E
ructose as a Dietary Sweetener in Diabetes Mellitus VEIKKO A. KOIVISTO
Human beings, including those with diabetes, have a desire for sweetness in the diet that cannot be ignored. The Food and Drug Administration ban of cyclamates and possible ban of saccharin have raised the question of alternative sweeteners for diabetic persons. Considerable interest has been focused on fructose, and both basic and clinical research has delineated its metabolic effects. This paper reviews the characteristics of fructose, as well as its physiology and metabolism in both normal and diabetic man. Findings seem to indicate that, in controlled diabetes, chronic or limited consumption of fructose at moderate doses has no adverse effects on the levels of blood glucose, cholesterol, or triglycerides. DIABETES CARE 1: 241-246, JULY-AUGUST 1978.
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uman beings have a strong desire for sweetness in the diet that cannot be ignored. This also is the case among individuals with diabetes. An inquiry of 500 subjects with diabetes in West Germany showed that 83 per cent of them were not willing to give up sweetening agents1 and in the United States more than 80 per cent of diabetic patients use at least one dietetic food.2 The ban of cyclamates and the possible ban of saccharin by the Food and Drug Administration (FDA) have now raised the question of alternative sweeteners for diabetic persons, since the consumption of sucrose may be contraindicated in the diabetic state. Recently there has been considerable renewed interest focused on fructose as an alternative sweetener for diabetic subjects. This is due to the basic differences between fructose and sucrose regarding their physiological and metabolic influences, differences which had already been recognized as early as 1874.3 Until the late 1960s the food use of fructose was limited because of its high price. A few years ago, however, an economical method was discovered to separate glucose and fructose from invert sugar solutions.4 This made feasible the industrial scale production of fructose at a reasonable price. Following the increased availability of fructose, both basic and clinical research have further delineated its metabolic effects. This paper reviews the characteristics of fructose, as well as its physiology and metabolism in both normal and
diabetic man, and provides a critical survey of clinical studies regarding the effects of fructose on control of diabetes. OCCURRENCE AND CHARACTERISTICS OF FRUCTOSE
Fructose, also known as fruit sugar or levulose, is one of the most commonly occurring sugars. It is largely found in plants and as a part of many polysaccharides similar to starch. The most common disaccharide, sucrose, is 50 per cent fructose, while honey is 41 per cent fructose. The amount of fructose in fruits and berries varies from 2 to 6 per cent of the fresh edible portion.5 In the human organism fructose may be formed from glucose or from sorbitol. Human blood normally contains only traces of fructose, but it occurs in measurable amounts in sperm, fetal blood, and amniotic fluid. Fructose is commercially available in a solid, crystalline form of more than 99.5 per cent purity and moisture content of less than 0.25 per cent. This is the yield from invert sugar after separation of the fructose and glucose moieties using ion exchange chromatography. Crystalline fructose is approximately 80 per cent sweeter than sucrose and more than twice as sweet as sorbitol.6 In solutions, the sweetness of fructose varies with temperature and pH, generally decreasing with increased temperature and acidity, while having greatest sweetness in cool, slightly acidic media.7
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Crystalline fructose is easily soluble in water. It withstands boiling and baking and is suitable for canning and freezing. Fructose is characterized by an agreeable sweetness without bitter aftertaste. Because fructose is hygroscopic, its presence enhances the freshness and shelf-life of bakery products. The exact caloric value of one gram of fructose is 3.75 kcal. or 16 KJ. ABSORPTION AND METABOLISM OF FRUCTOSE
T
he mechanism of gastrointestinal fructose absorption is probably facilitated diffusion, although an active transport process has also been demonstrated in vitro.8 The rate of fructose absorption, however, is lower than that of glucose.9 In man, up to 80 to 90 per cent of fructose is absorbed from the jejunum unmetabolized. There is only minor conversion of fructose to glucose or lactate during absorption.10 Slow absorption and rapid metabolism prevent rapid changes in the blood fructose levels after peroral administration. Thus it is difficult to achieve blood fructose levels above 25 mg. per deciliter after fructose ingestion in normal man.11'12 Fructose is metabolized mainly by the liver and to a lesser extent by the kidney and intestinal mucosa.13'14 Liver cells are freely permeable to fructose.15 The metabolism of fructose occurs mainly via the specific fructose-1-phosphate pathway. The first reaction is catalyzed by fructokinase, an enzyme, which is not dependent on insulin. This is in contrast to the first step in glucose metabolism, which is dependent on the presence of insulin.16 Thus, neither the entry of fructose into liver cells nor the first steps in its metabolism are dependent on insulin. For its part, the insulin secretory response to fructose is significantly lower than the insulin response to glucose or sucrose.12 Consequently a diabetic organism, too, can rapidly start to metabolize fructose even when glucose utilization is impaired.18"20 The first product of fructose metabolism, fructose-1-phosphate, is further converted to the trioses glyceraldehyde and dihydroxyacetone-phosphate. The final destiny of these trioses is dependent on insulin. When insulin is present, as occurs in diabetes under adequate control, trioses are oxidized to pyruvate and finally to Krebs cycle intermediates. This was shown by increments in the serum levels of pyruvate, lactate, alpha-ketoglutarate, and citrate after a fructose injection, even in diabetic patients.19'21 In insulin deprivation, such as during fasting or in poorly controlled diabetes, fructose-derived glyceraldehyde and dihydroxyacetone-phosphate are converted to glucose.16 The metabolism of fructose in man is very rapid, its half-life being approximately 18 minutes.17
experiments in which ingestion of fructose as a substitute for sucrose resulted in a reduction of glucosuria in diabetic patients. The author suggested that fructose could be used in the dietary management of diabetes. This conclusion was later supported by Minkowski when he reported contrasting effects of glucose and fructose in pancreatectomized dogs. When fructose was given, the amount of sugar and nitrogen excreted in the urine was diminished and the glyco gen content in the liver decreased as compared with glucose ingestion.22 Since these early findings several clinical studies have evaluated the role of dietary fructose in the management of diabetes.23"26 These studies showed that isocaloric replacement of glucose by fructose had beneficial effects in controlled diabetes, whereas this was not observed in untreated diabetes. After the first of these studies, the employment of fructose as a therapeutic agent in diabetes soon became unfashionable.27 Recently the question about the use of fructose in diabetes has been raised again. The issue now is whether or not it is possible to utilize fructose as a sweetener in diabetic diets without adverse effects. Recent studies have indicated that the rise in plasma glucose after fructose ingestion may be even lower than that seen after ingestion of complex carbohydrates.28 These findings support the use of fructose in the diabetic diet. Furthermore, the possibility of its use as a carbohydrate sweetener is a timely question for two reasons. First, if saccharin is banned, diabetic patients will need a sweetener that is also suitable from the standpoint of food technology. Secondly, Brunzell and coworkers have demonstrated that a high dietary content of carbohydrate may enhance the peripheral sensitivity to insulin, thus improving glucose tolerance in mild diabetes.29 Although these findings have been challenged by studies showing no difference in diabetic control by high- vs. low-carbohydrate diets,30'31 more recent studies employing high-carbohydrate, high-fiber diet support the original findings by Brunzell and coworkers; in insulin-dependent diabetes high-carbohydrate, high-fiber diet decreased the need of exogenous insulin and reduced the level of plasma glucose, cholesterol, and triglycerides.32 In addition, by increasing the proportion of carbohydrate in the diet, fat content can be decreased correspondingly, hopefully resulting in decreased serum lipid levels and perhaps thus decreasing the risk of development of atherosclerosis in diabetes.33 Since the use of fructose could serve for each of these purposes (as a sweetener and a dietary carbohydrate) it is therefore of particular interest to consider the metabolic effects of fructose in diabetes. Effects of Fructose on Carbohydrate Metabolism Comparison between fructose and glucose. As mentioned
