Fructose Metabolism

Fructose Metabolism

Overview of Fructose

  • Fructose is a sugar that is found naturally in many fruits as well as in honey. It is also a component of sucrose (table sugar).

  • In dietary terms, fructose is often consumed in the form of sucrose and high-fructose corn syrup (HFCS).

Relative Sweetness Scale

  • The sweetness of various sugars and sweeteners is relative to sucrose, which is assigned a sweetness rating of 100.

    • Relative Sweetness Ratings:

    • Sucrose: 100

    • Fructose: 140

    • High Fructose Corn Syrup (HFCS): 120-160

    • Glucose: 70-80

    • Galactose: 32.1

    • Maltose: 32.5

    • Lactose: 16

    • Invert Sugar: 74.3

    • Honey: 97

Fructose Consumption Trends

  • Historical Context:

    • Sucrose was traditionally the primary sweetener in foods.

    • However, hydrolyzed corn starch offers a more economical alternative, which has led to its increasing use in food products.

    • Corn starch is converted to glucose, which in turn is composed of 55% fructose when hydrolyzed and isomerized, leading to the production of high fructose corn syrup.

Sugar Consumption in the United States (2010-2025)

  • The USDA provides data on projected sugar consumption in million metric tons from 2010/11 to 2024/25.

    • The figures indicate steady consumption, with the projections nearing an average of 11 million metric tons over the years.

High Fructose Corn Syrup Consumption

  • The average per capita consumption of HFCS has shown a downward trend from 62.5 pounds in 2000 to approximately 40.5 pounds in 2019.

Phosphorylation of Hexoses

  • Hexokinase and Glucokinase:

    • Hexokinase has a Km of 0.05 mM for glucose, indicating high affinity, while glucokinase shows a Km of 5-12 mM.

    • Fructose is primarily phosphorylated by fructokinase (KHK), which has a very high activity in the liver with a lower Km (indicating lower substrate concentration needed for half-maximal velocity).

      • Ketohexokinase: The enzyme ketohexokinase (KHK) is crucial for the phosphorylation of fructose, catalyzing its conversion to fructose-1-phosphate, which plays a significant role in fructose metabolism.

        • Also called fructokinase

      • KHK-C: Liver

      • KHK-A: Primarily in muscle

    • First Pass Metabolism: The initial metabolism of fructose occurs in the liver, where fructokinase rapidly phosphorylates fructose to fructose-1-phosphate, facilitating its conversion into intermediates for glycolysis. This process is also significant as it bypasses the regulatory step of phosphofructokinase, leading to a rapid influx of energy and substrates into metabolic pathways.

Liver Metabolism of Fructose

  • Metabolic Pathway in Liver:

    • Fructose absorption occurs via the GLUT2 transporter.

    • The liver removes a significant amount of dietary fructose during its first pass through the organ.

    • Fructokinase (KHK-C), which is extremely active in the liver, phosphorylates fructose into fructose-1-phosphate (F-1-P).

      • Uses ATP and makes it into ADP

      • If you consume a lot, ADP + ADP → ATP + AMP

        • More AMP in the liver is catabolized to inosine monophosphate (IMP) and is further broken down, leading to increased levels of uric acid in the bloodstream.

    • Fructose 1-phosphate is broken into glyceraldehyde and dihydroxyacetone phosphate

      • Glyceraldehyde → gyceraldehyde-3-p through the action of the enzyme triose phosphate isomerase, which plays a critical role in the glycolytic pathway.

      • Dihydroxyacetone phosphate is broken down into glycerol-3-phosphate by the enzyme glycerol-3-phosphate dehydrogenase, which subsequently can be utilized in triglyceride synthesis or as a substrate for gluconeogenesis.

    • Fructose 1,6-Biphosphate can be broken down into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate, which further participate in glycolysis and gluconeogenesis, ultimately contributing to glucose homeostasis in the body.

    • The high activity of KHK-C and aldolase B allows rapid catabolism to produce glycolytic intermediates, specifically dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.

    • Glyceraldehyde 3-phosphate is broken into pyruvate, then acetylCo-A, which can be utilized in the citric acid cycle for energy production or converted to fatty acids, depending on the metabolic needs of the cell.

    • Glyceraldehyde-3-P can also be formed into fructose-1,6-diP, then fructose-6-p, then glucose-6-p, then glucose to be stored in the liver

  • Gout: A metabolic disorder caused by elevated levels of uric acid, which can occur as a result of excessive fructose metabolism leading to increased production of purines.

Regulation of Energy Homeostasis

  • Insulin Secretion:

    • Unlike glucose, fructose does not stimulate the secretion of insulin from pancreatic β-cells, resulting in lower post-prandial insulin levels.

    • This leads to reduced leptin levels since leptin is regulated by insulin.

    • The diminished levels of insulin and leptin could potentially increase the likelihood of weight gain.

De Novo Lipogenesis

  • Fructose consumption is linked with both acute and chronic increases in intrahepatic de novo lipogenesis (DNL).

  • Unregulated production of triose-P and secondary acetyl-CoA can lead to excessive fat accumulation in the liver, further exacerbating insulin resistance and metabolic dysfunction.

  • Increased expression of key lipogenic genes results in the conversion of excess fructose into fatty acids, which may contribute to hepatic steatosis and overall fat accumulation in the liver.

Exercise and Fructose Metabolism

  • Studies comparing carbohydrate oxidation rates during exercise show differences between glucose, fructose, and sucrose ingestion.

  • Peak exogenous carbohydrate oxidation rates were evaluated based on different types of carbohydrate consumption.

Dietary Sugar Recommendations

  • According to the American Heart Association (AHA):

    • Women's maximum added sugar intake should not exceed 6 teaspoons (25 grams) per day.

    • Men's limit is 9 teaspoons (38 grams) per day, while children's intake should range between 3-6 teaspoons (12-25 grams) daily.

  • The World Health Organization (WHO) recommends that less than 10% of an adult's caloric intake should come from added sugars, advocating for an optimal intake of less than 5%.

  • In contrast, the average American consumes approximately 19.5 teaspoons (82 grams) of added sugar daily, translating to about 66 pounds annually per person.

Correlation with Health Outcomes

  • Research indicates a concerning link between added sugar consumption and cardiovascular disease (CVD) mortality.

  • Data highlights how the percentage of calories derived from added sugar, specifically over 10% or 25%, correlates with increased hazard ratios for CVD mortality among adults in the U.S.

Glucose vs Fructose separate

25% of daily intake tested

We don’t consume individually, always combined