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Fructose in Medicine Jussi K. HUTTUNEN

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Fructose in Medicine Jussi K. HUTTUNEN Postgrad Med J: first published as 10.1136/pgmj.47.552.654 on 1 October 1971. Downloaded from Poitgraduate Medical Journal (October 1971) 47, 654-659. CURRENT SURVEY Fructose in medicine A review with particular reference to diabetes mellitus Jussi K. HUTTUNEN M.D. Third Department of Medicine, University of Helsinki, Finland Summary and in experimental animals. Earlier suggestions con- A review is given of the metabolism of fructose in the cerned with the atherogenic properties of fructose mammalian organism, and its significance in medicine. have recently been challenged. The apparent increase Emphasis is laid upon the absorption and assimilation in the incidence of coronary disease among sucrose of fructose through pathways not identical with those users seems to be a statistical artefact, caused by the of glucose. The metabolism of fructose is largely increased ingestion of coffee and soft drinks by insulin-independent, although the ultimate fate of cigarette smokers. fructose carbons is determined by the presence or the absence of insulin. Introduction Clinical and experimental work has suggested that The metabolism of fructose has engaged the atten- fructose may exert beneficial effects as a component tion of clinicians since 1874, when Kulz suggestedProtected by copyright. of the diet for patients with mild and well-balanced that diabetic patients can assimilate fructose better diabetes. Fructose is absorbed slowly from the gut, than glucose. These observations have been con- and does not induce drastic changes in blood sugar firmed in a number of experimental and clinical levels. Secondly, fructose is metabolized by insulin- studies (Minkowski, 1893; Naunyn, 1906; Joslin, independent pathways in the liver, intestinal wall, 1923), it being further shown that in some patients kidney and adipose tissue. fructose feeding brings a reduction in glucosuria and As a consequence of the rapid and efficient utiliza- the respiratory quotient. However, contradictory tion of fructose, it has been used widely for intra- reports, together with the discovery of insulin in venous feeding in medicine and surgery. However, it 1922, made the use of fructose in the treatment of has been shown that the rapid infusion of large diabetes less fashionable; it was virtually forgotten amounts of fructose may cause accumulation of for the next thirty years. Reports on the beneficial lactic acid in the extracellular fluid. The possibility effects of fructose in diabetic ketoacidosis (Darragh of lactate acidosis, with concomitant impament of et al., 1953; Miller et al., 1953), and its accelerating the acid-base balance, already disturbed, constitutes effect upon ethanol oxidation (Stuhlfauth & Neu- http://pmj.bmj.com/ a relative contraindication to the use of intravenous maier, 1951; Pletscher et al., 1952) gave rise to in- fructose in the treatment of diabetic ketoacidosis. tense research after 1953, resulting in several reports Fructose is known to accelerate ethanol metabolism on the various aspects of fructose metabolism and its in the liver. No well-documented reports on the use potential use in the treatment of diabetes. Early of fructose in the treatment of ethanol intoxication positive experience with fructose in the manage- have been published, although it has recently been ment of ketoacidosis was challenged in studies with more rigorous control, but the other potential indica- suggested that fructose might be of value in the on September 28, 2021 by guest. treatment of delirium tremens. tion for fructose, its employment as a sweetening agent, and as a carbohydrate source in mild, con- Fructose may be less cariogenic than sucrose, at trolled least in short-term experiments. Long-term trials are diabetes, has not been disputed. The and lack of further experience in this respect is lacking, thus the potential advantages of fructose attributable to the unavailability of commercial in preventive odontology have not been determined. fructose preparations, which has made it difficult Fructose does not seem to have any side-effects to engage in long-term trials. The purpose of this when used in reasonable amounts. However, it has paper is to provide a critical survey of the meta- been reported that the administration of fructose in bolism of fructose in the normal and diabetic larze amounts induces hyperlipidemia both in man organism, along with clinical studies concerned with Correspondence: Dr Jussi K. Huttunen, Third Depart. the effects of fructose upon the diabetic state. It is ment ofMedicine, University ofHelsinki, Haartmaninkatu 4, felt that a survey of this type is of value because 00290 Helsinki 29, Finland. of the need for a harmless sweetening agent and