Normal Roles for Dietary Fructose in Carbohydrate Metabolism

Abstract: Although there are many well-documented metabolic effects linked to the fructose component of a very high sugar diet, a healthy diet is also likely to contain appreciable fructose, even if confined to that found in fruits and vegetables. These normal levels of fructose are metabolized in specialized pathways that synergize with glucose at several metabolic steps. Glucose potentiates fructose absorption from the gut, while fructose catalyzes glucose uptake and storage in the liver. Fructose accelerates carbohydrate oxidation after a meal. In addition, emerging evidence suggests that fructose may also play a role in the secretion of insulin and GLP-1, and in the maturation of preadipocytes to increase fat storage capacity. Therefore, fructose undergoing its normal metabolism has the interesting property of potentiating the disposal of a dietary carbohydrate load through several routes.

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Alex’s Notes: To summarize the entire issue surrounding fructose, most of the studies that do indeed provide important health information are not relevant to many of us Super Humans, who only consume moderate amounts of fructose from foods. Aside from the fact that most these studies use a ridiculously high amount of fructose that only a soda guzzling Westerner could come close to consuming, most also used pure fructose. However, no natural food source contains only fructose; glucose likes to tag along. Thus, I thought it was prudent we have a quick review of how fructose is handled in normal situations where relatively normal amounts are consumed and in conjunction with glucose (bound or free).

To begin, it is important to understand that the fate of ingested fructose is determined by the absolute amount consumed, the amount of time in which it is absorbed from the gut (note that this is different from consumption), and the concentrations of fructose and glucose and their metabolic intermediates throughout the body. Fructose is absorbed into the bloodstream far more slowly than glucose and has blood levels 21-fold lower than glucose in the post-prandial state. However, these levels stay elevated for twice as long as glucose. From the gut, fructose enters the portal vein and heads for the liver – the major site of fructose metabolism.

For any tissue to uptake and utilized fructose, it must have the ability to transport fructose across its cell’s membranes. The two main transporter proteins are believed to be GLUT2 & GLUT5. GLUT2 is an insulin independent transporter for both glucose and fructose that exists in the small intestine, kidneys, liver, and pancreatic beta-cells. GLUT5 is highly specific for fructose and exists mainly in the intestines but also in the kidneys, fat, sperm, testes, brain, and skeletal muscle. In addition to transporters, the tissues must have enzymes to metabolize the fructose because fructose itself is unusable by the body. The liver, for example, has a specialized set of three enzymes that work to transform fructose into a glycotic intermediate. Some of these enzymes also exist in peripheral tissues such as the pancreas, intestine, brain, lung, eye, adipose, spleen, skeletal muscle, heart, uterus, and adrenal.

What the above should make perfectly clear is that the body is able to systemically metabolize fructose if need be. Many organs outside of the liver possess the ability to both uptake and metabolize fructose. That said, since all fructose stops at the liver first, it must be noted that there is a huge concentration gradient between the blood entering and leaving hepatic circulation.

One reason the liver is so responsive to fructose is because of those specialized enzymes it possesses. They allow the liver to metabolize fructose into an intermediate of glucose metabolism that will continue through the glycotic or gluconeogenic pathways depending on the body’s needs. In this way, most fructose is metabolized no differently than glucose. Indeed, 50% of ingested fructose is converted into glucose, 25% into lactate, at least 15% into liver glycogen, and the remainder is oxidized directly. Ultimately, the fraction stored as glycogen or released as glucose will depend on the current energy demands of the body and blood glucose concentrations, with the former being favored in the fed state, while the latter is favored during exercise. The irrelevant studies mentioned at the beginning have led to a common misconception that most fructose is converted into triglycerides and promotes excessive fat storage. In actuality, perhaps only 2-3% of ingested fructose is converted into triglycerides and overfeeding studies show that there is no difference in lipogenesis between glucose and sucrose – which is half fructose.

Getting back to glycogen, there is a fascinating synergy between glucose and fructose that further supports the notion that studies using massive quantities of pure fructose are useless for real-world application. This was best demonstrated in two studies that gave healthy and type-2 diabetic patients an oral glucose tolerance test of 75 grams glucose with or without 7.5 grams of fructose. Even though the addition of fructose increased the total sugar dose by 10%, plasma glucose was reduced by 19% in healthy people when fructose was included, and by 14% in those with diabetes. Although the insulin response was unaltered in healthy subjects, diabetics experienced a 21% reduction in plasma insulin when fructose was present. This demonstrates that even a small dose of fructose can increase glucose tolerance in insulin resistant people, and a large part of the means by which fructose increases glucose disposal is from its ability to up-regulate liver glycogen storage. In fact, net liver glycogen synthesis is increased almost four-fold when fructose is consumed with glucose, and the glycogen precursor is predominantly the ingested glucose, not fructose.

And what of insulin? Large doses of fructose appear to both independently stimulate insulin secretion and augment glucose-stimulated insulin secretion. This shouldn’t be surprising given our earlier discussion on the GLUT transporters, which do exist on pancreatic beta-cells.

Finally, we must look briefly at exercise. The ultimate end-point of fructose is oxidation in the form of glucose or lactate released from the liver. It is therefore surprising that GLUT5 – the highly fructose specific transporter – is the second most abundant sugar transporter in skeletal muscle, most notably in fast-twitch fibers. Thus, skeletal muscle has an incredible ability to metabolize fructose directly when its concentrations are elevated. This was demonstrated in young healthy fasted men exercising on a bicycle during a continuous infusion of fructose that raised blood levels to a magnitude higher than typical post-prandial concentrations. Fructose uptake during exercise exceeded splanchnic uptake, and remained comparable post-exercise. This also likely explains how physical activity can offset the negative effects of a high-fructose diet, and provides yet more evidence that muscle is metabolic currency.

Fructose is a normal part of the diet. Although there are numerous health risks for sedentary people on a sugar-rich diet, there are also important metabolic roles for modest amounts of fructose. It enhances glucose metabolism and acts to increase glucose disposal.

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