EFFECT OF FRUCTOSE ON DIABETES
In 1874 in his monograph on diabetes Kulz3 described 242
before, there are a number of clinical studies indicating that the isocaloric replacement of glucose by fructose decreases
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hyperglycemia and glucosuria in patients in whom diabetes is controlled—both in adult-onset and in juvenile-onset diabetes. Hiller examined 160 mildly diabetic patients on isocaloric glucose and fructose diets and found a significant decrease in both hyperglycemia and glucosuria during the fructose period. The tendency to hyperketonemia was also diminished in the group on fructose diet. In contrast, in three patients with severe insulin deficiency, no change in the clinical picture was observed during fructose use.34 Lamar compared the effect of glucose and fructose ingestion (100 gm.) on plasma glucose levels in 22 diabetic subjects, two of them being extremely labile. In all patients, postprandial (30 to 180 minutes) hyperglycemia and glucosuria was absent or significantly lower after the ingestion of fructose than after glucose.35 The beneficial effects of fructose compared with glucose in diabetes have similarly been shown by several other authors. 21~24>26>3? Thus, it would indeed appear that fructose is better utilized than glucose by the diabetic organism. Comparison between fructose and starch in adult subjects
with diabetes. An important question from the practical point of view is whether fructose is as well utilized by diabetic subjects as polysaccharides, i.e. starches. This has been recently studied both in diabetic adults and children. Pelkonen et al.37 studied the effects of an isocaloric replacement of 75 gm. of dietary starch by fructose in 10 insulin-dependent, moderately controlled diabetic patients. The study was carried out in three periods of 10 days each. During the first and third periods, starch was the major carbohydrate, while during the second period 75 gm. of the starch was replaced by fructose. The total amount of calories was 30 to 40 kcal. per kilogram per day, 40 per cent of that being carbohydrate. Fructose feeding did not alter diurnal blood glucose levels or urinary glucose output, as compared with the starch period. Nikkila38 compared the effect of fructose, starch, and sucrose on the diabetic control in six patients with untreated adult-onset diabetes. The length of three successive dietary periods varied from 10 to 20 days. Under each period the diet was isocaloric, containing 45 per cent carbohydrate, 35 per cent fat, and 20 per cent protein. During one of the periods 75 to 80 gm. fructose or sucrose was added and an equivalent amount of starch was omitted from the diet. Fructose was added as a powder on desserts and as a sweetener in coffee or tea. The mean fasting blood glucose levels did not differ significantly during the three periods. From the results taken together, the authors concluded that diabetic patients either treated with insulin or having adult-onset disease can consume 75 gm. of fructose daily without exacerbating hyperglycemia. However, the use of sucrose by diabetic patients was not condoned by the authors. Arvidsson-Lenner39 tested the effect of different breakfast meals, some of them containing fructose, on postprandial glucose concentrations in five subjects with insulin-treated diabetes and in nine patients with adult-onset diabetes. All
breakfasts derived 20, 35, and 45 per cent of energy from protein, fat, and carbohydrates, respectively. The amounts of oligosaccharides (sucrose, fructose, lactose) varied from 5 to 65 per cent of the total carbohydrates, the remainder being starch. Oligosaccharides were included in milk and orange juice, whereas white bread was the main source of starch. In adequately treated insulin-dependent diabetes, the postprandial level of blood glucose was not dependent on the type of breakfast ingested but was proportional to the premeal glucose levels. This finding thus emphasizes the importance of insulin rather than the type of diet in controlling the postprandial rise of blood glucose. In adult diabetes, the breakfasts with the high percentages of oligosaccharides and low amount of starch surprisingly resulted in smaller increases in postprandial glucose levels than did the diet with a low portion of oligosaccharides. The relative contribution of individual sugars (fructose, sucrose, lactose) to the rise in glycemia cannot be estimated, since at least two of the sugars were employed simultaneously. A somewhat surprising finding, that starch meal causes a higher rise in blood glucose than high-sucrose meal, was explained by the author as due to the fact that hydrolyzation of starch provides only glucose moieties, whereas sucrose gives rise to both glucose and fructose molecules.39 This is in keeping with previous findings that sucrose ingestion in normal man causes a smaller increase in blood glucose than ingestion of equal amounts of glucose or starch hydrolyzates.40 Taken together, these data suggest the possible use of oligosaccharides rather than starch, and fructose rather than sucrose by diabetic patients. It should be noted, however, that all the starches are not equally hyperglycemic, e.g. ingestion of potato may cause a twofold higher glycemia than corn.41 Thus, comparisons between complex and simple carbohydrates are affected by the type of starch used. In four out of five juvenile and three out of nine adult diabetic patients Arvidsson-Lenner found a tendency to postprandial hypoglycemia after feeding with the high oligosaccharide diet.39 Therefore, the author did not recommend oligosaccharides in diabetes, in contrast to the conclusion above. It is not clear, however, whether the hypoglycemic tendency was due to feeding with oligosaccharides or to some other factor. There was a great day-to-day variation in fasting blood glucose levels in both juvenile-onset (from 55 to 299 mg. per 100 ml.) and adult-onset (from 53 to 248 mg. per 100 ml.) diabetic subjects. However, no information was given regarding the metabolic control during different diets. Thus, differences in basal blood glucose levels may contribute to varying postprandial glucose levels after different meals. Effect of two to three weeks of fructose feeding on blood glucose level was recently studied in six hypertriglyceridemic subjects, two of them also having diabetes.42 Basal diets contained 45 per cent carbohydrate (dextromaltose), 40 per cent fat, and 14 per cent protein. The other test diet was
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fat free and contained 85 per cent carbohydrate. In both diets fructose was substituted for 20 per cent of calories, being 33 to 46 gm. per day in basal and 90 to 155 gm. per day in fat'free diet. No change was observed in the level of plasma glucose insulin or glucagon during fructose feeding as compared with diets with dextromaltose.42 In another study, when equal amounts of carbohydrates in the form of various sugars and foods were given to diabetic and healthy people, the postprandial rise in blood glucose level was smallest after fructose.28 If the rise in plasma glucose level after fructose is taken as 100 per cent, the rise after equicaloric amount of toasted white bread was 347 per cent, after rye bread 200 per cent, after oatmeal 300 per cent, after rice 252 per cent, after potatoes 233 per cent, and after pure glucose 476 per cent. Based on these findings the authors suggest that conventional exchange units, based on weight, should be replaced by the "biological equivalents," i.e. based on the effect on postprandial blood glucose.28 These data thus seem to indicate that in adult subjects with either insulin-dependent or maturity-onset diabetes substitution of a part of dietary starch by fructose does not cause worsening of metabolic control. In contrast, in some cases postprandial rise in blood glucose may be less after fructose than after starch ingestion. Comparison between fructose and starch in diabetic children.
