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High-fructose corn syrup (HFCS), also known as glucose–fructose, isoglucose and glucose–fructose syrup, is a sweetener made from corn starch. As in the production of conventional corn syrup, the starch is broken down into glucose by enzymes. To make HFCS, the corn syrup is further processed by D-xylose isomerase to convert some of its glucose into fructose. HFCS was first marketed in the early 1970s by the Clinton Corn Processing Company, together with the Japanese Agency of Industrial Science and Technology, where the enzyme was discovered in 1965.

As a sweetener, HFCS is often compared to granulated sugar, but manufacturing advantages of HFCS over sugar include that it is cheaper. "HFCS 42" and "HFCS 55" refer to dry weight fructose compositions of 42% and 55% respectively, the rest being glucose. HFCS 42 is mainly used for processed foods and breakfast cereals, whereas HFCS 55 is used mostly for production of soft drinks.

The United States Food and Drug Administration (FDA) states that it is not aware of evidence showing that HFCS is less safe than traditional sweeteners such as sucrose and honey. Uses and exports of HFCS from American producers have grown steadily during the early 21st century.

Food
In the U.S., HFCS is among the sweeteners that mostly replaced sucrose (table sugar) in the food industry. Factors contributing to the increased use of HFCS in food manufacturing include production quotas of domestic sugar, import tariffs on foreign sugar, and subsidies of U.S. corn, raising the price of sucrose and reducing that of HFCS, creating a manufacturing-cost advantage among sweetener applications. In spite of having a 10% greater fructose content, the relative sweetness of HFCS 55, used most commonly in soft drinks, is comparable to that of sucrose. HFCS provides advantages in food and beverage manufacturing, such as simplicity for formulation and stability, enabling processing efficiencies.

HFCS (or standard corn syrup) is the primary ingredient in most brands of commercial "pancake syrup," as a less expensive substitute for maple syrup. Assays to detect adulteration of sweetened products with HFCS, such as liquid honey, use differential scanning calorimetry and other advanced testing methods.

Process
In the contemporary process, corn is milled to extract corn starch and an "acid-enzyme" process is used, in which the corn-starch solution is acidified to begin breaking up the existing carbohydrates. High-temperature enzymes are added to further metabolize the starch and convert the resulting sugars to fructose. The first enzyme added is alpha-amylase, which breaks the long chains down into shorter sugar chains (oligosaccharides). Glucoamylase is mixed in and converts them to glucose. The resulting solution is filtered to remove protein, then using activated carbon, and then demineralized using ion-exchange resins. The purified solution is then run over immobilized xylose isomerase, which turns the sugars to ~50–52% glucose with some unconverted oligosaccharides and 42% fructose (HFCS 42), and again demineralized and again purified using activated carbon. Some is processed into HFCS 90 by liquid chromatography, and then mixed with HFCS 42 to form HFCS 55. The enzymes used in the process are made by microbial fermentation.

Composition and varieties
HFCS is 24% water, the rest being mainly fructose and glucose with 0–5% unprocessed glucose oligomers.

The most common forms of HFCS used for food and beverage manufacturing contain fructose in either 42% ("HFCS 42") or 55% ("HFCS 55") by dry weight, as described in the U.S. Code of Federal Regulations (21 CFR 184.1866).


 * HFCS 42 (approx. 42% fructose if water were ignored) is used in beverages, processed foods, cereals, and baked goods.
 * HFCS 55 is mostly used in soft drinks.
 * HFCS 70 is used in filling jellies

Commerce and consumption


The global market for HFCS is expected to grow from $5.9 billion in 2019 to a projected $7.6 billion in 2024.

China
HFCS in China makes up about 20% of sweetener demand. HFCS has gained popularity due to rising prices of sucrose, while selling for a third the price. Production was estimated to reach 4,150,000 tonnes in 2017. About half of total produced HFCS is exported to the Philippines, Indonesia, Vietnam, and India.

European Union
In the European Union (EU), HFCS is known as isoglucose or glucose–fructose syrup (GFS) which has 20–30% fructose content compared to 42% (HFCS 42) and 55% (HFCS 55) in the United States. While HFCS is produced exclusively with corn in the U.S., manufacturers in the EU use corn and wheat to produce GFS. GFS was once subject to a sugar production quota, which was abolished on 1 October 2017, removing the previous production cap of 720,000 tonnes, and allowing production and export without restriction. Use of GFS in soft drinks is limited in the EU because manufacturers do not have a sufficient supply of GFS containing at least 42% fructose content. As a result, soft drinks are primarily sweetened by sucrose which has a 50% fructose content.

Japan
In Japan, HFCS is also referred to as isomerized sugar. HFCS production arose in Japan after government policies created a rise in the price of sugar. Japanese HFCS is manufactured mostly from imported U.S. corn, and the output is regulated by the government. For the period from 2007 to 2012, HFCS had a 27–30% share of the Japanese sweetener market. Japan consumed approximately 800,000 tonnes of HFCS in 2016. The United States Department of Agriculture states that HFCS is produced in Japan from U.S. corn. Japan imports at a level of 3 million tonnes per year, leading 20 percent of corn imports to be for HFCS production.

Mexico
Mexico is the largest importer of U.S. HFCS. HFCS accounts for about 27 percent of total sweetener consumption, with Mexico importing 983,069 tonnes of HFCS in 2018. Mexico's soft drink industry is shifting from sugar to HFCS which is expected to boost U.S. HFCS exports to Mexico according to a U.S. Department of Agriculture Foreign Agricultural Service report.

On 1 January 2002, Mexico imposed a 20% beverage tax on soft drinks and syrups not sweetened with cane sugar. The United States challenged the tax, appealing to the World Trade Organization (WTO). On 3 March 2006, the WTO ruled in favor of the U.S. citing the tax as discriminatory against U.S. imports of HFCS without being justified under WTO rules.

Philippines
The Philippines was the largest importer of Chinese HFCS. Imports of HFCS would peak at 373,137 tonnes in 2016. Complaints from domestic sugar producers would result in a crackdown on Chinese exports. On 1 January 2018, the Philippine government imposed a tax of 12 pesos ($.24) on drinks sweetened with HFCS versus 6 pesos ($.12) for drinks sweetened with other sugars.

United States
In the United States, HFCS was widely used in food manufacturing from the 1970s through the early 21st century, primarily as a replacement for sucrose because its sweetness was similar to sucrose, it improved manufacturing quality, was easier to use, and was cheaper. Domestic production of HFCS increased from 2.2 million tons in 1980 to a peak of 9.5 million tons in 1999. Although HFCS use is about the same as sucrose use in the United States, more than 90% of sweeteners used in global manufacturing is sucrose.

Production of HFCS in the United States was 8.3 million tons in 2017. HFCS is easier to handle than granulated sucrose, although some sucrose is transported as solution. Unlike sucrose, HFCS cannot be hydrolyzed, but the free fructose in HFCS may produce hydroxymethylfurfural when stored at high temperatures; these differences are most prominent in acidic beverages. Soft drink makers such as Coca-Cola and Pepsi continue to use sugar in other nations but transitioned to HFCS for U.S. markets in 1980 before completely switching over in 1984. Large corporations, such as Archer Daniels Midland, lobby for the continuation of government corn subsidies.

Consumption of HFCS in the U.S. has declined since it peaked at 37.5 lb per person in 1999. The average American consumed approximately 22.1 lb of HFCS in 2018, versus 40.3 lb of refined cane and beet sugar. This decrease in domestic consumption of HFCS resulted in a push in exporting of the product. In 2014, exports of HFCS were valued at $436 million, a decrease of 21% in one year, with Mexico receiving about 75% of the export volume.

In 2010, the Corn Refiners Association petitioned the FDA to call HFCS "corn sugar," but the petition was denied.

Vietnam
90% of Vietnam's HFCS import comes from China and South Korea. Imports would total 89,343 tonnes in 2017. One ton of HFCS was priced at $398 in 2017, while one ton of sugar would cost $702. HFCS has a zero cent import tax and no quota, while sugarcane under quota has a 5% tax, and white and raw sugar not under quota have an 85% and 80% tax. In 2018, the Vietnam Sugarcane and Sugar Association (VSSA) called for government intervention on current tax policies. According to the VSSA, sugar companies face tighter lending policies which cause the association's member companies with increased risk of bankruptcy.

Nutrition
HFCS is 76% carbohydrates and 24% water, containing no fat, protein, or micronutrients in significant amounts. In a 100-gram reference amount, it supplies 281 calories, while in one tablespoon of 19 grams, it supplies 53 calories.

Obesity and metabolic syndrome
The global obesity epidemic has been paralleled by increased worldwide consumption of sugar-sweetened foods and beverages containing high-fructose corn syrup (HFCS) beginning in the late 1960s-early 1970s.

While the role of fructose and HFCS in metabolic syndrome is the subject of active investigations, there is a preponderance of high-quality, unbiased evidence linking the consumption of HFCS-sweetened food and beverages as a key contributor to the epidemic of obesity and metabolic syndrome due to high added sugar content, suppression of satiety, and incomplete compensation for total energy. Findings from large cross-sectional studies, in conjunction with those from well-powered prospective cohort studies with long periods of follow-up, show a positive association between greater intakes of HFCS sweetened beverages and weight gain and obesity in both children and adults.

Proposed Mechanisms
In 1962 a human geneticist named James Neel proposed the "thifty gene hypothesis" which, based on genetic and fossil evidence and Anthropological observations from studying indigenous populations such as the Yanomami in the Amazon, suggested the evolutionary development of a gene variant amongst human ancestors that made their bodies particularly “efficient in the intake and/or utilization of food,” thus allowing these ancestral humans to more efficiently store calories as fat.

This would have conferred a survival advantage in times of food scarcity and famine. Normally when the body digests carbohydrates, it produces glucose, which accumulates in the bloodstream. The pancreas responds by releasing insulin, which signals the liver and muscles to convert glucose into a starchlike energy-storage molecule called glycogen. When food is scarce, though, animals must persist in their foraging to survive, and their brain requires a steady supply of glucose to do so. For this reason, hungry animals from squirrels to warblers undergo a metabolic change that makes the body's cells start ignoring insulin's prompts. This “insulin resistance” keeps scarce glucose in their blood to supply their brain. Experiments by Richard J. Johnson, Takuji Ishimoto and Miguel Lanaspa showed that the fruit sugar (fructose) acted as a switch that alerted an animal's body to reduce insulin sensitivity and increase fat storage, in part through blunting the effect of the hormone leptin, which tells the brain it is time to stop eating. Fructose, unlike other sugars, produces uric acid when it is broken down inside cells. Elevated levels of uric acid amplify the fat-accumulation and insulin resistance effects of fructose metabolism. In most animals, the enzyme called uricase breaks down excess uric acid, however, in all modern great apes (gorillas, orangutans, chimpanzees and bonobos) and all modern humans, the gene coding for the uricase enzyme is mutated, blocking uricase production. In addition, both groups possess the same mutant form of the gene. By analyzing changes that occurred in the uricase gene over evolutionary time using a method known as the molecular clock, Naoyuki Takahata and Eric Gaucher independently determined that humans inherited the gene from a common ancestor we share with the great apes that lived between 17 million and 13 million years ago—the same tumultuous time period when European apes were struggling to survive seasonal famines. This lack of a working uricase and the resulting elevated uric acid levels would have helped apes turn fruit into fat and given them a survival advantage as winters became cool and dry beginning 15 million years ago, in the mid-Miocene. These discoveries have led to the proposal of the "fructose survival hypothesis for obesity" by Richard Johnson et al. which suggests that obesity and metabolic disorders may have developed from over-stimulation of an evolutionary-based biologic response (survival switch) characterized by hunger, thirst, foraging, weight gain, fat accumulation, insulin resistance, systemic inflammation and increased blood pressure. The process is initiated by the ingestion of fructose or by stimulating endogenous fructose production via the polyol pathway. Unlike other nutrients, fructose reduces the active energy (adenosine triphosphate) in the cell, while blocking its regeneration from fat stores. This is mediated by intracellular uric acid, mitochondrial oxidative stress, the inhibition of AMP kinase and stimulation of vasopressin. Mitochondrial oxidative phosphorylation is suppressed, and glycolysis stimulated. While this response is aimed to be modest and short-lived, the response in humans is exaggerated due to gain of ‘thrifty genes’ coupled with a western diet rich in foods that contain or generate fructose. The hypothesis proposes that "excessive fructose metabolism not only explains obesity but the epidemics of diabetes, hypertension, non-alcoholic fatty liver disease, obesity-associated cancers, vascular and Alzheimer's dementia, and even ageing."

A 2014 systematic review found little evidence for an association between HFCS consumption and liver diseases, enzyme levels or fat content.

A 2018 review found that lowering consumption of sugary beverages and fructose products may reduce hepatic fat accumulation, which is associated with non-alcoholic fatty liver disease. In 2018, the American Heart Association recommended that people limit total added sugar (including maltose, sucrose, high-fructose corn syrup, molasses, cane sugar, corn sweetener, raw sugar, syrup, honey, or fruit juice concentrates) in their diets to 9 teaspoons per day for men and 6 for women.

Cancer
Concurrent with the rise in global consumption of HFCS and sugar-sweetened beverages, there has been a significant increase in the rate of colorectal cancer incidence among young and middle aged adults.

In the United States from 1995 to 2014 the incidence for six of 12 obesity-related cancers (multiple myeloma, colorectal, uterine corpus, gallbladder, kidney, and pancreatic cancer) increased significantly in young adults (25–49 years) with steeper rises in successively younger generations in a step-wise manner.

There is concern that consumption of HFCS is a significant contributing factor to the increased incidence of colorectal cancer by promoting tumor growth, independent of the presence of obesity.

An enzyme in tumors (ketohexokinase) converts fructose to fructose-1-phosphate, which alters tumor cell metabolism and leads to enhanced cell growth.

Safety and manufacturing concerns
Since 2014, the United States FDA has determined that HFCS is safe (GRAS) as an ingredient for food and beverage manufacturing, and there is no evidence that retail HFCS products differ in safety from those containing alternative nutritive sweeteners. The 2010 Dietary Guidelines for Americans recommended that added sugars should be limited in the diet.

