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Metabolism and Transport. Fructose, a monosaccharide ketohexose, is present either as the free hexose (honey, soft drinks, sweets, biscuits, apples, pears) or is produced from hydrolysis of the dietary disaccharide sucrose (yielding glucose and fructose). In humans, it is absorbed largely intact into the portal blood and is almost totally cleared in a single passage through the liver. Thus, there is essentially no appreciable fructose in the blood. After a large oral dose of 1 g free fructose/kg body weight, the blood level will increase to 0.5 mmol/L in 30 minutes and then slowly decrease during the next 90 minutes. In the liver, fructose is phosphorylated by the abundant enzyme fructokinase into fructose-1-phosphate, which is cleaved by hepatic aldolase into glyceraldehyde and dihydroxyacetone phosphate (DHA phosphate). DHA phosphate is an intermediary metabolite in both the glycolytic and gluconeogenic pathways. Glyceraldehyde, while not intermediary in either pathway, can be converted by various liver enzymes into glycolytic intermediary metabolites available to be metabolized ultimately to produce glycogen. This glycogen can then be broken down into glucose by glycogenolysis.

Absorption. Although fructose is absorbed across the enterocytes of the small intestine, it is not a substrate for the SGLT cotransporters. The evidence for this is three-fold: (a) fructose absorption is normal in those with glucose-galactose malabsorption, who have defective SGLT-1 cotransporters; (b) fructose absorption is not reduced by phlorizin, the classic inhibitor of SGLT-1 cotransporters; and (c) fructose absorption is neither Na +-sensitive nor electrogenic like that of glucose or galactose. Recent studies on the expression of human GLUT 5 transporter in Xenopus oocytes showed that the transporter exhibited selectivity for high-affinity fructose transport that was not blocked by cytochalasin B, a potent inhibitor of facilitative glucose transport by glucose transporters ( 22). As GLUT 5 is also expressed in high levels in the brush border of enterocytes in the small intestine ( 4.7), the isoform is likely to be the fructose transporter of the small intestine. Indirect evidence for the likelihood of fructose transporting by GLUT 5 is the fact that it is expressed in high concentration in human spermatids and spermatozoa ( 47), cells known to metabolize fructose. GLUT 2, localized to the basolateral membrane of enterocytes, although having a much lower affinity for fructose transport than GLUT 5, probably mediates the exit of the absorbed fructose from the enterocytes into the blood. Recently, however, it has been reported that GLUT 5 is also localized on the basolateral membrane in the human jejunum (48), so fructose could also exit from the enterocytes by this transporter.

In humans, absorption of fructose from sucrose ingestion is more rapid than that from equimolar amounts of fructose ingestion. The numerous explanations for this phenomenon include differences in gastric emptying, enhanced fluid absorption initiated by the glucose entraining fructose, and cotransport of fructose and glucose by a disaccharidase-related transport system (49, 50).

Inborn Errors. Six genetically determined abnormalities in the metabolism of fructose have been described in humans ( 51). These are caused by deficiencies in fructo-kinase, aldolase A and B, fructose-1,6-diphosphatase, and glycerate kinase, and by fructose malabsorption. Limiting dietary fructose is favorable in each of these conditions except aldolase A deficiency. Fructokinase deficiency, manifest in the liver, causes fructosemia (high levels in blood) and fructosuria (excretion in urine). In contrast to the low levels of fructose observed in the blood of normal humans after ingestion of 1 g of free fructose/kg, the concentration in the fructokinase-deficient person approaches 3 mmol/L and is sustained for many hours. Despite the sustained high levels of fructose in the blood, cataracts do not develop, in sharp contrast to the cases of galactokinase deficiency and diabetes mellitus (see specific sections).

The three aldolases, A, B, and C, catalyze the reversible conversion of fructose-1-diphosphate into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. Each is coded for by a different gene: A is on chromosome 16, B on 9, and C on 17. Expression of the enzymes is regulated during development so that A is produced in embryonic tissues and adult muscle, B in adult liver, kidney, and intestine, and C in adult nervous tissue. Deficiency of A produces a syndrome of mental retardation, short stature, hemolytic anemia, and abnormal facies. The deficiency is probably detrimental because aldolase A is normally involved in fetal glycolysis. There is no treatment for the condition. Deficiency of aldolase B (hereditary fructose intolerance), the most frequent of the three deficiencies, was first observed in 1956 (52). When fructose is ingested, vomiting, failure to thrive, and liver dysfunction occur.

Deficiency of fructose-1-6-diphosphatase was described in 1970. Patients exhibit hypoglycemia, acidosis, ketonuria, and hyperventilation. Urinalysis shows many changes in organic acids, but excretion of glycerol is diagnostic. Treatment is to avoid dietary fructose.

D-Glyceric aciduria is rare and is caused by D-glycerate kinase deficiency. The presentation of the disease is highly variable, from no clinical symptoms to severe metabolic acidosis and psychomotor retardation, which suggests that perhaps among the 10 described cases, there are other, different enzyme deficiencies.

In fructose malabsorption, ingestion of the ketohexose in quantity creates abdominal bloating, flatulence, and diarrhea. Persons with this condition appear to have a defect in fructose absorption. No assessments of intestinal GLUT 5 or its controlling gene have yet been made in any of these patients. If either glucose or galactose is ingested with fructose, fructose absorption is enhanced, and often no symptoms of malabsorption occur (50, 51).

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