Whether fructose can be used as a sweetener by diabetic children has been studied by Akerblom et al. 43 The effect of fructose on postprandial glycemia after a breakfast meal was studied in 26 diabetic children under the age of 16 years. The breakfast provided 20 per cent of daily calories, 45 per cent of these were derived from carbohydrate, 35 per cent from fat, and 20 per cent from protein. During the fructose day, the children were given fructose at a level of 1 gm. per kilogram of weight, administered in lemon juice and chocolate. On the control day an equal amount of calories was derived from starch. The mean rise in blood glucose after breakfast was reduced by 75 to 85 per cent after fructose ingestion as compared with control meal (P < 0.02). The effects of prolonged use of fructose were studied in 16 diabetic children under home conditions.43 The daily caloric content of the diet was 1000 kcal. plus 100 kcal. per year for each year of age, with calories derived from carbohydrate, fat, and protein being 45 per cent, 35 per cent, and 20 per cent, respectively. The diet during the second and fourth weeks (fructose) was isocaloric with the diet in the control weeks, but a part of the carbohydrates from starch was substituted for by fructose at a rate of 1.5 gm. per kilogram of weight per day. Fructose was administered in beverage. The daily intake of carbohydrates was the same in control and fructose weeks. Glucosuria was similar during control and fructose weeks, the mean being from 1 to 1.5 per cent as measured at home from morning and evening specimens,43 indicating that diabetic children can use fructose in moderate amounts without exacerbating glucosuria. It was important, 244
however, that the child adhere to a quantitative diet, that fructose be used on an isocaloric basis, and that the child's mother supervise consumption.43 EFFECT ON LIPID METABOLISM
T
he effect of fructose on plasma lipids in diabetes is important when the use of fructose is considered a dietary component for diabetic patients. It has been reported that in healthy mean, high amounts of fructose (200 to 500 gm. per day) can increase the level of plasma friglycerides.38 In contrast, chronic consumption of fructose in moderate amounts (60 to 70 gm. per day) does not cause significant changes in serum triglyceride or cholesterol levels.44 Inasmuch as the turnover of fructose is dependent on insulin, it is necessary to consider the effect of fructose on plasma triglyceride levels in diabetes. In studies by Pelkonen et al. ,37 during the isocaloric replacement of starch by fructose (75 gm. per day) for 10 days, the level of plasma triglycerides in insulin-treated diabetic patients showed a mild, although not significant, increase from 1.00 ± 0.06 to 1.22 ± 0.08 mmol. per liter. An increasing tendency of plasma triglycerides was similarly observed in six untreated patients with hypertriglyceridemia and adult-onset diabetes. After 10 to 20 days of fructose feeding (75 to 90 gm. per day), the level of plasma triglycerides rose from 2.00 to 2.27 mmol. per liter, again a change that was not statistically significant.38 In contrast to this, Turner et al.42 did not find any change in plasma triglyceride or cholesterol levels after two to three weeks of fructose feeding in six hypertriglyceridemic patients, two of which also had diabetes. It is noteworthy that the daily amount of fructose ingested was substantial, 33 to 46 gm. in basal and 90 to 155 gm. in high-carbohydrate diet. Furthermore, in all six hypertriglyceridemic patients, with or without diabetes, fructose substitution decreased triglyceride production. Similarly, Akerblom et al.43 did not find any change in plasma triglyceride levels in diabetic children after two weeks use of fructose at a rate of 1.5 gm. per kilogram of weight per day. These findings thus seem to indicate that in controlled diabetes, acute or a few weeks of fructose consumption at moderate doses has no adverse effects on the levels of blood glucose, cholesterol, and triglycerides. CHRONIC FRUCTOSE CONSUMPTION
In addition to these acute or short-term follow-up studies, the effects of chronic fructose administration have been studied both in man and animals. In Turku sugar studies, 35 normal subjects used fructose as the only sweetener in their diet, the average dose being 60 to 70 gm. per day.44 During a two-year follow-up period, fructose failed to cause any changes in their plasma level of glucose, insulin, choles-
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terol, or triglycerides. In keeping with this, fructose administration at a dose of 30 gm. per day over a period of 18 months did not cause any adverse effects in 89 patients with adult-onset diabetes.45 The effects of high-dose chronic fructose feeding in animals seem to be more controversial, however. In obioh mice, which are hyperglycemic, hyperinsulinemic, and hyperlipemic, fructose administration for six months at a dose of 64 per cent of total calories reduced hyperglycemia, while plasma levels of insulin cholesterol and triglycerides were similar to animals fed with starch, sucrose, or glucose.46 In normal mice, fructose feeding reduced both glucose and triglyceride levels as compared with groups fed with the other three carbohydrates. These findings thus indicate that chronic fructose administration is superior to cornstarch, sucrose, or glucose feeding in obese or in normal mice. In contrast to these findings, a high fructose diet (72 per cent) for two months resulted in hypercholesterolemia and hypertriglyceridemia and impaired glucose tolerance to diabetic range in particular Hebrew University Strain (HUS) rats, which were selected based on their genetic predisposition to diabetes.47 The data from these animal studies may not be applicable to humans, since the diets were much higher in fructose than those generally consumed by humans. In addition, the heavy genetic predisposition to diabetes in HUS-rats may be different than that in humans. Taken together, chronic fructose consumption does not seem to have adverse metabolic effects in normal man or in patients with adult-onset diabetes, whereas in experimental diabetes, when fructose is used at pharmacological doses, the results are more controversial. FRUCTOSE AND DENTAL CARIES
Different sugars seem to have a different effect upon dental plaque formation and the development of caries. In normal man, a four-day fructose diet decreases the plaque formation by 30 per cent as compared with an equicaloric sucrose diet.48 Furthermore, an extensive two-year study showed that caries formation was decreased by 25 per cent in a group with fructose-containing diet (38 subjects) as compared with sucrose diet in 52 subjects.48 CONCLUSIONS
Fructose, fruit sugar, is one of the most commonly occurring sugars. It is sweeter than sucrose and is characterized by an agreeable sweetness without a bitter aftertaste. The metabolism of fructose is not as much dependent on insulin as that of sucrose. This provides a theoretical basis for fructose consumption in diabetes. Clinical studies seem to indicate that the hyperglycemic effect of fructose in diabetes is not higher than that of starches. No adverse effects of fructose consumption on glucose metabolism have
been observed in controlled diabetes. In some studies a tendency to increase plasma triglyceride level has been observed, but this finding has not been uniformly confirmed and the opposite finding of a decrease in triglyceride production has been observed with fructose consumption. Because fructose is sweeter than sucrose, it offers an alternative sweetener also for nondiabetic people who would like to restrict their total intake of sugar-derived calories. Furthermore, substitution of fructose for sucrose may reduce dental caries formation. From Yale University School of Medicine, New Haven, Connecticut. REFERENCES 1
Mehnert, H.: Uber den relativen Wert von Zuckerauschtoffen und Susstoffen in der Diabetesdiat. Wiss. Veroeff. Dtsch. Ges. Ernaehr. Darmstadt, Steinkopf, 1971, vol. 20. 2 Bender, A. E.: Nutrition and Dietetic Foods, 2nd edit. New York, Chemical Publishing Co., 1973, pp. 49-64. 3 Kulz, E.: Beitrage zur Pathologie und Therapie des Diabetes Mellitus. Marburg, 1874, p. 130. 4 Melaja, A.: Procedure for the separation of fructose from glucose of invert sugar. U. S. A. Pat. 3: 692-702, 1972. 5 Eheart, J. F., and Mason, B. S.: Sugar and acid in the edible portion of fruits. J. Am. Diet. Assoc. 50: 130-32, 1967. 6 Schallenberger, R. S.: Hydrogen bonding and the varying sweetness of the sugars. J. Food. Sci. 28: 584-89, 1963. 7 Doty, T. E.: Fructose sweetness: a new dimension. Cereal Foods World 21: 62-63, 1976. 8 Gracey, M., Burke, V., and Oshin, A.: Intestinal transport of fructose. Biochem. Biophys. Acta 266: 397-402, 1972. 9 Herman, R. H.: Hydrolysis and absorption of carbohydrates, and adaptive responses of the jejunum. In Sugars in Nutrition. Siple, H. L , and McNuff, K. W., Eds., New York, Academic Press, 1974, pp. 145-72. 10 Cook, G. C : Absorption products of D(-)-fructose in man. Clin. Sci. 37: 675-87, 1969. 11 Grace, N. D., Castelle, D. O., and Wennar, M. H.: A comparison of the oral fructose and ammonia tolerance tests in cirrhosis. Arch. Intern. Med. 124: 330-35, 1969. 12 Bohannon, N. J., Karam, J. K., and Forsham, P.: Comparison of prolonged responses to fructose, sucrose and glucose feeding. Abstracts of the 60th Annual Meeting of The American Dietetic Association, p. 20, 1977. 13 Mendeloff, A. I., and Weichselbaum, T. E.: Role of the human liver in the assimilation of intravenously administered fructose. Metabolism 2: 450-58, 1953. 14 Reinecke, R. M.: The kidney as a locus of fructose metabolism. Am. J. Physiol. 141: 669-76, 1944. 15 Cahill, G. F., Jr., Ashmore, J., Earle, A. S., and Zottu, S.: Glucose penetration into liver. Am. J. Physiol. 192: 491-96, 1958. 16 Huttunen, J. K.: Fructose in medicine. A review with particular reference to diabetes mellitus. Postgrad. Med. J. 47: 654-59, 1971. 17 Froesch, E. A.: Fructose metabolism in adipose tissue. Acta Med. Scand. Suppl. 542: 37-46, 1972. 18 Darragh, J. H., Womersley, R. A., and Meroney, W. H.:
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Fructose in the treatment of diabetic ketosis. J. Clin. Invest. 32: 1214-21, 1953. 19 Smith, L. H., Ettinger, R. H., and Seligson, D.: A comparison of the metabolism of fructose and glucose in hepatic disease and diabetes mellitus. J. Clin. Invest. 32: 273-82, 1953. 20 Miller, M , Craig, J. N . , Drucker, W . R., a n d Woodward, H . , Jr.: T h e metabolism of fructose in m a n . Yale J. Biol. Med. 29: 335-60, 1956. 21 Metz, R., Mako, M., Stevens, T., and Franklin, J.: The metabolism of fructose in diabetes mellitus. J. Lab. Clin. Med. 69: 494-503, 1967. 22 Minkowski, O . : Untersuchungen iiber d e n Diabetes mellitus n a c h Extirpation des Pancreas. A r c h . Exp. Pathol. U . Pharmakol. 31: 85-103, 1893. 23 Joslin, E. P.: Diabetic metabolism with high a n d low diets. Carnegie Institution of Washington, Publication N o . 323, Washington, D. C , 1923. 24
Moorhouse, J. A . , and Kark, R. M.: Fructose and diabetes. A m . J. Med. 23: 4 6 - 5 8 , 1957. 25 Vars, G . : U b e r die Fruktosetoleranz bei Diabetes mellitus.
Artzl. Wochenschr. 12: 627-31, 1957. 26 M e h n e r t , H . , Mahrhofer, E., a n d Forster, H . : Indikationen und Kontraindikationen fur die Verabreichung v o n Fructose and Diabetiker. Muench. Med. Wochenschr. 106: 193-202, 1964. 27 Joslin, E. P.: The treatment of diabetes mellitus, 4th edit., Philadelphia, Lea & Febiger, 1928, pp. 343-52. 28 Schauberger, C , Brinck, U. C , Guldner, G., Spaethe, R., Niklas, L., and Otto, H.: Exchange of carbohydrates according to their effect on blood glucose. Diabetes 26 (Suppl. 1): 415, 1977. 29 Brunzell, J. D., Lerner, R. L , Hazzard, W. R., Porte, D., Jr., and Bierman, E. L.: Improved glucose tolerance with high carbohydrate feeding in mild diabetes. N. Engl. J. Med. 284: 521-24, 1971. 30 Gulati, P. D . , Bhaskar Rao, M . , and Vaishnava, H . : Diet for diabetes. Lancet 2 : 2 9 7 - 9 8 , 1974. 31 Weinsier, R. L., Seeman, A . , Herrera, M . G . , Assal, J., Soeldner, J. S., and Gleason, R. E.: High- and low-carbohydrate diets in diabetes mellitus. Study of effects o n diabetic control, insulin secretion, and blood lipids. A n n . Intern. Med.
80: 332-41, 1974. 32 Anderson, J. W., and Ward, K.: Long-term effects of highcarbohydrate, high-fiber diets on glucose and lipid metabolism: a preliminary report on patients with diabetes. Diabetes Care I: 77-82, 1978. 33 Wood, F. C., and Bierman, E. L.: New concepts in diabetic diets. Nutr. Today 7: 4-12, 1972. 34 Hiller, J.: Die Laevuloseverwertung des acidotischen Diabetes mellitus. I Meggeilung. Zur Analyse der Acetonurie und Glucosurie. Z. Klin. Med., 153: 388-94, 1955.
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Lamar, C. P.: Comparative oral glucose and fructose tolerance tests in normal subjects and in diabetic patients. J. Fla. Med. Assoc. 46: 180-86, 1959. 36 Felber, J.-P., Renold, A. E., and Zahnd, G. R.: The comparative metabolism of glucose, fructose, galactose and sorbitol in normal subjects and in disease states. Med. Probl. Paediatr. 4: 482-87, 1959. 37 Pelkonen, R., Aro, A., and Nikkila, E.: Metabolic effects of dietary fructose in insulin dependent diabetes. Acta. Med. Scand. Suppl. 542: 187-93, 1972. 38 Nikkila, E. A . : Influence of dietary fructose and sucrose on serum triglycerides in hypertriglyceridemia and diabetes. In: Sugars in Nutrition. Siple, H . L., and McNuff, K. W . , Eds., New York, Academic Press, 1974, p p . 4 3 9 - 4 8 . 39 Arvidsson-Lenner, R.: Studies of glycemia a n d glucosuria in diabetes after breakfast meals of different composition. A m . J. Clin. Nutr. 2 9 : 7 1 6 - 2 5 , 1976. 40 Ziegler, E., Chimmello, G., and Marki, H. H.: T h e effect of the carbohydrate pattern of three isocaloric mixed breakfasts in the post-prandial concentrations of plasma glucose, insulin, growth hor- i mone and free fatty acids in normal man. Int. J. Vit. Nutr. Res. I 43: 2 1 2 - 2 6 , 1973. j 41 Crapo, P. A . , Reaven, G., and Olefsky, J.: Postprandial j plasma-glucose and -insulin responses to different complex carbo- i hydrates. Diabetes 26: 1 1 7 8 - 8 3 , 1977. ] 42 T u r n e r , J. L., Brunzell, J. D . , a n d Bierman, E. L.: Effect of dietary fructose o n triglyceride transport a n d glucoregulatory j h o r m o n e s in hypertriglyceridemic subjects. C l i n . Res. 25: 542A, j
1977 (Abstr.). j 43 Akerblom, H. K., Siltanen, I., and Kallio, A.-K.: Does j dietary fructose affect the control of diabetes in children? Acta ] Med. Scand. Suppl. 542: 195-202, 1972. j 44
H u t t u n e n , T . K., M a k i n e n , K., a n d S c h e i n i n , A . : Turku j sugar studies. XI. Effects of sucrose, fructose a n d xylitol o n glucose, j lipid a n d urate metabolism. A c t a O d o n t o l . Scand. 33 (Suppl. 70): ]
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S c h a r t o w , D . : Langzeitergebnisse n a c h Fructoseverabreichung o n Diabetiker. Doctoral thesis, M u n i c h 1965. Ref. in M e h n e r t , H.: Die V e r w e n d u n g v o n Fructose, Sorbit u n d Xylit. In: H a n d b u c h des Diabetes mellitus, 2 n d edit. Pfeiffer, E. F., Ed. M u n i c h , J. F. L e h m a n s Verlag, 1 9 7 1 , p . 1069. 46 T h e n e n , S. W . , a n d Mayer, J.: Effects of fructose a n d other dietary carbohydrates o n plasma glucose, insulin, a n d lipids in genetically obese {oblob) mice. Proc. S o c . Exp. Biol. Med. 153:
464-67, 1976. 47 Cohen, A. M., Teitelbaum, A., and Rosenman, E.: Diabetes induced by high fructose diet. Metabolism 26: 17-24, 1977. 48 Makinen, K. K.: Sugars and the formation of dental plaque. In Sugars in Nutrition. Siple, H. L., and McNuff, K. W., Eds. New York, Academic Press, 1974, pp. 645-87.
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ructose as a Dietary Sweetener in Diabetes Mellitus VEIKKO A. KOIVISTO
Human beings, including those with diabetes, have a desire for sweetness in the diet that cannot be ignored. The Food and Drug Administration ban of cyclamates and possible ban of saccharin have raised the question of alternative sweeteners for diabetic persons. Considerable interest has been focused on fructose, and both basic and clinical research has delineated its metabolic effects. This paper reviews the characteristics of fructose, as well as its physiology and metabolism in both normal and diabetic man. Findings seem to indicate that, in controlled diabetes, chronic or limited consumption of fructose at moderate doses has no adverse effects on the levels of blood glucose, cholesterol, or triglycerides. DIABETES CARE 1: 241-246, JULY-AUGUST 1978.
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uman beings have a strong desire for sweetness in the diet that cannot be ignored. This also is the case among individuals with diabetes. An inquiry of 500 subjects with diabetes in West Germany showed that 83 per cent of them were not willing to give up sweetening agents1 and in the United States more than 80 per cent of diabetic patients use at least one dietetic food.2 The ban of cyclamates and the possible ban of saccharin by the Food and Drug Administration (FDA) have now raised the question of alternative sweeteners for diabetic persons, since the consumption of sucrose may be contraindicated in the diabetic state. Recently there has been considerable renewed interest focused on fructose as an alternative sweetener for diabetic subjects. This is due to the basic differences between fructose and sucrose regarding their physiological and metabolic influences, differences which had already been recognized as early as 1874.3 Until the late 1960s the food use of fructose was limited because of its high price. A few years ago, however, an economical method was discovered to separate glucose and fructose from invert sugar solutions.4 This made feasible the industrial scale production of fructose at a reasonable price. Following the increased availability of fructose, both basic and clinical research have further delineated its metabolic effects. This paper reviews the characteristics of fructose, as well as its physiology and metabolism in both normal and
diabetic man, and provides a critical survey of clinical studies regarding the effects of fructose on control of diabetes. OCCURRENCE AND CHARACTERISTICS OF FRUCTOSE
Fructose, also known as fruit sugar or levulose, is one of the most commonly occurring sugars. It is largely found in plants and as a part of many polysaccharides similar to starch. The most common disaccharide, sucrose, is 50 per cent fructose, while honey is 41 per cent fructose. The amount of fructose in fruits and berries varies from 2 to 6 per cent of the fresh edible portion.5 In the human organism fructose may be formed from glucose or from sorbitol. Human blood normally contains only traces of fructose, but it occurs in measurable amounts in sperm, fetal blood, and amniotic fluid. Fructose is commercially available in a solid, crystalline form of more than 99.5 per cent purity and moisture content of less than 0.25 per cent. This is the yield from invert sugar after separation of the fructose and glucose moieties using ion exchange chromatography. Crystalline fructose is approximately 80 per cent sweeter than sucrose and more than twice as sweet as sorbitol.6 In solutions, the sweetness of fructose varies with temperature and pH, generally decreasing with increased temperature and acidity, while having greatest sweetness in cool, slightly acidic media.7
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Crystalline fructose is easily soluble in water. It withstands boiling and baking and is suitable for canning and freezing. Fructose is characterized by an agreeable sweetness without bitter aftertaste. Because fructose is hygroscopic, its presence enhances the freshness and shelf-life of bakery products. The exact caloric value of one gram of fructose is 3.75 kcal. or 16 KJ. ABSORPTION AND METABOLISM OF FRUCTOSE
T
he mechanism of gastrointestinal fructose absorption is probably facilitated diffusion, although an active transport process has also been demonstrated in vitro.8 The rate of fructose absorption, however, is lower than that of glucose.9 In man, up to 80 to 90 per cent of fructose is absorbed from the jejunum unmetabolized. There is only minor conversion of fructose to glucose or lactate during absorption.10 Slow absorption and rapid metabolism prevent rapid changes in the blood fructose levels after peroral administration. Thus it is difficult to achieve blood fructose levels above 25 mg. per deciliter after fructose ingestion in normal man.11'12 Fructose is metabolized mainly by the liver and to a lesser extent by the kidney and intestinal mucosa.13'14 Liver cells are freely permeable to fructose.15 The metabolism of fructose occurs mainly via the specific fructose-1-phosphate pathway. The first reaction is catalyzed by fructokinase, an enzyme, which is not dependent on insulin. This is in contrast to the first step in glucose metabolism, which is dependent on the presence of insulin.16 Thus, neither the entry of fructose into liver cells nor the first steps in its metabolism are dependent on insulin. For its part, the insulin secretory response to fructose is significantly lower than the insulin response to glucose or sucrose.12 Consequently a diabetic organism, too, can rapidly start to metabolize fructose even when glucose utilization is impaired.18"20 The first product of fructose metabolism, fructose-1-phosphate, is further converted to the trioses glyceraldehyde and dihydroxyacetone-phosphate. The final destiny of these trioses is dependent on insulin. When insulin is present, as occurs in diabetes under adequate control, trioses are oxidized to pyruvate and finally to Krebs cycle intermediates. This was shown by increments in the serum levels of pyruvate, lactate, alpha-ketoglutarate, and citrate after a fructose injection, even in diabetic patients.19'21 In insulin deprivation, such as during fasting or in poorly controlled diabetes, fructose-derived glyceraldehyde and dihydroxyacetone-phosphate are converted to glucose.16 The metabolism of fructose in man is very rapid, its half-life being approximately 18 minutes.17
experiments in which ingestion of fructose as a substitute for sucrose resulted in a reduction of glucosuria in diabetic patients. The author suggested that fructose could be used in the dietary management of diabetes. This conclusion was later supported by Minkowski when he reported contrasting effects of glucose and fructose in pancreatectomized dogs. When fructose was given, the amount of sugar and nitrogen excreted in the urine was diminished and the glyco gen content in the liver decreased as compared with glucose ingestion.22 Since these early findings several clinical studies have evaluated the role of dietary fructose in the management of diabetes.23"26 These studies showed that isocaloric replacement of glucose by fructose had beneficial effects in controlled diabetes, whereas this was not observed in untreated diabetes. After the first of these studies, the employment of fructose as a therapeutic agent in diabetes soon became unfashionable.27 Recently the question about the use of fructose in diabetes has been raised again. The issue now is whether or not it is possible to utilize fructose as a sweetener in diabetic diets without adverse effects. Recent studies have indicated that the rise in plasma glucose after fructose ingestion may be even lower than that seen after ingestion of complex carbohydrates.28 These findings support the use of fructose in the diabetic diet. Furthermore, the possibility of its use as a carbohydrate sweetener is a timely question for two reasons. First, if saccharin is banned, diabetic patients will need a sweetener that is also suitable from the standpoint of food technology. Secondly, Brunzell and coworkers have demonstrated that a high dietary content of carbohydrate may enhance the peripheral sensitivity to insulin, thus improving glucose tolerance in mild diabetes.29 Although these findings have been challenged by studies showing no difference in diabetic control by high- vs. low-carbohydrate diets,30'31 more recent studies employing high-carbohydrate, high-fiber diet support the original findings by Brunzell and coworkers; in insulin-dependent diabetes high-carbohydrate, high-fiber diet decreased the need of exogenous insulin and reduced the level of plasma glucose, cholesterol, and triglycerides.32 In addition, by increasing the proportion of carbohydrate in the diet, fat content can be decreased correspondingly, hopefully resulting in decreased serum lipid levels and perhaps thus decreasing the risk of development of atherosclerosis in diabetes.33 Since the use of fructose could serve for each of these purposes (as a sweetener and a dietary carbohydrate) it is therefore of particular interest to consider the metabolic effects of fructose in diabetes. Effects of Fructose on Carbohydrate Metabolism Comparison between fructose and glucose. As mentioned
