Fructose: endocrine and metabolic effects

By Dr. Giancarlo Monteforte

Fructose is a natural monosaccharide with peculiar metabolic properties. These properties are essentially due to 2 factors:

Low glycemic index
Entering the glycolysis bypassing the regulation of the enzyme phosphofructokinase (which catalyzes the phosphorylation of glucose 6 phosphate into fructose 1, 6 bisphosphate, determining the definitive and irreversible immission of glucose into the glycolytic process; this reaction is considered the limiting step of the entire speed glycolysis).

Intestinal absorption

All monosaccharides (hence also fructose) are absorbed in the jejunum and placed in the portal circle. Fructose is absorbed by enterocytes by diffusion facilitated by a specific carrier (GLUT5) located on the apical membrane; on the basolateral membrane there is instead another carrier (GLUT2) which introduces fructose into the circulation (fig. n. 1). GLUT5 has a Km = 5, so it is easily saturated, so the ingestion of large quantities of fructose can be followed by intestinal disorders such as swelling and abdominal pain, diarrhea.

From the intestinal villi fructose passes into the portal vein, then into the liver. In humans about half of the fructose present in the portal vein is sequestered and metabolized by the liver, 20% by the kidneys, the remainder by adipose tissue and skeletal muscles.

The entry of fructose into the cells of all tissues and organs is mediated by GLUT5 and is independent of insulin.

Fructose metabolism

There are two metabolic pathways responsible for fructose metabolism, a specific pathway and an aspecific pathway.

The specific route: liver and kidney (box 1) . It is characterized by two enzymes: fructochinase and aldolase B. Fructochinase catalyzes the phosphorylation of fructose to fructose 1 phosphate, which is split into two trioses: glyceraldehyde and dihydroxyacetosphate. The glyceraldehyde is phosphorylated by the triose kinase and is introduced into the glycolysis, the dihydroxyacetate phosphate is converted into glyceraldehyde.
The aspecific pathway: adipose tissue, skeletal muscle, heart (box2). It is made up of enzymes that metabolize gucose: hexokinase, phosphofructokinase, aldolase A.

The specific route is much more efficient than the non-specific route, the latter being inhibited by glucose. In the adipose tissue, given the almost zero concentration of glucose, there is no competition between glucose and fructose and this is metabolized sufficiently in the aspecific way.


Box 1. Hepatic fructose metabolism	Box 2. Extra-hepatic fructose metabolism
Fructose is phosphorylated by fructokinase and then separated from aldolase B. The triose formed is introduced into glycolysis at the level of the triose phosphates, skipping the regulation of phosphofruttokinase. Green arrows indicate the uncontrolled flow of fructose in glycolysis. Depending on the metabolic conditions, trioses can be condensed into glucose to replenish liver glycogenesis.	Fructose is metabolized by the same enzymes that metabolize glucose: hexokinase and aldolase A. This metabolic pathway is inhibited by the presence of glucose.

Unregulated glycolysis: metabolic disorders mediated by fructose

The main control of the glycolytic pathway is the enzyme phosphofructokinase, fructose escapes this control and this can lead to an uncontrolled accumulation of intermediate metabolites.

Metabolic consequences:

accumulation of fructose 1 phosphate → accumulation ADP → increased purine catabolism

lactate accumulation → acidosis

acetylCoA accumulation → ketone bodies, lipogenesis

accumulation of glycerol → lipogenesis

From a clinical point of view, all this translates into: