I want Candy

People say you should eschew sugar. My own take is a little more nuanced. I think it’s OK to chew, providing your levels of physical activity are sufficiently high for your skeletal muscle to be able to soak up enough of it from the blood stream, and your oral hygiene is good enough to keep your teeth intact.

Starch, however, usually gets a pass – which is odd, because starch is basically slow sugar.

Potatoes, bread, rice and pasta are all broken down at various rates into sugars in the small intestine, which impact directly on blood glucose levels. So when we warn people off sugar, should we also be cautioning against excess consumption of all digestible carbohydrates?

Research such as the mammoth PURE study examined the relationship between dietary glycemic index (which relates to the speed and height of your blood glucose spike), glycemic load (which is more closely aligned to blood glucose AUC) and major cardiovascular events, plus death from all causes (1). This was very large-scale, and must have been hideously expensive; 137,851 participants from 20 countries were followed for a decade, using nation-specific food-frequency questionnaires.

The researchers found that a high-GI diet (containing lots of sugar) raised the risk of cardiovascular events and death from all causes.

A high-GL diet (typically, one containing sugar and plenty of starch too) had similar effects in those subjects who had cardiovascular disease at baseline, but did not seem to be so damaging in subjects who did not have CV disease at the start.

A large-scale study carried out in Japan (2) published broadly similar findings; a high GI-diet increased the risk of death from all causes, and the high-GL diet increased risk of death from cardiovascular disease. Two Chinese research groups (3, 4) published parallel findings, and given previous and similar results in Holland (5), Italy (6) and elsewhere, it was not surprising that three recent meta-analyses (7-9) came up with the same basic recommendations to reduce dietary GI and, to a slightly lesser extent, GL.

John Yudkin’s book ‘Pure, White and Deadly’ first rang the sugar alarm in 1972, and these epidemiological studies, plus recent mechanistic work, show that he was broadly correct. It is probably not sugar per se but its glycolytic metabolites glyceraldehyde 3-phosphate and/or dihydroxyacetone phosphate that do much of the damage (10-13), together with negative effects on uric acid levels (14) – but in the real world, this still means cutting down on sugar.

There is a theoretical sugar / cancer connection too, but when other teams looked at the impact of GI and GL on cancer they came up with minor or null findings. The risk of cancers of the pancreas (15), breast (16), lung (16, 18), endometrium (17), gastrointestinal tract (19, 20), ovaries and prostate (19) were not much affected. It is only when metabolic syndrome or Type 2 diabetes develops that chronic hyperinsulinemia, the accompanying spike in insulin-like growth factors,inflammatory stress and mTORC1 that provide established risk factors for cancer (ie 13, 20–23). 

So, back to the heart.

The relatively minor differences between the different cardiovascular study results were likely due to the varying presence of dietary macro-components (ie proteins, fats) which modify GI by slowing digestion and absorption; other risk-modifying dietary micro-components (ie polyphenols, tocopherols, tocotrienols) which occur at different levels in different national diets; varying levels of physical activity; and in some cases, distinct male / female behaviors.

The above variables mean that GI, which is calculated rather than measured, is not as accurate a measure of the impact of food on the body as, for example, post-prandial blood glucose or C–peptide. However, the GI / GL studies all point in broadly the same direction.

It is not healthy to eat too many foods which spike your blood sugar and then your insulin levels, particularly if your lifestyle is a sedentary one.

This is consistent with the role of the pro-ageing gene DAF-2, which is switched on by insulin (24, 25).

We can fine-tune starch too. A recent Iranian investigation (26)compared rates of heart disease in people whose diets were high in refined grain products, and in those who consumed whole grain foods with similar GL but significantly lower GI values.Refined characters who ate refined grain foods were significantly more likely to develop coronary artery disease in middle-age than the rougher characters who chowed down on healthier whole grains.

Q: Why refine? A: White flour has a longer shelf life than wholewheat flour, and provides baked goods with a lighter texture. You can’t have, for example, wholegrain challah (Jewish brioche, more or less) or croissants. Unless some inspired chef or food technologist can prove me wrong …

Lighter texture, however, comes at a price. The milling process removes bran and germ, stripping out cardio-protective micronutrients, phytonutrients and fibers. It leaves only the endosperm, which is basically starch, and which is ground to produce refined flours.

These are built into many of the foods we love. Breads and pasta are processed foods, not great for sedentary types but not awful. Cakes and biscuits (cookies for American readers) are a step down, because the addition of sugar can hike the GI index by 20-30 points. A second step down takes you into the nutritional basement where the ultra-processed foods are stored.

There are not many whole grains in ultra-processed foods but there is plenty of refined flour, because this is easily integrated into the matrix of ultra-processed products. These matrices introduce a delicious new set of nutritional sins (27).

In many ultra-processed foods, plant oils and sugars are added to the starch. This unhealthy combination reduces satiety, while increasing calorie density and inflammatory potential (28, 29). If it’s a savory kibble, added salt creates an electrolyte imbalance which increases arteriolar (and bronchiolar) smooth muscle hyperactivity (30, 31), contributing to hypertension and respiratory difficulties.

All these ultra-processed foods drive neuroinflammation (32), hippocampal atrophy (33, 34), distortion of appetite (35, 36), impaired mental health and intelligence (37–39), Type 2 diabetes (40) and significantly accelerated cardiac ageing (41), which fits in with PURE and the related studies. They also confer an increased risk of early death (42).

A range of food additives are in the mix. Some of these are harmless or even beneficial; the nutrients ascorbate, lecithin and modified starch are among the most commonly used additives(43). Others such as nitrites, sulphites, trans fats and FD&C yellow 5 and 6, may increase the risk of health problems in some individuals. Plasticisers are added incidentally, via packing materials.