EFFECT OF FRUCTOSE ON DIABETES
In 1874 in his monograph on diabetes Kulz3 described 242
before, there are a number of clinical studies indicating that the isocaloric replacement of glucose by fructose decreases
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hyperglycemia and glucosuria in patients in whom diabetes is controlled—both in adult-onset and in juvenile-onset diabetes. Hiller examined 160 mildly diabetic patients on isocaloric glucose and fructose diets and found a significant decrease in both hyperglycemia and glucosuria during the fructose period. The tendency to hyperketonemia was also diminished in the group on fructose diet. In contrast, in three patients with severe insulin deficiency, no change in the clinical picture was observed during fructose use.34 Lamar compared the effect of glucose and fructose ingestion (100 gm.) on plasma glucose levels in 22 diabetic subjects, two of them being extremely labile. In all patients, postprandial (30 to 180 minutes) hyperglycemia and glucosuria was absent or significantly lower after the ingestion of fructose than after glucose.35 The beneficial effects of fructose compared with glucose in diabetes have similarly been shown by several other authors. 21~24>26>3? Thus, it would indeed appear that fructose is better utilized than glucose by the diabetic organism. Comparison between fructose and starch in adult subjects
with diabetes. An important question from the practical point of view is whether fructose is as well utilized by diabetic subjects as polysaccharides, i.e. starches. This has been recently studied both in diabetic adults and children. Pelkonen et al.37 studied the effects of an isocaloric replacement of 75 gm. of dietary starch by fructose in 10 insulin-dependent, moderately controlled diabetic patients. The study was carried out in three periods of 10 days each. During the first and third periods, starch was the major carbohydrate, while during the second period 75 gm. of the starch was replaced by fructose. The total amount of calories was 30 to 40 kcal. per kilogram per day, 40 per cent of that being carbohydrate. Fructose feeding did not alter diurnal blood glucose levels or urinary glucose output, as compared with the starch period. Nikkila38 compared the effect of fructose, starch, and sucrose on the diabetic control in six patients with untreated adult-onset diabetes. The length of three successive dietary periods varied from 10 to 20 days. Under each period the diet was isocaloric, containing 45 per cent carbohydrate, 35 per cent fat, and 20 per cent protein. During one of the periods 75 to 80 gm. fructose or sucrose was added and an equivalent amount of starch was omitted from the diet. Fructose was added as a powder on desserts and as a sweetener in coffee or tea. The mean fasting blood glucose levels did not differ significantly during the three periods. From the results taken together, the authors concluded that diabetic patients either treated with insulin or having adult-onset disease can consume 75 gm. of fructose daily without exacerbating hyperglycemia. However, the use of sucrose by diabetic patients was not condoned by the authors. Arvidsson-Lenner39 tested the effect of different breakfast meals, some of them containing fructose, on postprandial glucose concentrations in five subjects with insulin-treated diabetes and in nine patients with adult-onset diabetes. All
breakfasts derived 20, 35, and 45 per cent of energy from protein, fat, and carbohydrates, respectively. The amounts of oligosaccharides (sucrose, fructose, lactose) varied from 5 to 65 per cent of the total carbohydrates, the remainder being starch. Oligosaccharides were included in milk and orange juice, whereas white bread was the main source of starch. In adequately treated insulin-dependent diabetes, the postprandial level of blood glucose was not dependent on the type of breakfast ingested but was proportional to the premeal glucose levels. This finding thus emphasizes the importance of insulin rather than the type of diet in controlling the postprandial rise of blood glucose. In adult diabetes, the breakfasts with the high percentages of oligosaccharides and low amount of starch surprisingly resulted in smaller increases in postprandial glucose levels than did the diet with a low portion of oligosaccharides. The relative contribution of individual sugars (fructose, sucrose, lactose) to the rise in glycemia cannot be estimated, since at least two of the sugars were employed simultaneously. A somewhat surprising finding, that starch meal causes a higher rise in blood glucose than high-sucrose meal, was explained by the author as due to the fact that hydrolyzation of starch provides only glucose moieties, whereas sucrose gives rise to both glucose and fructose molecules.39 This is in keeping with previous findings that sucrose ingestion in normal man causes a smaller increase in blood glucose than ingestion of equal amounts of glucose or starch hydrolyzates.40 Taken together, these data suggest the possible use of oligosaccharides rather than starch, and fructose rather than sucrose by diabetic patients. It should be noted, however, that all the starches are not equally hyperglycemic, e.g. ingestion of potato may cause a twofold higher glycemia than corn.41 Thus, comparisons between complex and simple carbohydrates are affected by the type of starch used. In four out of five juvenile and three out of nine adult diabetic patients Arvidsson-Lenner found a tendency to postprandial hypoglycemia after feeding with the high oligosaccharide diet.39 Therefore, the author did not recommend oligosaccharides in diabetes, in contrast to the conclusion above. It is not clear, however, whether the hypoglycemic tendency was due to feeding with oligosaccharides or to some other factor. There was a great day-to-day variation in fasting blood glucose levels in both juvenile-onset (from 55 to 299 mg. per 100 ml.) and adult-onset (from 53 to 248 mg. per 100 ml.) diabetic subjects. However, no information was given regarding the metabolic control during different diets. Thus, differences in basal blood glucose levels may contribute to varying postprandial glucose levels after different meals. Effect of two to three weeks of fructose feeding on blood glucose level was recently studied in six hypertriglyceridemic subjects, two of them also having diabetes.42 Basal diets contained 45 per cent carbohydrate (dextromaltose), 40 per cent fat, and 14 per cent protein. The other test diet was
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fat free and contained 85 per cent carbohydrate. In both diets fructose was substituted for 20 per cent of calories, being 33 to 46 gm. per day in basal and 90 to 155 gm. per day in fat'free diet. No change was observed in the level of plasma glucose insulin or glucagon during fructose feeding as compared with diets with dextromaltose.42 In another study, when equal amounts of carbohydrates in the form of various sugars and foods were given to diabetic and healthy people, the postprandial rise in blood glucose level was smallest after fructose.28 If the rise in plasma glucose level after fructose is taken as 100 per cent, the rise after equicaloric amount of toasted white bread was 347 per cent, after rye bread 200 per cent, after oatmeal 300 per cent, after rice 252 per cent, after potatoes 233 per cent, and after pure glucose 476 per cent. Based on these findings the authors suggest that conventional exchange units, based on weight, should be replaced by the "biological equivalents," i.e. based on the effect on postprandial blood glucose.28 These data thus seem to indicate that in adult subjects with either insulin-dependent or maturity-onset diabetes substitution of a part of dietary starch by fructose does not cause worsening of metabolic control. In contrast, in some cases postprandial rise in blood glucose may be less after fructose than after starch ingestion. Comparison between fructose and starch in diabetic children.
Whether fructose can be used as a sweetener by diabetic children has been studied by Akerblom et al. 43 The effect of fructose on postprandial glycemia after a breakfast meal was studied in 26 diabetic children under the age of 16 years. The breakfast provided 20 per cent of daily calories, 45 per cent of these were derived from carbohydrate, 35 per cent from fat, and 20 per cent from protein. During the fructose day, the children were given fructose at a level of 1 gm. per kilogram of weight, administered in lemon juice and chocolate. On the control day an equal amount of calories was derived from starch. The mean rise in blood glucose after breakfast was reduced by 75 to 85 per cent after fructose ingestion as compared with control meal (P < 0.02). The effects of prolonged use of fructose were studied in 16 diabetic children under home conditions.43 The daily caloric content of the diet was 1000 kcal. plus 100 kcal. per year for each year of age, with calories derived from carbohydrate, fat, and protein being 45 per cent, 35 per cent, and 20 per cent, respectively. The diet during the second and fourth weeks (fructose) was isocaloric with the diet in the control weeks, but a part of the carbohydrates from starch was substituted for by fructose at a rate of 1.5 gm. per kilogram of weight per day. Fructose was administered in beverage. The daily intake of carbohydrates was the same in control and fructose weeks. Glucosuria was similar during control and fructose weeks, the mean being from 1 to 1.5 per cent as measured at home from morning and evening specimens,43 indicating that diabetic children can use fructose in moderate amounts without exacerbating glucosuria. It was important, 244
however, that the child adhere to a quantitative diet, that fructose be used on an isocaloric basis, and that the child's mother supervise consumption.43 EFFECT ON LIPID METABOLISM
T
he effect of fructose on plasma lipids in diabetes is important when the use of fructose is considered a dietary component for diabetic patients. It has been reported that in healthy mean, high amounts of fructose (200 to 500 gm. per day) can increase the level of plasma friglycerides.38 In contrast, chronic consumption of fructose in moderate amounts (60 to 70 gm. per day) does not cause significant changes in serum triglyceride or cholesterol levels.44 Inasmuch as the turnover of fructose is dependent on insulin, it is necessary to consider the effect of fructose on plasma triglyceride levels in diabetes. In studies by Pelkonen et al. ,37 during the isocaloric replacement of starch by fructose (75 gm. per day) for 10 days, the level of plasma triglycerides in insulin-treated diabetic patients showed a mild, although not significant, increase from 1.00 ± 0.06 to 1.22 ± 0.08 mmol. per liter. An increasing tendency of plasma triglycerides was similarly observed in six untreated patients with hypertriglyceridemia and adult-onset diabetes. After 10 to 20 days of fructose feeding (75 to 90 gm. per day), the level of plasma triglycerides rose from 2.00 to 2.27 mmol. per liter, again a change that was not statistically significant.38 In contrast to this, Turner et al.42 did not find any change in plasma triglyceride or cholesterol levels after two to three weeks of fructose feeding in six hypertriglyceridemic patients, two of which also had diabetes. It is noteworthy that the daily amount of fructose ingested was substantial, 33 to 46 gm. in basal and 90 to 155 gm. in high-carbohydrate diet. Furthermore, in all six hypertriglyceridemic patients, with or without diabetes, fructose substitution decreased triglyceride production. Similarly, Akerblom et al.43 did not find any change in plasma triglyceride levels in diabetic children after two weeks use of fructose at a rate of 1.5 gm. per kilogram of weight per day. These findings thus seem to indicate that in controlled diabetes, acute or a few weeks of fructose consumption at moderate doses has no adverse effects on the levels of blood glucose, cholesterol, and triglycerides. CHRONIC FRUCTOSE CONSUMPTION
In addition to these acute or short-term follow-up studies, the effects of chronic fructose administration have been studied both in man and animals. In Turku sugar studies, 35 normal subjects used fructose as the only sweetener in their diet, the average dose being 60 to 70 gm. per day.44 During a two-year follow-up period, fructose failed to cause any changes in their plasma level of glucose, insulin, choles-
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terol, or triglycerides. In keeping with this, fructose administration at a dose of 30 gm. per day over a period of 18 months did not cause any adverse effects in 89 patients with adult-onset diabetes.45 The effects of high-dose chronic fructose feeding in animals seem to be more controversial, however. In obioh mice, which are hyperglycemic, hyperinsulinemic, and hyperlipemic, fructose administration for six months at a dose of 64 per cent of total calories reduced hyperglycemia, while plasma levels of insulin cholesterol and triglycerides were similar to animals fed with starch, sucrose, or glucose.46 In normal mice, fructose feeding reduced both glucose and triglyceride levels as compared with groups fed with the other three carbohydrates. These findings thus indicate that chronic fructose administration is superior to cornstarch, sucrose, or glucose feeding in obese or in normal mice. In contrast to these findings, a high fructose diet (72 per cent) for two months resulted in hypercholesterolemia and hypertriglyceridemia and impaired glucose tolerance to diabetic range in particular Hebrew University Strain (HUS) rats, which were selected based on their genetic predisposition to diabetes.47 The data from these animal studies may not be applicable to humans, since the diets were much higher in fructose than those generally consumed by humans. In addition, the heavy genetic predisposition to diabetes in HUS-rats may be different than that in humans. Taken together, chronic fructose consumption does not seem to have adverse metabolic effects in normal man or in patients with adult-onset diabetes, whereas in experimental diabetes, when fructose is used at pharmacological doses, the results are more controversial. FRUCTOSE AND DENTAL CARIES
Different sugars seem to have a different effect upon dental plaque formation and the development of caries. In normal man, a four-day fructose diet decreases the plaque formation by 30 per cent as compared with an equicaloric sucrose diet.48 Furthermore, an extensive two-year study showed that caries formation was decreased by 25 per cent in a group with fructose-containing diet (38 subjects) as compared with sucrose diet in 52 subjects.48 CONCLUSIONS
Fructose, fruit sugar, is one of the most commonly occurring sugars. It is sweeter than sucrose and is characterized by an agreeable sweetness without a bitter aftertaste. The metabolism of fructose is not as much dependent on insulin as that of sucrose. This provides a theoretical basis for fructose consumption in diabetes. Clinical studies seem to indicate that the hyperglycemic effect of fructose in diabetes is not higher than that of starches. No adverse effects of fructose consumption on glucose metabolism have
been observed in controlled diabetes. In some studies a tendency to increase plasma triglyceride level has been observed, but this finding has not been uniformly confirmed and the opposite finding of a decrease in triglyceride production has been observed with fructose consumption. Because fructose is sweeter than sucrose, it offers an alternative sweetener also for nondiabetic people who would like to restrict their total intake of sugar-derived calories. Furthermore, substitution of fructose for sucrose may reduce dental caries formation. From Yale University School of Medicine, New Haven, Connecticut. REFERENCES 1
Mehnert, H.: Uber den relativen Wert von Zuckerauschtoffen und Susstoffen in der Diabetesdiat. Wiss. Veroeff. Dtsch. Ges. Ernaehr. Darmstadt, Steinkopf, 1971, vol. 20. 2 Bender, A. E.: Nutrition and Dietetic Foods, 2nd edit. New York, Chemical Publishing Co., 1973, pp. 49-64. 3 Kulz, E.: Beitrage zur Pathologie und Therapie des Diabetes Mellitus. Marburg, 1874, p. 130. 4 Melaja, A.: Procedure for the separation of fructose from glucose of invert sugar. U. S. A. Pat. 3: 692-702, 1972. 5 Eheart, J. F., and Mason, B. S.: Sugar and acid in the edible portion of fruits. J. Am. Diet. Assoc. 50: 130-32, 1967. 6 Schallenberger, R. S.: Hydrogen bonding and the varying sweetness of the sugars. J. Food. Sci. 28: 584-89, 1963. 7 Doty, T. E.: Fructose sweetness: a new dimension. Cereal Foods World 21: 62-63, 1976. 8 Gracey, M., Burke, V., and Oshin, A.: Intestinal transport of fructose. Biochem. Biophys. Acta 266: 397-402, 1972. 9 Herman, R. H.: Hydrolysis and absorption of carbohydrates, and adaptive responses of the jejunum. In Sugars in Nutrition. Siple, H. L , and McNuff, K. W., Eds., New York, Academic Press, 1974, pp. 145-72. 10 Cook, G. C : Absorption products of D(-)-fructose in man. Clin. Sci. 37: 675-87, 1969. 11 Grace, N. D., Castelle, D. O., and Wennar, M. H.: A comparison of the oral fructose and ammonia tolerance tests in cirrhosis. Arch. Intern. Med. 124: 330-35, 1969. 12 Bohannon, N. J., Karam, J. K., and Forsham, P.: Comparison of prolonged responses to fructose, sucrose and glucose feeding. Abstracts of the 60th Annual Meeting of The American Dietetic Association, p. 20, 1977. 13 Mendeloff, A. I., and Weichselbaum, T. E.: Role of the human liver in the assimilation of intravenously administered fructose. Metabolism 2: 450-58, 1953. 14 Reinecke, R. M.: The kidney as a locus of fructose metabolism. Am. J. Physiol. 141: 669-76, 1944. 15 Cahill, G. F., Jr., Ashmore, J., Earle, A. S., and Zottu, S.: Glucose penetration into liver. Am. J. Physiol. 192: 491-96, 1958. 16 Huttunen, J. K.: Fructose in medicine. A review with particular reference to diabetes mellitus. Postgrad. Med. J. 47: 654-59, 1971. 17 Froesch, E. A.: Fructose metabolism in adipose tissue. Acta Med. Scand. Suppl. 542: 37-46, 1972. 18 Darragh, J. H., Womersley, R. A., and Meroney, W. H.:
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Fructose in the treatment of diabetic ketosis. J. Clin. Invest. 32: 1214-21, 1953. 19 Smith, L. H., Ettinger, R. H., and Seligson, D.: A comparison of the metabolism of fructose and glucose in hepatic disease and diabetes mellitus. J. Clin. Invest. 32: 273-82, 1953. 20 Miller, M , Craig, J. N . , Drucker, W . R., a n d Woodward, H . , Jr.: T h e metabolism of fructose in m a n . Yale J. Biol. Med. 29: 335-60, 1956. 21 Metz, R., Mako, M., Stevens, T., and Franklin, J.: The metabolism of fructose in diabetes mellitus. J. Lab. Clin. Med. 69: 494-503, 1967. 22 Minkowski, O . : Untersuchungen iiber d e n Diabetes mellitus n a c h Extirpation des Pancreas. A r c h . Exp. Pathol. U . Pharmakol. 31: 85-103, 1893. 23 Joslin, E. P.: Diabetic metabolism with high a n d low diets. Carnegie Institution of Washington, Publication N o . 323, Washington, D. C , 1923. 24
Moorhouse, J. A . , and Kark, R. M.: Fructose and diabetes. A m . J. Med. 23: 4 6 - 5 8 , 1957. 25 Vars, G . : U b e r die Fruktosetoleranz bei Diabetes mellitus.
