Fructose

Fructose
Fructose (also levulose or laevulose) is a simple sugar (monosaccharide) found in many foods and is one of the three important dietary monosaccharides along with glucose and galactose. Honey, tree fruits, berries, melons, and some root vegetables, such as beets, sweet potatoes, parsnips, and onions, contain fructose, usually in combination with glucose in the form of sucrose. Fructose is also derived from the digestion of granulated table sugar (sucrose), a disaccharide consisting of glucose and fructose, and high-fructose corn syrup (HFCS). Crystalline fructose and high-fructose corn syrup are often mistakenly confused as the same product. The former is simply pure (100%) fructose. The latter is composed of nearly equal amounts of fructose and glucose.

Classification And Structure
Fructose also referred to as fruit sugar is a simple monosaccharide with a ketone functional group. Fructose is an isomer of glucose with the same molecular formula (C6H12O6) but with a different structure. Fructose is a 6-carbon polyhydroxyketone. When dissolved in solution, it forms ring structures similar to glucose, which are classified as cyclic hemiketals as opposed to the cyclic hemiacetals formed by aldoses such as glucose. When fructose forms a 5-member ring, the OH group on the fifth carbon atom attaches to the carbonyl group that is on the second carbon atom (D-Fructofuranose). Alternatively, the OH group on the sixth carbon may attach to the carbonyl carbon to form a 6-member ring (D-Fructopyranose).

Metabolism
Fructose is readily absorbed and rapidly metabolized by the human liver. For thousands of years humans consumed fructose amounting to 16–25 grams per day, largely from fresh fruits. Westernization of diets has resulted in significant increases fructose consumption, leading to typical daily ingestion of 85–100 grams of fructose. The (over) 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. 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. 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.

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. 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.

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 favored 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. 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.

Insulin Resistance
Increasingly, questions have been raised as to whether dietary carbohydrate and fructose intake are directly related to the development of type 2 diabetes. As insulin resistance is often associated with circulating C-peptide concentrations, a cross-sectional study was performed to assess dietary fructose and carbohydrate, and glycemic loads related to C-peptide concentrations. It was found that the highest quintile of fructose intake had 13.9% higher C-peptide concentrations than the lowest quintile. Of note, subjects with high intakes of cereal fiber had 15.6% lower C-peptide concentrations, indicating that these types of nutrients may have opposing roles in the development of insulin resistance. A definite relationship has also been found between metabolic syndrome and hyperhomocysteinemia, which is associated with cardiovascular and cerebrovascular diseases.

Although fructose does not appear to acutely increase insulin levels, chronic exposure seems to indirectly cause hyperinsulinemia and obesity through other mechanisms. One proposed mechanism involves GLUT5, a fructose transporter that is found to have significantly higher expression levels in young Zucker obese rats compared to lean controls. As the rats age and become diabetic, GLUT5 abundance and activity is compromised, causing an even more marked insulin resistance over lean rats, implying a possible role of GLUT5 receptors in the pathology of metabolic syndrome associated with fructose feeding and insulin resistance. In rats fed 66% fructose for 2 weeks, insulin receptor mRNA, and subsequent insulin receptor numbers in skeletal muscle and liver were significantly lower compared to rats fed a standard chow diet. Also, blood pressure and plasma TG increased in the fructose-fed rats, even though there was no change in plasma insulin, glucose, or body weight. Evidence shows these early steps in insulin signaling are important for insulin's metabolic effects. In a different study, it was found that after 28 days of fructose feeding there were no changes in insulin receptor concentration, but, insulin stimulated autophosphorylation, a mechanism necessary for insulin action, was reduced to 72% in the liver.

Lipogenic Nutrient?
There is considerable evidence supporting the ability of high fructose diets to up regulate the lipogenesis pathway, leading to increased TG production. Insulin and glucose are known to directly regulate lipid synthesis and secretion. Insulin controls hepatic sterol regulatory element binding protein (SREBP) expression, which is a key transcription factor responsible for regulating fatty acid and cholesterol biosynthesis. SREBP binds to sterol responsive elements (SRE) found on multiple genes, and can activate a cascade of enzymes involved in cholesterol biosynthetic pathways. Miyazaki et al. reported an induction of the hepatic SREBP-1 isoform and lipogenic gene expression including FAS, acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase (SCD) in mice following 7 days on a 60% fructose diet. It is known that SREBPs are regulated by intracellular sterol concentrations. However, more recently, it has been established that hormones such as insulin and platelet derived growth factor play a role in regulating these transcription factors. Expression of SREBP is enhanced by insulin in all three major insulin target tissues, liver, fat, and skeletal muscle. Similarly, levels of SREBP are enhanced in the presence of hyperinsulinemia. There is evidence that the insulin-mediated stimulation of SREBP occurs through the MAP kinase pathway, with ERK1/2 being shown to activate the SREBP-1a isoform by phosphorylating serine 117). Despite the fact that SREBP-1 is directly stimulated via insulin signaling, the depletion of insulin and insulin signaling through streptozotocin (STZ) treatment paradoxically induces SREBP-1c expression upon glucose, fructose, or sucrose feeding. It would have been expected that SREBP-1c would be downregulated concomitantly along with the reduced insulin availability, but this is not the case. Glucose feeding causes a short-term peak induction, whereas fructose caused a gradual extended increase in SREBP-1c activity, providing evidence that lipogenesis can be independent of insulin signaling, given carbohydrate, and particularly fructose, availability.

Heath Based Concluding Remarks
The alarming increase in fructose consumption may be an important contributor to the epidemic of obesity and insulin resistant diabetes in both pediatric and adult populations. For thousands of years, the human diet contained a relatively small amount of naturally occurring fructose from fruits and other complex foods. Adaptation of humans to a high glucose/low fructose diet has meant that hepatic carbohydrate metabolism is designed to actively metabolize glucose with a limited capacity for metabolizing a small daily intake of fructose. The increasing application of high fructose sweeteners over the past few decades has resulted in a considerable rise in the dietary intake of fructose. A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, disturbs normal hepatic carbohydrate metabolism leading to (potentially) major health consequences.

Performance Based Concluding Remarks
Due to its diverged chemistry and metabolic pathways fructose has major applications in blood sugar management and glycogen repletion in context of high intensity strength training. Fructose could be used as a non-insulin dependent hepatic CHO source for rapid repletion of liver glycogen, potentially making workout period recovery times more brief! Quicker more complete hepatic glycogen re-synthesis could unlock the potential for more frequent training sessions……………..there for more monthly/yearly training volume.


B.”EvilGenius”Chavez
www.EvilGSP.com