Fructose infusion

A prerequisite for the development of cell necrosis is the loss of cellular ATP reserves. However, 15-20% of the normal ATP reservoir are sufficient to prevent cell lysis. In the same way, fructose (a glycolytic ATP donor) has been shown to inhibit cell necrosis in laboratory experiments. This could be an explanation for the fact that fructose infusion was formerly considered to be effective in liver diseases. 

Nilsson, L., and Hultman, E. (1974). Liver and muscle glycogen in man after glucose and fructose infusion. Scatul. j. Clin. Lab. invesl. 33,3-10. 

TABLE 4.8 Effects of Glucose and Fructose infusions on Human Subjects... 

The total purine nucleotide constant of mouse liver fell within three minutes of fructose infusion, and remained at the reduced level for at least 30 minutes. The total nucleotide content fell after glucose infusion also, although somewhat less than after fructose. However, ADP content did not fall after glucose, whereas it fell significantly after fructose, and when the nucleotide changes were expressed in terms of inhibitory j)otential for amidophosphoribosyitransferase, that is, specifically in terms of those ribonucleotides that inhibit the enzymes such as AMP and GMP, this inhibitory potential fell only following fructose infusion. Tlie fall was statistically significant at 30 minutes. 

J.E. Seegmiller, Stimulation of human purine synthesis novo by fructose infusion. Metabolism 24 861-869 (1975). 

Four fasting gouty patients were infused with 0.5 gm/Kg of a 20% fructose solution over a 10 minute period. Two of these patients were restudied after pretreatment with allopurinol, 600 mg per day. Figure 1 illustrates the changes in the serum urate concentration in the 180 minutes after the start of the fructose infusion. The serum urate showed a 33% increase over control values at 30 minutes, while this change was not seen in the two patients taking allopurinol. These data confirm the initial observation that the rapid infusion of fructose does produce a substantial increase in the serum urate concentration. 

Based on our understanding of fructose metabolism, we have examined four potential mechanisms to account for fructose-induced hyperuricemia in man. 1) Shift in the uric acid pool, 2) decreased renal clearance of uric acid, 3) increased purine synthesis novo by stimulating PP-ribose-P production,and 4) accelerated degradation of purine ribonucleotides. Our studies were designed to distinguish which of these mechanisms in man could account for the hyperuricemia observed after fructose infusion. 

Blood lactate levels were determined before and 30 minutes after the start of fructose infusion (Table 1). Hyper1acticacidemia with a mean increase of 256% of control values was observed 30 minutes after the start of the fructose infusion. The hyperlactic-acidemia also occurred in the patients treated with allopurinol even though the serum urate concentration did not change with the infusion of fructose under these conditions. 

The urinary uric acid excretion and the urinary oxypurine excretion were measured up to 180 minutes after the start of the fructose infusion (Figure 4). A mean increase in the urinary uric acid excretion to 144% of control values and in urinary oxypurine excretion to 397% of control values occurred in the first hour after infusion. The marked rise in urinary oxypurines resulted primarily from a rise in hypoxanthine excretion. A striking increase in the excretion of inosine was also noted. No change was observed in the fractional clearance of uric acid. Pretreatment with allopurinol enhanced the absolute increase in urinary oxypurine excretion. These observations suggest that fructose-induced hyperuricemia is related to stimulation of uric... 

Fig. 3. Effect of fructose infusion on plasma total reducing substances, glucose and phosphate. Results are expressed in mg/100 ml. (From Fox and Kelley, 1972).

Fig. 5. Effect of fructose infusion on concentration of PP-ribose-P, ribose-5-phosphate, and ATP in erythrocytes. Results are expressed as per cent of control values. Control values represent mean S.D. (vertical bars) of three different samples obtained during a 60 min. period immediately preceeding infusion of fructose. Open squares, patient J.W. closed squares, patient L.L. open circles, patient H.M. and closed circles, patient A.B. (From Fox and Kelley, 1972).

Since ATP normally inhibits 5 -nucleotidase and inorganic phosphate inhibits AMP deaminase, these changes would be expected to stimulate the catabolism of AMP to inosine. This hypothesis would most readily account for the rapid rise in serum urate concentration, the increased urinary excretion of inosine, oxypurines and uric acid, and the lack of an increase in intracellular PP-ribose-P levels following fructose infusion. 

According to our results the xylitol-induced hyperuricemia can be best explained by a rapid degradation of purine nucleotides, a situation similar to the observations during fructose infusions (1,2,5). 

Gouty patients or people with primary asymptomatic hyperuricemia show a sustained increase in serum uric acid following fructose infusion Both patients were infused (1 0 g/kg body weight/hr) for two hours It was striking that the patient W., immediately after beginning the infusion, showed a significant rise in serum uric acid (fig 2). During the entire infusion time the concentration of uric acid continued to increase The uric acid level remained constant after completion of the infusion ... 

This type of serum uric acid curve is usually representative for gouty patients (13) During fructose infusion in patient E the serum uric acid did not change significantly, a type of reaction characteristic for metabolically healthy persons ... 

Figure 2 Changes of serum uric acid during fructose infusion (1.0 g/kg body weight/hr).

However, it has become apparent (Bergstrbm et al, 1971) that in healthy subjects fructose infusion raises the blood lactate concentration (see Figure 1). 

As is shown in Figure 7, serum lactate concentration increased most after fructose infusion. But sorbitol was nearly as effective and glucose also caused a significant increase in blood lactate. However, confirming the liver perfusion studies, lactate increased only slightly after xylitol infusions. Xylitol infusion caused... 

At the end of the experimental period, using sorbitol or fructose infusions, there was a rise in blood glucose concentration whereas the blood glucose concentrations during xylitol infusion was nearly identical with that of glucose infusions. 

An increased production of PP-ribose-P has been produced in vitro by several compounds which increase ribose-5-P availability and could potentially accelerate the rate of purine biosynthesis de novo. Methylene blue, 10 to 100 pM, has been shown to increase intracellular PP-ribose-P in Ehrlich tumor ascites cells, in human erythrocytes, and in diploid human fibroblasts. In the latter cells a concomitant increase in purine biosynthesis de novo was observed. Intravenous methylene blue (2 mg/Kg) given to 2 patients did not alter erythrocyte PP-ribose-P levels (Fig. 3). Glucose, fructose and ribose also increase erythrocyte PP-ribose-P levels in vitro. However, as noted above, fructose infusions in vivo had an opposite effect. 

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