Postgrad Med J: first published as 10.1136/pgmj.47.552.654 on 1 October 1971. Downloaded from Current survey 655 carbohydrate source for diabetics. This is especially tion to glycerate by aldehyde dehydrogenase. important in the light of the emphasis recently laid Glycerol may either be further oxidized in mito- upon the dietary management of diabetes and the chondria, or used as the substrate for triglyceride potential hazards involved in the use of artificial synthesis in the cytoplasm. The two other meta- sweeteners. bolites of glyceraldehyde, glycerate and glycer- aldehyde phosphate, are incorporated into the Biochemistry and metabolism of fructose Embden-Meyerhof pathway, and metabolized to The absorption of fructose from the duodenum glucose or pyruvate. Currently, it is unknown which occurs by passive diffusion, in contrast to the active of these pathways is quantitatively most important. transport mechanism of glucose (Wilson & Vincent, In any case, it is clear that the ultimate fate of triose 1955). For this reason, and possibly others as well, fragments is determined by the same factors as the rate of absorption of fructose is slower than that those that determine the direction of metabolite of glucose. Slow absorption and rapid metabolism flow in glycolysis and gluconeogenesis. Thus, when in the liver (vide infra) effectively prevent rapid gluconeogenesis dominates, as during fasting, or changes in the serum levels of fructose after peroral with a high fat diet, or severe diabetes, triose phos- administration, and it is difficult to attain concen- phates generated from fructose are converted to trations of fructose exceeding 30-40 mg/100 ml after glucose. However, after feeding with a high carbo- the ingestion of fructose or sucrose. Some meta- hydrate diet and in the presence of insulin, trioses bolism of fructose occurs in the intestinal wall, are oxidized to pyruvate, and finally to citric acid which contains an active fructose-metabolizing cycle intermediates. pathway. The extent of intestinal metabolism Two inborn errors of fructose metabolism have appears to vary from one species to another. been described (Schapira et al., 1961; Froesch et al., Estimations in human subjects have suggested that 1963). Thefirstenzyme of thefructokinase pathway is Protected by copyright. 10-20% of the fructose consumed is metabolized in lacking in essential fructosuria, whereas in hereditary the gut wall (Miller et al., 1956). Fructose is utilized fructose intolerance the block is causedbythe absence at the same rate as glucose in the intact organism of fructose-i-phosphate aldolase. Despite the virtual (Smith, Ettinger & Seligson, 1953). As an indicator absence of fructose metabolism in the liver, more of fructose assimilation, the blood levels of lactate, than 80% of the fructose given is assimilated by pyruvate, a-ketoglutarate and citrate rise more patients with these two defects. Alternative routes rapidly after a fructose than a glucose load (Craig for fructose utilization must consequently exist in et al., 1957). A rapid fall in serum phosphate occurs the body. The metabolism of fructose is also known after the injection of fructose, indicating that fruc- to occur in muscle and adipose tissue, whereas little tose is phosphorylated by the intracellular kinases or no utilization takes place in the brain. This (Smith, Ettinger & Seligson, 1953; Miller, Craig & results at least partially from the blood-brain Drucker, 1956). barrier, which prevents the effective uptake of Approximately one half of the fructose adminis- fructose by brain cells (Park et al., 1957). tered intravenously is utilized by the liver (Mendeloff The metabolism of fructose in muscle proceeds http://pmj.bmj.com/ & Weichelsbaum, 1953) through the specific fructose- through the same metabolic pathways as that of 1-phosphate pathway (Cori et al., 1951). The same glucose. Fructose is phosphorylated by the same metabolic pathway, which is not dependent upon kinase as glucose, and is rapidly metabolized when insulin, is also operative in the kidney and the present in the interstitial fluid in sufficiently high intestinal wall. The first reaction of this pathway is concentrations. High concentrations of glucose the conversion of fructose to fructose-i-phosphate (> 200 mg/100 ml) inhibit fructose assimilation, but by a specific kinase, fructokinase. In contrast to the the inhibition is not augmented by insulin (Froesch, corresponding enzyme of glucose metabolism, the 1965). At low concentrations (<50 mg/100 ml), on September 28, 2021 by guest. activity of fructokinase is not regulated by insulin. fructose is not utilized under in vitro conditions, The fructose-i-phosphate is split by aldolase into which suggests that, at the low concentrations equal parts of dihydroxyacetone-phosphate and obtaining after oral fructose
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