Fructose: how much is too much?
The saying “sometimes it’s less about making the right decision and more about not making the wrong one” applies to sugar consumption. If there is nothing else that we are willing to do to improve our health, shunning sugars alone, particularly fructose, may yield more benefits than we can fathom. This article will address the specific effects that fructose has on our health according to the most up-to-date science findings I could get my hands on.
The rise in obesity and metabolic dysregulations paralleling the unrestrained inclusion of fructose and high fructose corn syrup, a cost-effective and addictive sweetener, into our processed food system, from baby food, sweetened drinks and desserts to virtually all fast foods, has raised many flags within the scientific community in the past few decades. Research has resoundingly investigated the impact fructose has on our metabolic and hormonal health, and it continues to do so. Some of the studies conducted throughout the last few decades, conveniently funded by processed food manufacturers, have been swift and cagey in dismissing the notion that glucose and fructose impact human biology differently; other studies have been inconclusive, arguably due to marred methodologies. Nevertheless, a body of independent research has produced alarming evidence of serious health outcomes stemming from the consumption of isolated (industrial) fructose on metabolic processes, mitochondrial health and neuronal activity.
The flawed reasoning behind the inclusion of fructose in some outdated fad diets was that it does not require insulin to be absorbed, making it less metabolically harmful than glucose, a theory since overturned by science. From an evolutionary standpoint, the human body is designed to only metabolize an average of 20 grams of fructose per day, and today’s daily average in the US is a direful 100 grams. Nonetheless, as I will detail ahead, while the ill effects of glucose and fructose both tally with excessive and prolonged consumption, those carried out by fructose are more stringently inherent to its biochemical conduct.
Chemically, fructose and glucose are siblings with different behavioral traits. They are both monosaccharides, made of single monomers, and mostly occur in nature paired in fruit, honey and root vegetables, as well as combined in our processed food system as table sugar (which is 50/50 glucose and fructose), agave syrup and the infamous high fructose corn syrup; they share akin molecular structures with the same formula C6H12O6, though glucose forms a 6-carbon ring and fructose a 5-carbon ring, a seemingly small difference that is not negligible from a metabolic standpoint.
In the mouth, a saliva enzyme called amylase quickly detaches monosaccharides from disaccharides, two-sugar molecules like sucrose, or polysaccharides, compounds made up of multiple sugar molecules like starches. Enzymatic digestion of sugars continues in the small intestine, which does not have to work hard to break them down (exception made for the lactose sugar, as the lactase enzyme is often insufficient). However, while glucose is cleaved through a process called glycolysis and utilized in the generation of ATP, our cellular energy currency, fructose takes a different path. To be clear, under normal dietary intake, as was the case in the past when fruits and vegetables were the daily source of fructose, the majority of the ingested fructose is metabolized in the small intestine primarily to glucose, which is then delivered to the systemic circulation. The problem with our current intake is that it overwhelms the ability of the small intestine to metabolize it all and under these conditions, a significant amount of fructose is shuttled straight to the liver, where it gets exceedingly converted into fats, causing a rise in plasma triglycerides.
It is important to note that as a naturally occurring sugar, fructose does not take away the benefits of fruit, due to the vitamins, minerals, and fiber it contains. However, cultivation of fruits and vegetables has changed considerably over the course of the last century: over-exploitation of crops, yield-focused farming practices and the use of hormone disrupting chemicals have lessened the nutritional value of fruits and caused an increase in fructose content relative to the amount of beneficial nutrients. Fruit consumption tips in a low-carb regime will be covered in a separate article.
For the purpose of this discussion, we will look at how added fructose, in the Western diet, contributes to the pathogenesis of chronic disease, by listing some of the biological functions it corrupts.
1. The role of fructose in obesity and diabetes: NAFLD, non alcoholic fatty liver disease
The consumption of fructose is more tightly associated with NAFLD, or nonalcoholic fatty liver disease, than that of glucose. This outcome stems from the way fructose gets metabolized in comparison with glucose. For those who care to delve into some simple biochemistry, here are some key differences that explain why the metabolism of fructose, unlike that of glucose, is virtually unstoppable:
Glucose is absorbed from the intestinal lumen into intestinal endothelial cells, then transported out into the bloodstream, and escorted into all tissues and organ cells by the pancreatic hormone insulin.
Glucose is recognized by an enzyme called glucokinase, which initiates a process called glycolysis, that cleaves glucose molecules so they can be utilized in the generation of ATP (our cellular energy currency) in the cell mitochondria. Glucokinase is inhibited by increasing concentrations of its by-products, meaning it has a negative feedback system and wanes once enough glucose has been metabolized for energy needs: hence, energy production from glucose is biologically controlled.
Fructose also gets initially absorbed the same way into intestinal endothelial cells, but the bulk of it travels via the portal vein straight to the liver, its primary metabolic site, and is taken up by hepatocytes through a non-insulin dependent transport system.
In the liver, fructose is not recognized by glucokinase. Instead, an enzyme called fructokinase, or KHK, initiates a process called fructolysis. This chemical process differs from glycolysis (glucose breakdown and uptake) in that it lacks two crucial enzymatic steps of the glucose pathway: firstly, KHK has no negative feedback, its metabolism of fructose moves forward whether the liver is in a fed or fasted state. Secondly, an enzyme present in glycolysis, called phosphofructokinase 1 or PFK1 is missing; PFK1 is a highly regulated transferase that stimulates glycolysis when cellular energy is low and shuts it down during energy surplus states (ATP and citrate inhibit it). In short, while glycolytic PFK1, present in glucose metabolism, ensures glucose is metabolized only as needed and prevents the synthesis of glucose from other non-sugar precursor substrates (as in gluconeogenesis), this rate limiting step is absent in fructolysis. To sum this all up: the absence of insulin, glucokinase and PFK1 means the fructose energy pathway is never downregulated, or, in more simple terms, the body keeps absorbing it.
Additionally, the end product of fructolysis is an overproduction of Acetyl CoA, which leads to the conversion of almost all the fructose into fatty acids in the liver. To make matters worse, the chemicals produced during fructose breakdown also have the ability to esterify those fatty acids, which means fructose can independently produce triglycerides. Prolonged overproduction of triglycerides, as we know, leads to obesity and consequently the onset of diabetes. One could say the body handles fructose the same way as alcohol!
It is paradoxical that although fructose does not require insulin to be metabolized, and is therefore often touted as safe for diabetics, it significantly impacts insulin functionality by causing NAFLD, or non alcoholic fatty liver disease, leading to diabetes and related metabolic diseases. The odds of developing diabetes are also increased by the fact that high insulin increases uric acid in the body, which further compromises the effectiveness of insulin, in a vicious cycle. You can read more about the NAFLD paradox here.
2. The effects of fructose on appetite and energy metabolism: pathway dysregulations
The need and desire to eat are regulated in the body by an interplay of endogenous chemicals, and influenced by exogenous factors. Specialized neuronal cells and several hormones are involved in a complex system of feedback signals between the GI tract and the hypothalamic region of the brain, a connection referred to as the gut-brain axis, to regulate our feeding and fasting states by turning the appetite switch on and off. Here we investigate the way fructose alters these signaling pathways, promoting overfeeding:
The main hormone involved in hunger signaling and fat storage, called ghrelin, a growth hormone stimulating peptide produced mainly by the stomach, rises slowly during fasting, signaling to the brain that it should initiate a hunger stimulus, and attenuates during feeding until it reaches a low, 30 to 60 minutes after a meal. Ghrelin does not taper off in response to fructose consumption, mainly due to its unregulated energy metabolism, which prompts us to continue eating. Persistent dysregulation of ghrelin is involved in the pathogenesis of overeating and obesity.
Once the energy demands of the cells have been fulfilled, after ingestion and metabolism of any energy substrate such as protein, fats and glucose, the body sends another signal to the brain via a neurohormone called leptin, which is manufactured by fat cells in adipose tissues. Leptin is known as the satiety hormone, in that it shuts off the appetite response once energy needs have been met. By inducing insulin resistance and hyperinsulinemia, due to its unrestrained lipogenesis and consequent weight gain, fructose eventually causes the leptin response by the brain to get blunted as well, so the hunger signal never wanes. It is very important to remark that there is such a thing as leptin resistance, which is similar to insulin resistance in its etiology. In obese individuals, the overproduction of leptin, or hyperleptinemia, causes the hypothalamus to lose its ability to transduce the leptin signal, much like a constant flush of insulin causes the cells to become callous to its nudges. The overproduction of leptin in obesity is closely linked to hyperinsulinemia (which almost uniformly affects obese subjects) since insulin stimulates leptin production in the adipocytes (fat cells): excess insulin = excess leptin, and, ineluctably, insulin resistance = leptin resistance. This is one of the reasons why improving insulin parameters and cellular response to insulin is paramount to the success of any weight loss regimen, as well as to the prevention of diabetes. Fructose-induced leptin resistance has serious consequences on brain health as well, as I will discuss later in this article.
Aside from quantitative signaling by ghrelin and leptin, which gauges nourishment needs, energy homeostasis and appetite are subject to a more elusive biological response, the dopaminergic effect of foods, or the flush of dopamine (the reward and motivation neurohormone) that it elicits in our brain. Out taste buds are directly connected to neurons in the frontal region of the brain, where the dopamine response takes place; the perception of sweet taste, whether it is from glucose or fructose, is tightly linked to a flurry of dopamine and other feel-good neurotransmitters. The hedonic effect of sugar on the sensory motor cortex, the front part of the brain, generally explains the massive and repetitive consumption of sugary foods, and obviously informs the colossal business behind it. But the narcotic effect of industrial fructose, and of the processed foods that contain it, has been likened by research conducted through functional MRIs to the effects of certain drugs such as cocaine, nicotine and alcohol, in that it has a specific affinity for the reward center of the brain, the actual site where the dopamine response occurs. The problem with fructose consumption is that while it amplifies the brain reward circuits, making us want to eat more on cue, it actually stimulates that reward system to a lesser degree than glucose, meaning more fructose is needed more frequently, compared to glucose, to generate that reward response. As a result, our taste buds and dopamine receptors become desensitized over time, requiring higher and higher quantities to achieve a feeling of satisfaction. In the words of Dr. Robert Lustig, Professor emeritus of Pediatrics at UCSF and world leading expert in metabolic dysfunctions, “every substance and behavior that drives up your reward triggers will just as quickly drive down your reward receptors”.
3. The impact of fructose on brain development: neuronal activity disruption and mitochondrial dysfunction
Fructose has been shown to induce brain neuron derangement and contribute to the onset of degenerative diseases such as Alzheimer’s and dementia. The leptin pathway interference, mentioned in paragraph 2, also impairs dendritic activity in the brain (dendrites are branch-like neuron extensions), impeding communications among neurons. A study published by a team of sugar metabolism and neuroscience researchers from the University of Colorado Anschutz Medical Campus explained how excessive amounts of fructose in the Western diet can disrupt cerebral metabolism and neuronal function. The authors noted that fructose "activates a survival pathway to protect animals from starvation by lowering energy in cells in association with adenosine monophosphate (which plays a role in energy regulation) degradation to *uric acid”[cit.] While triggering appetite, this mechanism also decreases cellular energy, hence mitochondrial function, the energy that neurons need to work. That same mitochondrial dysfunction results in high homocysteine levels, triggering inflammation and raising risk for cardiovascular disease.
A study published in 2018 in the National Library of Medicine showed that excessive intake of fructose by pregnant women impairs brain activity, particularly in the hippocampus area, in their offspring, by way of an epigenetic modification of the Brain Derived Neurotropic Factor, (BDNF) a protein involved in emotional and cognitive function through promoting the growth, maturation (differentiation), maintenance and survival of neuronal cells.
*For reference: normal uric acid levels must be under 5mg per deciliter
4. Fructose, oxygen radicals, cellular aging
As if all of the above wasn’t enough to make you stay away from fructose, carbonated beverages and processed foods, here’s another nefarious, undesirable effect of fructose on the body, and it refers to accelerated aging. Cellular aging is largely an effect of Advanced Glycation End Products (AGEs) which are modifications of macromolecules like proteins, amino acids and fats, by sugars like glucose and fructose. AGEs are deleterious molecules and are found to be increased in the plasma of physiological aging and age-related diseases, diabetes mellitus, and autoimmune/inflammatory rheumatic diseases, including lupus, rheumatoid arthritis, systemic sclerosis and psoriasis. The sugars attach to other molecules, more notably tissue collagens or lens crystalline, causing browning and structural damage, a process known as the Maillard reaction (the term is commonly used in culinary science to indicate the browning that occurs on protein at high temperatures). During the Maillard reaction, Reactive Oxygen Species (ROS), or oxygen radicals, are produced in excess of the body’s own antioxidant defense system, leading to oxidative distress and inflammation, which cause cellular dysfunction and damage to lipid layer of the cell, protein and DNA, leading to apoptosis, or cell death. Fructose reacts with proteins through the Maillard reaction seven times faster than glucose because of its 5-ring structure (which I mentioned at the outset of this discussion), that causes the fructose molecule to be less stable than its 6-ring glucose cousin; this may account for several complications caused by fructose of diabetes mellitus such as neuropathy, and accelerated aging.
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*My next article will look at how accelerated aging can be fiercely counteracted by decreasing sugar intake, eliminating all sources of refined fructose and processed foods, and increasing intake of antioxidants, along with supplementing with a metabolically superior form of collagen.
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