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Q.1- Discuss the mechanism of digestion and absorption of fructose.

Answer-Fructose exists in foods as either a monosaccharide (free fructose) or as a unit of a disaccharide (sucrose). Free fructose is absorbed directly by the intestine; however, when fructose is consumed in the form of sucrose, digestion occurs entirely in the upper small intestine.As sucrose comes into contact with the membrane of the small intestine, the enzyme sucrase catalyzes the cleavage of sucrose to yield one glucose unit and one fructose unit. Fructose is absorbed in the small intestine, then enters the hepatic portal vein and is directed toward the liver.

Fructose absorption occurs on the mucosal membrane via facilitated transport involving GLUT5 transport proteins (Figure-1).Since the concentration of fructose is higher in the lumen, fructose is able to flow down a concentration gradient into the enterocytes, assisted by transport proteins. Fructose may be transported out of the enterocyte across the basolateral membrane by either GLUT2 or GLUT5, although the GLUT2 transporter has a greater capacity for transporting fructose and therefore the majority of fructose is transported out of the enterocyte through GLUT2. Fructose transfer activity increases with dietary fructose intake.The presence of fructose in the lumen causes increased mRNA transcription of GLUT5, leading to increased transport proteins.









Figure-1- showing the transport of fructose

Fructose Malabsorption- fructose malabsorption, formerly named “dietary fructose intolerance,” is a digestive disorder in which absorption of fructose is impaired by deficient fructose carriers (GLUT 5) in the small intestine’s enterocytes. This results in an increased concentration of fructose in the entire intestine. In the large intestine, fructose that hasn’t been adequately absorbed osmotically reduces the absorption of water and is metabolized by normal colonic bacteria to short chain fatty acids and the gases hydrogen, carbon dioxide and methane. This abnormal increase in hydrogen is detectable with the hydrogen breath test.

The physiological consequences of fructose malabsorption include increasing osmotic load, providing substrate for rapid bacterial fermentation and changing gastrointestinal motility. The presence of gases and organic acids in the large intestine causes gastrointestinal symptoms such as bloating, diarrhea, flatulence, and gastrointestinal pain.

 Restricting dietary intake of free fructose and/or fructans may provide symptomatic relief in a high proportion of patients. 

Q.2- How is fructose metabolized in the body? 

Answer- Much of the ingested fructose is metabolized by the liver, using the fructose 1-phosphate pathway (Figure-2). The first step is the phosphorylation of fructose to fructose 1-phosphate by fructokinase. Fructose 1-phosphate is then split into Glyceraldehyde and Dihydroxyacetone phosphate, an intermediate in glycolysis. This aldol cleavage is catalyzed by a specific fructose 1-phosphate aldolase. Glyceraldehyde is then phosphorylated to Glyceraldehyde 3-phosphate, a glycolytic intermediate, by triose kinase.

Figure-2 -showing the metabolism of fructose

Alternatively, fructose can be phosphorylated to fructose 6-phosphate by hexokinase. However, the affinity of hexokinase for glucose is 20 times as great as it is for fructose. In extrahepatic tissues, hexokinase catalyzes the phosphorylation of most hexose sugars, including fructose, but glucose inhibits the phosphorylation of fructose, since it is a better substrate for hexokinase. Little fructose 6- phosphate is formed in the liver because glucose is so much more abundant in this organ. Moreover, glucose, as the preferred fuel, is also trapped in the muscle by the hexokinase reaction. Because liver and muscle phosphorylate glucose rather than fructose, adipose tissue is exposed to more fructose than glucose. Hence, the formation of fructose 6- phosphate is not competitively inhibited to a biologically significant extent, and most of the fructose in adipose tissue is metabolized through fructose 6-phosphate. Fructose-6-p is phosphorylated by PFK-1 and is subsequently cleaved to form the two triose phosphates.

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.

Conversion of glucose to fructose- Fructose is found in seminal plasma. Glucose is reduced to Sorbitol in the presence of Aldose reductase(AR) and Sorbitol dehydrogenase(SD) is responsible for the conversion of Sorbitol into fructose (Figure-3). Fructokinase is present in the liver and seminal vesicles, hence fructose is metabolized by fructose-1-p pathway in these tissues.
















Figure 3 showing the conversion of glucose to fructose in the liver and seminal vesicles by sorbitol pathway

Q.3- Why is it said that ingestion of large quantities of fructose or fructose containing syrups leads to dyslipidemia?


Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity’, Justify the statement.

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

Synthesis of triglycerides – Carbons from dietary fructose are found in both the free fatty acid and glycerol moieties of plasma triglycerides. Fructose undergoes more rapid glycolysis in the liver than does glucose, because it bypasses the regulatory step catalyzed by phosphofructokinase (Figure-4). This allows fructose to flood the pathways in the liver. High fructose consumption can lead to excess pyruvate production, causing a buildup of Krebs cycle intermediates. 

















Figure 4- showing the cause of hypertriglyceridemia upon excessive fructose consumption

Accumulated citrate can be transported from the mitochondria into the cytosol of hepatocytes, converted to acetyl CoA by citrate lyase and directed toward fatty acid synthesis. Additionally, DHAP can be converted to glycerol 3-phosphate as previously mentioned, providing the glycerol backbone for the triglyceride molecule. Triglycerides are incorporated into very low density lipoproteins (VLDL), which are released from the liver destined toward peripheral tissues for storage in both fat and muscle cells. Excessive fatty acid and triglyceride levels are convincingly tied to development of the metabolic syndrome, hypertension, glucose intolerance and type 2 diabetes. Excessive fructose consumption is also believed to contribute to the development of non-alcoholic fatty liver disease.

In addition, unlike glucose, fructose does not stimulate insulin secretion or enhance leptin production. Because insulin and leptin act as key afferent signals in the regulation of food intake and body weight, this suggests that dietary fructose may contribute to increased energy intake and weight gain. Furthermore, calorically sweetened beverages may enhance caloric over consumption. Thus, the increase in consumption of HFCS (High fructose corn syrup) has a temporal relation to the epidemic of obesity, and the over consumption of HFCS in calorically sweetened beverages may play a role in the epidemic of obesity.

Q.4- What is the cause of hyperuricemia upon excessive fructose ingestion?

Answer– 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 6 ) causing intracellular phosphate depletion, activation of AMP deaminase (Figure 5). AMP deaminase enzyme causes conversion of AMP to IMP (Inosine monophosphate). IMP, is subsequently converted to Hypoxanthine then to Xanthine and finally to Uric acid. Excessive uric acid generation leads to gout or renal stones.








Figure 5- AMP deaminase is inhibited by normal cellular concentrations of Pi. When these levels drop, the inhibition is released and AMP is converted to IMP and, ultimately, uric acid .
















Figure-6 showing the cause of hyperuricemia on excessive fructose consumption



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