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.
Figure-1- Showing metabolism of fructose. The uninhibited fructokinase causes ATP depletion. The resulting metabolites are finally converted to uric acid.
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).
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.Please help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!
The mean annual consumption of sucrose plus fructose in developed countries is approximately 25% of the caloric intake. Because of the differences in the hepatic metabolism of fructose and glucose ,fructose is more lipogenic than glucose and is therefore more readily converted in the liver to triglyceride, which can be exported and stored in adipose tissue.
Metabolism of fructose
Much of the ingested fructose is metabolized by the liver, using the fructose 1-phosphate pathway (See figure-1) .
1) The first step is the phosphorylation of fructose to fructose 1-phosphate by fructokinase.
2) Fructose-1-phosphate is then split into glyceraldehyde and Dihydroxyacetone phosphate, an intermediate in glycolysis. Since there is only one phosphate attached to Fructose, it goes to only one of the trioses, the other is subsequently phosphorylated. This aldol cleavage is catalyzed by a specific fructose 1-phosphate aldolase.
3) Glyceraldehyde is then phosphorylated to glyceraldehyde -3-phosphate, a glycolytic intermediate, by triose kinase.
4) Alternatively, fructose can be phosphorylated to fructose 6-phosphate by hexokinase. The two triose phosphates, Dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, may be degraded by glycolysis or may be substrates for aldolase and hence gluconeogenesis, which is the fate of much of the fructose metabolized in the liver. (See figure-1 and follow the steps)
Figure-1-showing the metabolism of fructose. Excess fructose consumption can lead to increase in adipose mass as well as increase in glycogen stores
Biochemical Basis of fructose induced metabolic alterations
Fructose undergoes more rapid glycolysis in the liver than does glucose, because it bypasses the regulatory step catalyzed by phosphofructokinase (Figure-1). This allows fructose to flood the pathways in the liver. High fructose consumption can lead to excess pyruvate production, causing a buildup of acetyl CoA which is directed toward fatty acid synthesis. Additionally, DHAP can be converted to glycerol3-phosphate providing the glycerol backbone for the triglyceride molecule. Triglycerides are incorporated into very low density lipoproteins (VLDL), the carriers for transportation of endogenously synthesized lipids , which are released from the liver destined toward peripheral tissues for storage in both fat and muscle cells.causing obesity (Figure-2).
Figure- 2 showing the fructose related metabolic complications.
Excessive fructose consumption is also believed to contribute to the development of non-alcoholic fatty liver disease (hepatic steatosis) In addition, several studies have demonstrated that fructose increases circulating triglyceride levels in the postprandial period and evidence indicates that this effect is more pronounced in persons with existing hyperlipidemia or insulin resistance .Thus, long-term consumption a diet high in fructose may increase the risk of atherosclerosis or other cardiovascular disease.
In addition, recent data indicate that compared with glucose, consuming fructose with meals, which does not stimulate insulin secretion, results in a reduction of circulating leptin concentrations and an attenuated postprandial suppression of ghrelin, a hormone produced by the stomach that stimulates hunger and increases food intake .
Insulin and leptin are important long-term regulators of food intake and energy balance. Both insulin and leptin act in the central nervous system to inhibit food intake and to increase energy expenditure, most likely by activating the sympathetic nervous system (SNS). Insulin is secreted from the β-cells in the endocrine pancreas in response to circulating nutrients (glucose and amino acids) and to the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which are released during meal ingestion and absorption. Insulin can also act indirectly by stimulating leptin production from adipose tissue via increased glucose metabolism.
In contrast, dietary fat and fructose do not stimulate insulin secretion and therefore do not increase leptin production. 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, with respect to the hormones insulin, leptin, and ghrelin that are involved in the long-term endocrine regulation of food intake, energy balance, and body adiposity ,dietary fructose behaves more like dietary fat than do other types of carbohydrate that are composed of glucose . The lack of effect of fructose on these hormones suggests that chronic consumption of a diet high in fructose could contribute, along with dietary fat and inactivity, to increased energy intake, weight gain, and obesity. Obesity eventually leads to insulin resistance, diabetes mellitus and metabolic syndrome.Please help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!