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Excessive fructose intake (>50g/d) has been found to be one of the underlying etiologies of obesity, insulin resistance and metabolic syndrome. Diets high in sucrose or in high-fructose syrups (HFS) used in manufactured foods and beverages can lead to large amounts of fructose (and glucose) entering the hepatic portal vein.

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)

Fructose metabolism















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).

fructose induced metabolic changes














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.

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