause hypertriglyceridemia and gastrointestinal symptoms . Even with the early positive results, researchers noticed accompanying "unfavorable" influences of these so-called diabetic sugars on obesity and weight gain. Certain metabolic differences exist between glucose and fructose, and the results that were once thought favorable, proved exacerbating to insulin resistance and obesity. In a study comparing normal and diabetic patients, glycemic effects of HFCS were compared to glucose. The negative results of HFCS on immunoreactive insulin, glycemic effect, and immunoreactive C-peptide did not support its use as a substitute for glucose in diabetic patients .
Unfortunately, one out of every four children in the United States consumes above the recommended 25% of total energy intake from sweeteners  and the harmful effects of fructose have been extensively studied in healthy, non-diabetic patients. Studies involving commonly consumed fruit juices showed that natural fructose carbohydrates can alter lipid and protein oxidation biomarkers in the blood, and mediate oxidative stress responses in vivo . A comparative study by Raben et al. examined overweight men and women who consumed fructose-containing sucrose, as opposed to artificial sweeteners as supplements to their diet. Weight, fat mass, and blood pressure were found to be lower in the artificial sweetener-consuming group compared to the sucrose-consuming group, and the sucrose group did not decrease intake of other nutrients to compensate for their increased calorie consumption from the sucrose. Subjects consuming the sweetener did not exhibit increases in energy intake, weight, and blood pressure that seen in the sucrose-consuming subjects . Research in the metabolism of fructose has left more questions about the difference between short-term positive effects, and the negative effects of chronic, long-term use of fructose sugars . The long-term negative effects can include changes in digestion, absorption, plasma hormone levels, appetite, and hepatic metabolism, leading to development of insulin resistance, diabetes, obesity, and inevitably cardiovascular disease.
When the metabolic pathways and characteristics of fructose are examined more closely, many of the questions about its positive and negative effects can be answered. Fructose is a potent regulator of glycogen synthesis and liver glucose uptake. Therefore any catalytic improvements are due to hepatic glucokinase and glucose uptake facilitation. However, as mentioned, the beneficial effects do not continue with chronic fructose utilization . Because of its lipogenic properties, excess fructose in the diet can cause glucose and fructose malabsorption, and greater elevations in TG and cholesterol compared to other carbohydrates . There are key differences in the metabolic pathways that glucose and fructose follow. Upon gastric absorption both fructose and glucose are delivered via the portal vein to the liver. It is believed that the ability of the liver to metabolize high doses of fructose is responsible for the disruption in energy stores and fuel metabolism observed [49-52]. In the liver, fructose is metabolized into glyceraldehyde and dihydroxyacetone phosphate. These particular fructose end products can then readily converge with the glycolytic pathway. Of key importance is the ability of fructose to by-pass the main regulatory step of glycolysis, the conversion of glucose-6-phosphate to fructose 1,6-bisphosphate, controlled by phosphofructokinase. Thus, while glucose metabolism is negatively regulated by phosphofructokinase, fructose can continuously enter the glycolytic pathway. Therefore, fructose can uncontrollably produce glucose, glycogen, lactate, and pyruvate, providing both the glycerol and acyl portions of acyl-glycerol molecules. These particular substrates, and the resultant excess energy flux due to unregulated fructose metabolism, will promote the over-production of TG (reviewed in ).
The glycemic index (GI) has been commonly used to differentiate and compare various nutrients, as well as to describe how different foods produce different plasma glucose levels after ingestion. The GI can range from 100 for glucose and baked potato compared to approximately 20 for fructose and whole barley . Foods with varying GIs have different time courses associated with satiety. High GI carbohydrates have been reported to reduce appetite in the short term, whereas low GI carbohydrates possess a more delayed effect on energy intake controls . Fructose appears to have differing effects on appetite compared to glucose, contributing to its negative properties. Anderson et al. determined the association between food intake and blood glucose, comparing glucose and a fructose mixture. Glucose was administered as a high GI preload, which resulted in lower mealtime energy intakes compared to the low GI preload of the glucose-fructose mixture. An inverse relationship was seen between GI (and blood glucose concentrations), and appetite with consequent increased food intakes seen with fructose . In 2002, Vozzo et al. studied the comparative effects of glucose and fructose on blood glucose, insulin, and acute food intake. When subjects drank equienergetic preloads of glucose or fructose before an ad libidum buffet lunch, glucose concentrations were lower in the fructose group compared to glucose, and insulin concentrations were 50% higher in the fructose group in type 2 diabetics than in non-diabetics. The authors concluded that fructose may be a suitable replacement for glucose in diabetic patients although it was found that satiating efficiencies of fructose certainly offered no advantages . This study differs from others with regards to insulin secretion, but the trend is clear between GI, glucose concentrations, and appetite. An explanation for the variation in glucose and fructose glycemic responses appears to be dependent on rates of hydrolysis and absorption of glucose, and gastric emptying . The variations observed in GI and appetite control of glucose and fructose can also be explained by differences in stimulation of insulin and leptin, important players in the long-term regulation of energy homeostasis. Fructose will generally produce smaller insulin excursions upon consumption because it does not stimulate the secretion of insulin from pancreatic beta cells, whereas glucose does. Insulin-regulated leptin will also have a reduced concentration and a decreased net effect on reducing appetite. Limited effects on appetite suppression, combined with the fact that fructose is favoured by the liver to be metabolized into lipid, will subsequently lead to weight gain, hyperinsulinemia, and the associated insulin resistance . Glucose and fructose comparison studies continued examining new hormonal targets. In 2004, Teff et al. showed that subjects served meals with either 30% glucose beverages, or 30% fructose beverages, had differing hormonal and metabolic responses. Glycemic excursions and insulin responses were reduced by 66% and 65%, respectively, in the fructose-consuming subjects. There was a concomitant reduction in circulating leptin both in the short and long-term as well as a 30% reduction in ghrelin (an orexigenic gastroenteric hormone) in the fructose group compared to the glucose group. A prolonged elevation of TG was also seen in the high fructose subjects . Both fat and fructose consumption usually results in low leptin concentrations which, in turn, leads to overeating in populations consuming energy from these particular macronutrients. An adipocyte hormone, adiponectin, also plays an important role in lipid homeostasis and insulin action . The insulin sensitizer agonist, peroxisome proliferator-activated receptor-gamma, stimulates adiponectin production and adiponectin is in fact thought to be part of this agonist's mechanism lowering circulating fatty acids and increasing fat oxidation. The net effect is to decrease liver TG and increase insulin sensitivity . Chronic fructose consumption reduces adiponectin responses, contributing to insulin resistance .
Animal studies have illustrated various differences between glucose and fructose metabolism. In 2002, Miller et al. injected fructose into the cerebroventricles of rats, and observed enhanced food intake, whereas similar concentrations of injected glucose suppressed appetite-agonist stimulated food intake . Feeding rats either 32% glucose, fructose, or sucrose solutions, resulted in increased weight gain, and energy consumption compared to chow fed controls. Rats given the fructose and sucrose solutions also had a decreased ability to tolerate a glucose load, and fructose animals had greater serum TG levels over all other conditions (. This is likely because the hepatic metabolism of fructose favours de novo lipogenesis. In combination with alterations in insulin signaling and leptin regulation, weight gain and unregulated energy intake can occur . In 1986, Levine et al. found that fructose, administered in the form of the disaccharide sucrose, promotes obesity more than glucose because fructose does not stimulate thermogenesis . These hormonal and physiological changes illustrate the important connections between energy intake, appetite control, weight gain, and insulin resistance.
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