One consumer concern about HFCS is that processing of corn is more complex than used for common sugar sources, such as fruit juice concentrates or agave nectar, but all sweetener products derived from raw materials involve similar processing steps of pulping, hydrolysis, enzyme treatment, and filtration, among other common steps of sweetener manufacturing from natural sources. In the contemporary process to make HFCS, an "acid-enzyme" step is used in which the corn starch solution is acidified to digest the existing carbohydrates, then enzymes are added to further metabolize the corn starch and convert the resulting sugars to their constituents of fructose and glucose. Analyses published in 2014 showed that HFCS content of fructose was consistent across samples from 80 randomly selected carbonated beverages sweetened with HFCS.

One prior concern in manufacturing was whether HFCS contains reactive carbonyl compounds or advanced glycation end-products evolved during processing. This concern was dismissed, however, with evidence that HFCS poses no dietary risk from these compounds.

Through the early 21st century, some factories manufacturing HFCS had used a chlor-alkali corn processing method which, in cases of applying mercury cell technology for digesting corn raw material, left trace residues of mercury in some batches of HFCS. In a 2009 release, The Corn Refiners Association stated that all factories in the American industry for manufacturing HFCS had used mercury-free processing over several previous years, making the prior report outdated.

Taste difference
Most countries, including Mexico, use sucrose, or table sugar, in soft drinks. In the U.S., soft drinks, such as Coca-Cola, are typically made with HFCS 55. HFCS has a sweeter taste than sucrose. Some Americans seek out drinks such as Mexican Coca-Cola in ethnic groceries because they prefer the taste over that of HFCS-sweetened Coca-Cola. Kosher Coca-Cola, sold in the U.S. around the Jewish holiday of Passover, also uses sucrose rather than HFCS.

Beekeeping
In apiculture in the United States, HFCS is a honey substitute for some managed honey bee colonies during times when nectar is in low supply. However, when HFCS is heated to about 45 C, hydroxymethylfurfural, which is toxic to bees, can form from the breakdown of fructose. Although some researchers cite honey substitution with HFCS as one factor among many for colony collapse disorder, there is no evidence that HFCS is the only cause. Compared to hive honey, both HFCS and sucrose caused signs of malnutrition in bees fed with them, apparent in the expression of genes involved in protein metabolism and other processes affecting honey bee health.

Public relations
There are various public relations concerns with HFCS, including how HFCS products are advertised and labeled as "natural." As a consequence, several companies reverted to manufacturing with sucrose (table sugar) from products that had previously been made with HFCS. In 2010, the Corn Refiners Association applied to allow HFCS to be renamed "corn sugar," but that petition was rejected by the FDA in 2012.

In August 2016, in a move to please consumers with health concerns, McDonald's announced that it would be replacing all HFCS in their buns with sucrose (table sugar) and would remove preservatives and other artificial additives from its menu items. Marion Gross, senior vice president of McDonald's stated, "We know that they [consumers] don't feel good about high-fructose corn syrup so we're giving them what they're looking for instead." Over the early 21st century, other companies such as Yoplait, Gatorade, and Hershey's also phased out HFCS, replacing it with conventional sugar because consumers perceived sugar to be healthier. Companies such as PepsiCo and Heinz have also released products that use sugar in lieu of HFCS, although they still sell HFCS-sweetened products.

History
Commercial production of corn syrup began in 1964. In the late 1950s, scientists at Clinton Corn Processing Company of Clinton, Iowa, tried to turn glucose from corn starch into fructose, but the process they used was not scalable. In 1965–1970, Yoshiyuki Takasaki, at the Japanese National Institute of Advanced Industrial Science and Technology developed a heat-stable xylose isomerase enzyme from yeast. In 1967, the Clinton Corn Processing Company obtained an exclusive license to manufacture glucose isomerase derived from Streptomyces bacteria and began shipping an early version of HFCS in February 1967. In 1983, the FDA accepted HFCS as "generally recognized as safe," and that decision was reaffirmed in 1996.

Prior to the development of the worldwide sugar industry, dietary fructose was limited to only a few items. Milk, meats, and most vegetables, the staples of many early diets, have no fructose, and only 5–10% fructose by weight is found in fruits such as grapes, apples, and blueberries. Most traditional dried fruits, however, contain about 50% fructose. From 1970 to 2000, there was a 25% increase in "added sugars" in the U.S. When recognized as a cheaper, more versatile sweetener, HFCS replaced sucrose as the main sweetener of soft drinks in the United States.

Since 1789, the U.S. sugar industry has had trade protection in the form of tariffs on foreign-produced sugar, while subsidies to corn growers cheapen the primary ingredient in HFCS, corn. Accordingly, industrial users looking for cheaper sugar replacements rapidly adopted HFCS in the 1970s.