The Biochemistry of High Fructose Corn Syrup

Just in case any of you wanted to hear me get my nerd on… I’m posting the assignment I’ve just written for my introduction to nutritional biochemistry class. We were asked to write about the biochemical properties and metabolism of high fructose corn syrup, how it relates to sucrose metabolism, and possible consequences of excess HFCS consumption on human health. Enjoy! (PS – I’m not advocating artificial sweeteners in the end, I’m just summarizing the current position of the FDA)

High Fructose Corn Syrup
Issues and Alternatives

High fructose corn syrup (HFCS) is made by the chemical and enzymatic hydrolysis of corn starch containing amylose and amylopectin to corn syrup containing mostly glucose followed by the isomerization of the glucose in corn syrup to fructose to yield HFCS. (1) The process involves heat, mechanical breakdown, chemicals, and enzymatic action to reduce the corn starch into a syrup that contains 90% fructose. This is then mixed with glucose syrup to produce different varieties of HFCS, such as “HFCS-55” which is sweeter than sucrose and is used in carbonated drinks, and “HFCS-42” which is less sweet and is used in canned fruits, sauces, soups, condiments, baked goods, and many other processed foods. (1)

HFCS is composed of fructose and glucose, much like beet and cane sugar. Sugar is mostly pure sucrose, composed of 50% glucose and 50% fructose. These two monosaccharides are linked by a glycosidic bond. HFCS, depending on the variety, has a different composition than sugar. HFCS-55 has 55% fructose, and HFCS-42 has 42% fructose. The monosaccharides are not linked in HFCS. (2) This means that the fructose and glucose in HFCS is easier to be absorbed and utilized, since they do not need to be broken down by a disaccharidase enzyme.

Sucrose is broken down into glucose and fructose by the enzyme sucrase in the small intestine. The mucosal cells contain different transporter channels that allow monosaccharides to cross the membrane of the cells in order to be transported to the bloodstream. Glucose is co-transported with sodium by the sodium-dependent transporter called SGLUT-1 across the epithelial membrane in the small intestine. Fructose, conversely, is not transported with a sodium-dependent mechanism, and instead is transported independently by the GLUT-5 channel. Both glucose and fructose are then transported through the GLUT-2 channel into the hepatic portal circulation. This blood flows to the liver, where kinase enzymes glucokinase or fructokinase can be activated to begin the catabolism of these monosaccharides. Glucokinase phosphorylates glucose to glucose-6-phosphate, which is the first stage of glycolysis. Glucokinase activity is modulated in the liver, is regulated by insulin, and is specific for glucose. (4) Fructose is phosphorylated by fructokinase, which is independent from glucose metabolism and not regulated by insulin. (5) Fructokinase produces fructose-1- P, which bypasses fructose-6-P in glycolysis and can prevent the inhibition of glucokinase in the liver. (5) Both glucose and fructose eventually enter the glycolytic pathway as glyceraldehyde-3-phosphate.

For both glucose and fructose, the glycolytic pathway eventually converts these monosaccharides into Acetyl-CoA, which is one of the major substrates for fatty acid synthesis. Acetyl-CoA is also combined with oxaloacetate to form citrate, which, in high levels, also up-regulates the synthesis of fatty acids.

A 2010 study (6) demonstrated that rats fed high-fructose corn syrup gained significantly more weight than those fed table sugar (sucrose), even when their overall caloric intake was the same. The fat gained was predominantly in the abdominal area, and blood triglycerides also increased substantially in those rats fed HFCS. Rats fed diets high in glucose or high in fat did not develop the same weight gain and biomarkers for obesity as the rats fed HFCS.

These observed results make sense in light of the biochemical differences between the digestion and metabolism of sucrose compared to HFCS. Since HFCS is composed of free monosaccharides, it can be absorbed into the bloodstream far more rapidly than sucrose. Also, fructose does not require any sodium co-transporter to be absorbed into the epithelial cells, so absorption is not regulated. Fructose does not require insulin to be taken up by the cells, so this is another regulatory step that is bypassed by fructose. The activity of fructokinase, which phosphorylates fructose and begins the catabolism of the molecule, is not regulated by the presence of fatty acids. Fructokinase is only expressed in the liver, so around 70% of fructose is metabolized directly by the liver. (7) Since the catabolism of fructose is not subject to the same regulatory mechanisms as glucose, it is quickly sent through the glycolytic pathway and converted into Acetyl-CoA, which is used in lipogenesis when present in high amounts. Since much of these fats are being created by the liver from fructose metabolism, this would explain why high fructose consumption is correlated with the development of non-alcoholic fatty liver disease. (8) Fat accumulation in the liver, present in 20-30% of American adults, greatly reduces the function of the hepatocytes, interfering with insulin function and mitochondrial beta-oxidation. (9) Non-alcoholic fatty liver disease can lead to metabolic syndrome, steatohepatitis, cirrhosis of the liver, and ultimately, liver failure.