Artzl. Wochenschr. 12: 627-31, 1957. 26 M e h n e r t , H . , Mahrhofer, E., a n d Forster, H . : Indikationen und Kontraindikationen fur die Verabreichung v o n Fructose and Diabetiker. Muench. Med. Wochenschr. 106: 193-202, 1964. 27 Joslin, E. P.: The treatment of diabetes mellitus, 4th edit., Philadelphia, Lea & Febiger, 1928, pp. 343-52. 28 Schauberger, C , Brinck, U. C , Guldner, G., Spaethe, R., Niklas, L., and Otto, H.: Exchange of carbohydrates according to their effect on blood glucose. Diabetes 26 (Suppl. 1): 415, 1977. 29 Brunzell, J. D., Lerner, R. L , Hazzard, W. R., Porte, D., Jr., and Bierman, E. L.: Improved glucose tolerance with high carbohydrate feeding in mild diabetes. N. Engl. J. Med. 284: 521-24, 1971. 30 Gulati, P. D . , Bhaskar Rao, M . , and Vaishnava, H . : Diet for diabetes. Lancet 2 : 2 9 7 - 9 8 , 1974. 31 Weinsier, R. L., Seeman, A . , Herrera, M . G . , Assal, J., Soeldner, J. S., and Gleason, R. E.: High- and low-carbohydrate diets in diabetes mellitus. Study of effects o n diabetic control, insulin secretion, and blood lipids. A n n . Intern. Med.
80: 332-41, 1974. 32 Anderson, J. W., and Ward, K.: Long-term effects of highcarbohydrate, high-fiber diets on glucose and lipid metabolism: a preliminary report on patients with diabetes. Diabetes Care I: 77-82, 1978. 33 Wood, F. C., and Bierman, E. L.: New concepts in diabetic diets. Nutr. Today 7: 4-12, 1972. 34 Hiller, J.: Die Laevuloseverwertung des acidotischen Diabetes mellitus. I Meggeilung. Zur Analyse der Acetonurie und Glucosurie. Z. Klin. Med., 153: 388-94, 1955.
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Lamar, C. P.: Comparative oral glucose and fructose tolerance tests in normal subjects and in diabetic patients. J. Fla. Med. Assoc. 46: 180-86, 1959. 36 Felber, J.-P., Renold, A. E., and Zahnd, G. R.: The comparative metabolism of glucose, fructose, galactose and sorbitol in normal subjects and in disease states. Med. Probl. Paediatr. 4: 482-87, 1959. 37 Pelkonen, R., Aro, A., and Nikkila, E.: Metabolic effects of dietary fructose in insulin dependent diabetes. Acta. Med. Scand. Suppl. 542: 187-93, 1972. 38 Nikkila, E. A . : Influence of dietary fructose and sucrose on serum triglycerides in hypertriglyceridemia and diabetes. In: Sugars in Nutrition. Siple, H . L., and McNuff, K. W . , Eds., New York, Academic Press, 1974, p p . 4 3 9 - 4 8 . 39 Arvidsson-Lenner, R.: Studies of glycemia a n d glucosuria in diabetes after breakfast meals of different composition. A m . J. Clin. Nutr. 2 9 : 7 1 6 - 2 5 , 1976. 40 Ziegler, E., Chimmello, G., and Marki, H. H.: T h e effect of the carbohydrate pattern of three isocaloric mixed breakfasts in the post-prandial concentrations of plasma glucose, insulin, growth hor- i mone and free fatty acids in normal man. Int. J. Vit. Nutr. Res. I 43: 2 1 2 - 2 6 , 1973. j 41 Crapo, P. A . , Reaven, G., and Olefsky, J.: Postprandial j plasma-glucose and -insulin responses to different complex carbo- i hydrates. Diabetes 26: 1 1 7 8 - 8 3 , 1977. ] 42 T u r n e r , J. L., Brunzell, J. D . , a n d Bierman, E. L.: Effect of dietary fructose o n triglyceride transport a n d glucoregulatory j h o r m o n e s in hypertriglyceridemic subjects. C l i n . Res. 25: 542A, j
1977 (Abstr.). j 43 Akerblom, H. K., Siltanen, I., and Kallio, A.-K.: Does j dietary fructose affect the control of diabetes in children? Acta ] Med. Scand. Suppl. 542: 195-202, 1972. j 44
H u t t u n e n , T . K., M a k i n e n , K., a n d S c h e i n i n , A . : Turku j sugar studies. XI. Effects of sucrose, fructose a n d xylitol o n glucose, j lipid a n d urate metabolism. A c t a O d o n t o l . Scand. 33 (Suppl. 70): ]
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S c h a r t o w , D . : Langzeitergebnisse n a c h Fructoseverabreichung o n Diabetiker. Doctoral thesis, M u n i c h 1965. Ref. in M e h n e r t , H.: Die V e r w e n d u n g v o n Fructose, Sorbit u n d Xylit. In: H a n d b u c h des Diabetes mellitus, 2 n d edit. Pfeiffer, E. F., Ed. M u n i c h , J. F. L e h m a n s Verlag, 1 9 7 1 , p . 1069. 46 T h e n e n , S. W . , a n d Mayer, J.: Effects of fructose a n d other dietary carbohydrates o n plasma glucose, insulin, a n d lipids in genetically obese {oblob) mice. Proc. S o c . Exp. Biol. Med. 153:
464-67, 1976. 47 Cohen, A. M., Teitelbaum, A., and Rosenman, E.: Diabetes induced by high fructose diet. Metabolism 26: 17-24, 1977. 48 Makinen, K. K.: Sugars and the formation of dental plaque. In Sugars in Nutrition. Siple, H. L., and McNuff, K. W., Eds. New York, Academic Press, 1974, pp. 645-87.
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