fructose

see also:

• carbohydrates and sugars
• obesity and weight management
• diabetes mellitus

• fructose is a naturally occurring sugar found in many fruits and in honey
  • apples and pears have a high amount of fructose and a high fructose:glucose ratio which may cause more malabsorption issues
  • grapes, figs and bananas also have high levels of fructose but similar amounts of glucose hence unlikely to cause malabsorption issues
  • fructose is also found in the manufactured sweetener, high-fructose corn syrup (HFCS), which is produced by treating corn syrup with enzymes, converting glucose into fructose as it is sweeter
  • often added to fruit juices and carbonated drinks
• fructose is also a metabolite of sucrose (which is a glucose molecule joined to a fructose molecule forming a “disaccharide”) when it is broken down in the gut before it can be absorbed
• at room temperature, the 6-membered ring form of fructose is much sweeter than the other sugars (it forms the less sweet 5-membered ring form when warmed, but this is still as sweet as sucrose)
• fructose is more soluble than sucrose and thus more difficult to crystallize
• fructose has a glycaemic index of 23, compared with 100 for glucose and 60 for sucrose

• small intakes of sucrose or fructose are converted to glucose by enterocytes in the small bowel which is then metabolised by the whole body as needed in an insulin-dependent manner - most of the absorbed glucose goes to skeletal muscle and the brain where it is metabolised to CO2 and water, some is converted within fat cells into triglycerides
• excessive intakes of sucrose or fructose results in fructose either malabsorption of fructose or being absorbed into the circulation and then it must be metabolised into fat or glycogen almost completely within the liver in humans
  • absorption rate of fructose alone from the small intestine is slower than that of glucose as fructose is absorbed at a slower rate from the lower part of duodenum and jejunum both passively and actively by the brush-border membrane transporter 5 (GLUT-5) and transported into blood also by GLUT2
  • when glucose is also present, malabsorption of fructose is significantly attenuated
    • pure fructose alone produced dose-dependent evidence of malabsorption starting from 12 gram ingestion loads
    • glucose and sucrose individually produced no intolerance up to 50 gram ingestion loads
    • incremental amounts of added free glucose to a 50 gram fructose load dose-dependently attenuated malabsorption symptoms, and at the equimolar mixture of the two (up to 100 grams total sugars), no malabsorption was observed
    • sucrose can replace glucose in the ability to reduce malabsorption of fructose loads as the hydrolysis of sucrose does not appear to be rate limiting for uptake
    • in contrast to the high plasma glucose levels following a glucose bolus, bolus or divided doses of 50–150 g fructose only produce plasma concentrations of 3–11 mg/dl of fructose (10-50x less than the glucose rise from a similar glucose load) as it is rapidly taken up by hepatocytes ²⁾
    • fructose elicits only a modest insulin response
  • The slower absorption and prolonged contact time with the luminal intestinal wall would be expected to result in the stimulation of regulatory and satiety signals and release of hormones from enteroendocrine cells

• see https://en.wikipedia.org/wiki/Fructolysis
• fructose uptake into hepatocytes is not insulin dependent
• while there are hexokinases that can metabolize fructose to glucose, nearly all of the absorbed fructose is rapidly metabolized in the liver by fructokinases to fructose-1-phosphate which becomes trapped in the cell (where it can potentially reduce the intracellular phosphorylation ability and impede other intracellular functions - hence why iv fructose is not given in TPN), and then more slowly metabolized via aldolases to either glyceraldehyde or DHAP
  • either glyceraldehyde or DHAP can be then converted to glyceraldehyde-3-phosphate (GA-3-P)
    • high concentrations of DHAP and GA-3-P can then drive a gluconeogenic route to form glycogen
  • alternatively, the glyceraldehyde or the DHAP can be converted to glycerol-3-P which can then be esterified with fatty acids derived from GA-3-P being metabolized to pyruvate and acetyl-CoA, to form triglycerides
  • approximately 25% of a diet load of fructose is metabolized to lactate via pyruvate within a few hours
  • approximately 30% of a diet load of fructose is converted to glucose and used for energy, the proportion depending on exercise condition, gender, and health status ³⁾
  • some of the acetyl-CoA may be utilized in the citric acid cycle to form CO2 and ATP

• Fructose consumption results in the insulin-independent induction of several important hepatic lipogenic enzymes including pyruvate kinase, NADP+-dependent malate dehydrogenase, citrate lyase, acetyl CoA carboxylase, fatty acid synthase, as well as pyruvate dehydrogenase.
• fructose feeding has an effect on hepatic glucose production and whole body glucose disposal

• The hypertriglyceridemic effects observed are a hallmark of increased dietary carbohydrate, and fructose appears to be dependent on a number of factors including the amount of dietary fructose consumed and degree of insulin resistance.

• it is thought that many dietary substances which are not readily absorbed by the gut may result in irritable bowel syndrome (IBS) when ingested in excess amounts which exceed the small bowel's ability to metabolize and absorb them, thereby allowing metabolism by gut flora with production of increased flatus.

• In contrast to the anorexigenic effect of hypothalamic glucose metabolism, the metabolism of fructose in the brain exerts an orexigenic effect - in other words it makes you hungry! ⁴⁾
• It is likely that the increase in leptin following fructose consumption represents leptin resistance, which could account for the increased food intake observed in fructose-fed animals. ⁵⁾

• it appears fructose is an important driver of metastasis in women with high-grade serous ovarian cancer (HGSOC) who have undergone chemotherapy and cells have become senescent and begin secreting various substances collectively known as the senescence-associated secretory phenotype (SASP). ⁶⁾
• glucose-fructose mix in sugary drinks
  • appears to fuel metastasis speed of colorectal cancer (bowel cancer) to the liver by activating an sorbitol dehydrogenase (SORD), which boosts glucose metabolism and triggers the cholesterol pathway, ultimately driving metastasis ⁷⁾
  • appears to give a 2-3x risk of stomach cancer just having one carbonated sugary drink per day⁸⁾

• genetic lack of fructokinase means that the liver cannot metabolize fructose and thus blood levels of fructose increase and then is excreted in the urine once it exceeds the limit for renal tubular reabsorption
• it is a benign, asymptomatic condition

• absence of fructose-1-phosphate aldolase (aldolase B) results in the accumulation of fructose 1 phosphate in hepatocytes, kidney and small intestines
• when a large fructose meal is ingested, the accumulation of fructose-1-P results in inhibition of glycogenolysis and gluconeogenesis, resulting in severe hypoglycaemia, abdominal pain, vomiting, hemorrhage, jaundice, hepatomegaly, and hyperuricaemia eventually leading to liver and/or renal failure and death.
• incidence is 1/12,000 - 1/58,000 live births

• AR disease
• results in severely impaired hepatic gluconeogenesis and leads to episodes of hypoglycemia, apnea, hyperventilation, ketosis and lactic acidosis and can be fatal in the neonatal period
• later in life episodes are triggered by fasting and febrile infections.