One popular calorie-free sweetener that has been used in the food supply is stevia, also known as Stevioside, which is a natural sweetener extracted from leaves of the Stevia rebaudiana plant. (10) In a few countries stevia has been consumed as a food and medicine for many years, including Japan and Paraguay. Several clinical studies have demonstrated that stevioside may offer therapeutic benefits for subjects with hypertension and type 2 diabetes due to reduced blood pressure and increased postprandial glucose homeostasis. (10)

Since stevia is “generally recognized as safe” by the FDA, it is a widely available alternative and natural sweetener that would be a good replacement for HFCS and sucrose, as it does not appear to affect blood sugar levels. (11) There are some controversies around stevia, and studies suggest that large doses of stevia extract could possibly cause fertility problems, blood sugar regulation issues, and possibly even cancer. However, the research on this compound is scant and there is no conclusive evidence to suggest that this natural sweetener, which has been used for many years in other countries, is dangerous when consumed in low to moderate amounts. More research should be done to test the safety of this sweetener substitute.

Artificial sweeteners have been a subject of controversy in recent years. Interestingly, scientists haven’t been able to reach a consensus about the safety of most artificial sweeteners. There may be short term benefits to consuming foods sweetened with artificial sweeteners, since they replace the high levels of sugar or HFCS that would be necessary to provide the same level of sweet taste. Consuming sweetened food and beverages instead of artificially sweetened foods would greatly increase the caloric density of the diet and negatively impact blood sugar levels and eventually lead to fat synthesis, insulin resistance, and possible obesity.

However, the long term effects of artificial sweetener consumption have not been thoroughly researched, and there may be some health consequences that may come from excessive use of artificial sweeteners such as aspartame, sucralose, and saccharin. Recent research has demonstrated a link between aspartame consumption and liver and lung cancer in rats and mice. (12) One study found that the sweetener Splenda caused a reduction in beneficial fecal microflora in mice. (13) However, the general consensus from the US government and the FDA is that these artificial sweeteners do not pose a significant risk to consumers, and are generally recognized as safe. (14)

While artificial sweeteners may help reduce obesity and diabetes when used in place of sugar or HFCS, I personally feel that a reduction in all sweeteners would be beneficial for most people. Since the science is not conclusive about the safety of artificial sweeteners, and it is fairly evident that the excess consumption of sugar and HFCS is linked with obesity, diabetes, and liver disease, I feel it would be best for all people to limit their consumption of added sweeteners, and learn how to appreciate the natural sweetness of foods such as fruit, and to use natural sweeteners in moderation.


  1. Parker, K., Salas, M., Nwosu, V.C. High fructose corn syrup: Production, use and public health concerns. Biotechnology and Molecular Biology Review 5, no. 5 (2010): 71-­‐78.
  2. “High Fructose Corn Syrup vs Sugar.”
  3. “Absorption of Monosaccharides.”
  4. “Carbohydrate Metabolism.”
  5. “Role of Glucose Transporters in Regulation of Blood Glucose.”
  6. “A sweet problem: Princeton researchers find that high-fructose corn syrup prompts considerably more weight gain.”
  7. “Why is fructose so bad for you?”
  8. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, Johnson RJ, Abdelmalek MF. Fructose consumption as a risk factor for non-alcoholic fatty liver disease.  J Hepatol. 2008 Jun;48(6):993-9. Epub 2008 Mar 10.
  9. Tilg H, Kaser A. Treatment strategies in nonalcoholic fatty liver disease. Nat Clin Pract Gastroenterol Hepatol. 2005 Mar;2(3):148-55.
  10. Carakostas MC, Curry LL, Boileau AC, Brusick DJ. Overview: the history, technical function and safety of rebaudioside A, a naturally occurring steviol glycoside, for use in food and beverages. Food Chem Toxicol. 2008 Jul;46 Suppl 7:S1-S10. Epub 2008 May 16.
  11. “Stevia FAQ.”
  12. Soffritti M, Belpoggi F, Manservigi M, Tibaldi E, Lauriola M, Falcioni L, Bua L.  Aspartame administered in feed, beginning prenatally through life span, induces cancers of the liver and lung in male Swiss mice. Am J Ind Med. 2010 Dec;53(12):1197-206.
  13. Abou-Donia MB, El-Masry EM, Abdel-Rahman AA, McLendon RE, Schiffman SS. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. J Toxicol Environ Health A. 2008;71(21):1415-29.
  14. Artificial sweeteners: Understanding these and other sugar substitutes.
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  1. Wow, that was a fantastic read! I don’t understand all the technical terms, but I’ve never seen the HFCS pathways laid out like that before! Thanks so much for sharing this!

    1. You need to be careful coping other people’s information! It is called Plagiarism. You need to put this in your own words or use quotations marks.