Articles

Poisonous Calories

 

Professor Philip Home, DM, DPhil

Professor of Diabetes Medicine, Newcastle University, UK.

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A poison is 'a substance that causes death or harm when introduced into or absorbed by a living organism' [Oxford English Dictionary].  Most of us conceptualize this as something toxic in small amounts, but in reality damage is simply a function of quantity, and that quantity may have to be quite large.  Carrots may help our night vision if we do not get enough carotene from other sources, but if you eat vast quantities, sometime after your skin turns a peculiar shade of orange your liver will fail.  Iron is of course essential to every one of our cells, but iron overload will wreck nearly every organ in your body, given time.  I once rescued a man treated for too long with high doses of vitamin D – he was in kidney failure as a result and had calcified many body tissues – my case presentation was of 'calcified man'. 

But even the very common elements and substances can be poisonous.  Oxygen can be poisonous to divers and to new born babies.  At the extreme of potentially common poisons is water, which constitutes 60+% of the human body (less in obese people or females), but with which doctors kill a few people e every year (mistakenly) through inadvertent intravenous water overload.  But by far the most common poison in modern society is the group of substances which is collectively known as 'food', and its manifestations, when in excess, tend like other poisons to affect a diversity of organs.  Often, when talking about food, debates rage around the three main types (plus one), namely carbohydrates, protein, fats and ethanol. To avoid confusion in this article, and because the main effect is simply one of combined excess load, the term ‘poisonous calories' will be used.

That fact that the calories are the problem should also take us above specific aspects of food as a source of poisonous substances.  I am not referring to these, but it is helpful to list them to acknowledge them and to deny them individually as the problem discussed here.  Ethanol is of course consumed already in its fundamental form, but other foods are digested to toxic substances for the sake of gut absorption and transport in the blood.  Monosaccharides, like glucose, fructose and galactose, are toxic in anything above the concentrations normally found in the blood.  For glucose this is clearly evidenced by the ravages of high levels in diabetes, and by the extraordinary complex ways glucose is stored and later made available after a meal, processes which waste around 30% of the precious energy content in avoiding hyperglycaemia.  Galactosaemia, the inability to covert galactose to glucose, is toxic to infants.  The body also has complex mechanisms for limiting the effects of the toxic reactive oxygen species generated during glucose metabolism.

The body degrades any excess of amino acids from digestion of proteins, as can be determined from the colour of urine, except in those people with genetic defects of the enzymes responsible for those removal pathways – over 20 specific genetic disorders are known, some of which kill in infancy.  Fatty acids, one of the two breakdown products of fat, are highly toxic, and not just when they drive ketoacidosis in diabetic hyperglycaemia crises.  One prime, usually forgotten, function of the albumin in our blood and tissue fluid is to bind and transport fatty acids safely – the huge transport capacity is high affinity, and a small proportion can safely be taken up by acylated insulins and other medications. 

It might be worth noting why all these substances can be toxic.  Essentially, they are all fuels and highly reactive – you can burn oils, and sugar with oxidizing agents is a good explosive (try throwing sugar on a fire).  All fuels and powers are manageable in controlled amounts (gas/gasoline, nuclear, electricity, coal, hydrogen), and all are highly dangerous when not so controlled. The brain and heart burn glucose and fatty acids constantly and are dependent on them. 

Ideally the body packs away any excess of these toxic food products safely or degrades them.  Notably the liver will convert the carbon chains of these substances into fatty acids (if not already such) and in combination with glycerol in the peripheral tissues will store the excess away in a low turnover environment, adipose or fat tissue.  In more gross excess we term this storage condition obesity.  Obesity is known from the last 2000-3000 years but is not a normal human state of hunter-gatherer communities, who have little peripheral fat whatever the season.  Further some ethnic groups are resistant to laying down peripheral fat.  The regulatory signals from fat tissue which reduce feeding in rodents, notably the hormone leptin, do not operate in humans, where, for reasons that are unclear, but which include learnt behaviour in childhood, culture seem to override metabolism.  Leptin does operate in women, as a signal of female fitness to endure a future pregnancy. 

The regulatory biochemistry goes back billions of years and is therefore fundamental.  Bacteria and archaea had to be able to regulate their metabolism according to the wild swings in the availability of nutrients in the medium around them.  This would not simply be a matter of inducing uptake and metabolism if a particular nutrient was poorly available, but also protection in times of excess.  In humans the liver products of glycolysis, the prime metabolic pathway of glucose and fructose, induce regulatory proteins that inhibit the enzymes that take up glucose, and enhance the enzymes that release glucose into the blood – this condition at its extreme is known as diabetes.  This effect makes the liver resistant to other metabolic modulators – hence insulin resistance.   Some glucose can be stored, but the liver has a low maximum capacity for glycogen and is quickly saturated by high food intake and lack of exercise.

But excess calories must go somewhere, and in the liver they are converted to fat.  This is further driven by insulin which activates the enzyme that promotes fat synthesis, and, due to the insulin resistance noted above, insulin levels are high as the body tries to compensate.  In some people large amounts of fat are packaged and stored safety in peripheral fat tissue, but in extremes and in those whose bodies have reduced capacity for that (notably many Asians) the fat is retained in the liver – referred to as a fatty liver.  Fat in the liver is not by itself toxic to the organ, but again there is limited storage capacity. If the supply chain backs up toxic intermediates accumulate resulting in liver and systemic inflammation (steatohepatitis or NASH) and eventually liver failure. 

The same processes appears to operate in other tissues, but our understanding of this is remarkably poor.  Skeletal muscle is the major immediate store of ingested glucose (to protect against high glucose levels in the blood), but again storage capacity is limited, and since in muscle glucose cannot go anywhere else the cells resist further uptake –  resulting in peripheral insulin resistance.  In the islet B-cell, which produces and secretes our insulin, the sensor for blood glucose concentration is glycolysis, and the same protective biochemistry is likely to operate, so insulin secretion is reduced in proportion to glucose level.  Further the islet B-cell interacts with fatty acid concentrations, and the islets even lay down fat. There is evidence fat metabolism is a key toxic mechanism for defective insulin secretion and islet cell death. 

One important question is how quickly these effects can be reversed.  If liver and islet damage has not gone too far then calorie deprivation will reverse diabetes in just one week.  Of course, at that point peripheral and liver fat levels are still high (obesity thus does not cause diabetes), emphasizing it is the acute metabolic toxicity of calories that is the problem, not stored fat. 

Does any of this help us with the metabesity epidemic?   At the least it emphasizes that no medication or other intervention which does not either reduce calorie intake or disposal will be able to have major effects on a secondary condition like type 2 diabetes or NASH (non-alcoholic steatohepatitis).  Disposal such as by uncoupling agents, promotion of storage of peripheral fat (thiazolidinediones), or enhanced glucosuria (SGLT-2 blockers), has capacity limitations, which leads us back to regulating food intake.  With few exceptions any adult who has tried to lose weight will know they are programmed from childhood to maintain a particular body weight, but the brain-gut neurohormonal cycle which does this can be reset or interrupted as gut by-pass surgery illustrates.  Damning particular foods is incorrect, except as so far that most animals are attracted to sweeter foods, and sugars, notably glucose and fructose, that are easily consumed in high quantities, and as noted above have a fundamental role in the dysregulation of metabolism in humans. 

In conclusion, excess food is toxic.  This can be a useful media message.  The reasons for this toxicity are reasonably well understood and obey the laws of physics (overload must go somewhere) as well as biology.  Ultimately, we will only overcome the toxic food epidemic, metabesity, by controlling calorie intake. 

 

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