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More facts related to excessive fruits / fructose consumption

1) Fructose excess can cause gouty arthritis and renal stones

Fructose is mainly metabolized through Fructose-1-P pathway. Unlike phosphofructokinase, which is involved in glucose metabolism, fructokinase has no negative feedback system to prevent it from continuing to phosphorylate its substrate, i.e. Fructose to form fructose -1-phosphate, and as a consequence ATP can be depleted,(Figure-1) causing intracellular phosphate depletion, and activation of AMP deaminase (Figure -2).

 AMP deaminase enzyme causes conversion of AMP to IMP (Inosine monophosphate) and is inhibited by inorganic phosphate. Phosphate depletion causes loss of inhibition and thus it is activated, IMP is subsequently degraded to Inosine, Hypoxanthine , Xanthine and finally to Uric acid (Figure-1). Excessive uric acid generation leads to gout or renal stones (Urate stones). Thus excessive fruit consumption should be avoided by such patients.

Fructose induced hyperuricemia 

Figure-1- Showing metabolism of fructose. The uninhibited fructokinase causes ATP depletion. The resulting metabolites are finally converted to uric acid.

 Mechanism of action of AMP deaminase

Figure-2- Showing degradation of AMP, the key enzyme AMP deaminase is inhibited by inorganic phosphate. ATP depletion caused by active Fructokinase causes loss of inhibition of AMP deaminase by inorganic phosphate resulting in over activity of enzyme and overproduction of IMP and thus excess Uric acid.

2) Reasons to discourage fructose to treat hypoglycemia

Fructose has often been suggested as a treatment for hypoglycemia. It does contribute towards formation of Glucose and glycogen but there are several good reasons to discourage it as a treatment of hypoglycemia

The mechanism of glucose production is as follows- 

Increased concentrations of Dihroxyacetone phosphate (DAP) and glyceraldehyde- 3-phosphate (GAP) produced from the metabolism of fructose in the liver drive the pathway toward glucose and subsequent glycogen synthesis (See figure-3).

 Mechanism of glucose production from fructose

Figure-3- Dihydroxyacetone phosphate(DAP) and glyceraldehyde -3-P produced from fructose metabolism condense together in the presence of Aldolase to form Fructose 1,6 bisphosphate, that is cleaved by fructose 1,6 bisphosphatase (FD pase) to form fructose-6-P. Glucose-6-P produced from Fructose-6-P by the action of Phospho hexose isomerase is converted to free glucose by the action of glucose-6-phosphatase. Hence by these reactions, Glucose is produced from fructose, blood glucose level rises. Surplus glucose-6-P can enter pentose phosphate pathway or can be converted to Glucose-1-P under the effect of Phosphoglucomutase and can be used up for the formation of Glycogen.

There are several good reasons to discourage the use of fructose to treat hypoglycemia

1) The process of formation of glucose from fructose is not an immediate process.
2) Secondly the conversion of fructose to glucose uses 2 ATPs. One ATP is spent at the first step for the formation of fructose-1-P and the second ATP is spent for the conversion of glyceraldehyde to Glyceraldehyde-3-P (Figure-3).Normal hepatic activity alone utilizes all of the liver’s ATP-synthesizing capacity.There is no good reason to increase hepatic ATP utilization for fructose metabolism. Glucose metabolism on the other hand produces ATP instead of utilizing.
3) Moreover fructose is not a direct energy source for brain and muscle as these tissue lack fructokinase and fructose transporters while Glucose is a preferred fuel for brain and can be utilized in almost all the cells of the body. Hence Glucose (also called dextrose) instead of fructose can be given orally or intravenously depending upon the situation to treat hypoglycemia.

3) What is the reason that even after consumption of lots of fruits or a large amount of fructose rich drink appetite is not suppressed?

1) Fructose does not stimulate release of insulin. One of insulin’s important functions is central regulation of hunger.Fructose does not affect the hypothalamus directly or through insulin.Fructose does not appear to dampen the sense of hunger.

Insulin release can modulate food intake by at least two mechanisms. First, insulin concentration in the central nervous system has a direct inhibitory effect on food intake. In addition, insulin may modify food intake by its effect on leptin secretion, which is mainly regulated by insulin-induced changes in glucose metabolism in fat cells.. Thus, a low insulin concentration after ingestion of fructose would be associated with lower average leptin concentrations than would be seen after ingestion of glucose. Because leptin inhibits food intake, the lower leptin concentrations induced by fructose would tend to enhance food intake and thus the appetite is not suppressed.

2) Ghrelin, a hormone produced by endocrine cells in the stomach, increases food intake and decreases fat oxidation and appears to have an anabolic role in long-term regulation of energy balance. Ghrelin secretion is normally suppressed after meals, but it is not suppressed by fructose consumption.

Thus this is another reason for non suppression of appetite even upon excessive consumption of fruits and also the reason for fructose related obesity and the obesity related complications.

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