These issues have been seized on by consumers, but they are notthe main problem at all.

More importantly, the food matrix and marketing methods deliver an integrated onslaught of calories, flavor and imagery designed to overwhelm consumer reserve, encourage addiction (44–47) and drive over-consumption (44–49). Hence weight gain (ie 50).

But what about the GI / GL values of ultra-processed foods?

The redoubtable Jennie Brand-Miller’s group found, perhaps counter-intuitively, that ultra-processed foods have GI and GL values LOWER than those of minimally processed foods (51).Reduced GI values are in some cases due to the co-presence of large amounts of lipids in these foods, which slow the absorption of sugars (ie 52, 53). But that does not exonerate them; ultra-processed foods contribute most of the sugar we do eat, because they now form such a large percentage of our diet (54, 55).

Moreover, the matrix of those ultra-processed foods accelerates the absorption of the lipids they contain, causing substantial post-prandial hyper-lipidemia (56–59). And now we have arrived, metaphorically, at something of an ileo-cecal junction.

Many foods with high GI and GL values cause high post-prandial lipidemia. Is it possible that the epidemiological studies which documented the negative effect of dietary GI and GL on cardiovascular endpoints, were actually identifying the negative clinical impact of spiking plasma lipid levels?

Probably, at least to some extent. The TyG index, an algorithm combining fasting glucose and triglyceride levels, may besuperior to triglyceride or glycemic markers alone in predicting cardiovascular events in non-diabetics (and diabetics) with coronary artery disease (60–62). And it is very noteworthy that the ability of ultra-processed foods to deliver large amounts of fats and sugars is at the heart of their addictive potential (44-49, 68).

Given our historically low levels of physical activity, consuming large amounts of sugars and simple carbs inevitably promotes insulin resistance and therefore raises triglycerides and dense LDL cholesterol (63), two of the most heavily weighted risk factors for cardiovascular disease. Consuming large amounts of fats also boosts these risk factors, but likely only when the diet is deficient in omega 3 HUFA’s (64, 65) – which today’s diet undoubtedly is.

From this perspective, it would appear that the most dangerousfoods are also likely to be the most addictive ones. On the TyGchart the highest scoring products – and therefore candidates for the unhealthiest – are milk chocolate (66) and full fat ice cream (67). These are, indeed, commonly cited as the two most addictive foods (68).

In future, if our species has one, I see health warnings appearing on Kit Kats, and plain pack Pringles being kept under the counter with the cigarettes. After all, these food products are as damaging to public health as tobacco (69, 70).

Glucose is not exonerated, because hyperglycemia drives non-enzymatic glycative reactions which contribute to chronic inflammatory stress via RAGE (ie 71). They also causeincreased arterial stiffness via collagen cross-linking (72), and both of these factors are drivers for cardiovascular and other pathologies (71–75).

While the impact of glycative stress on vascular health is recognised (72, 75), the lipotoxic effects of high levels of circulating triglycerides and associated free fatty acids on endothelial health may be equally significant (hence the TyGindex). The effects of lipidemia are mediated by increased levels of ceramides, lipid peroxidation products and membrane destabilization. These lead, collectively, to vasoconstriction, elevated blood pressure, apoptosis of endothelial cells and chronic inflammation in the artery (and venous) linings (76–78).

The chronic inflammation driven by hyperglycemia and hyperlipidemia contributes to insulin resistance (79), and the vicious cycle continues.

Not all fatty acids are equal.

Omega 3 fatty acids improve endothelial health and function in a number of diseases (80–83).

The omega 6 fatty acids dominant in ultra-processed foods counter many of those benefits (84, 85). The case against plant oils, however, is still open. Some believe that the omega-6 LA may offer a degree of cardio-protection (86), possibly via cholesterol reduction. Others disagree (87).

If there really is a relationship between LA and lower risk of CVD, this may reflect the impact of cardio-protective phytonutrients in dietary sources of LA other than plant oils, butthis is speculation. The extent and diversity of dietary and lifestyle variables make clear causative connections difficult to identify with any degree of clinically relevant accuracy.

This is why pharmaco-centric docs love the much simpler polypill, an idea launched two decades ago by Nick Wald and Malcolm Law of London’s St Bartholomew’s Hospital (88).

They say that you can tell a man from Barts, but you cannot tell him anything. This seems to apply to the World Heart Federation also. In a recent Lancet article (89), two senior WHF cardiologists write that ’Global health has paid a deadly price for not using simple, low-cost blood pressure lowering drugs, statins and aspirin widely in the form of a single pill (polypill), which would substantially reduce the risk of cardiovascular disease and be affordable for most people globally.’

The clear implication is that the world gets fatter and our diet worsens, we will all eventually need polypills. This is Big Pharma’s wet dream.

Polypills achieve a significant reduction in major cardiac adverse events (ie 90, 91), and extended polypills are clearly helpful in the growing numbers of those with heart disease and NIDDM (92). However, the formulation and definition of the polypill is not yet finalised (ie 93). More importantly,medicalizing the masses (more than they already are) is unethical and unpalatable when safer and more profound protection can be gained by a combination of dietary modification (94–96), a pinch of exercise (97) and the effective pharmaco-nutritional targeting of endothelial dysfunction (98).

Poor diet and lack of exercise were two of the three leading causes of death in 2000 (99), with tobacco making up the third.

Diet, activity levels and body mass have all deteriorated in the last 2 decades. Against this morbid backdrop, the combination of diet, exercise and pharmaconutrition (a natural polypill),provides safe and substantial protection against heart disease,and all the other non-communicable degenerative diseases that disfigure public health today.

Might there be a place for exercise mimetics in this approach?

Given the complexity and redundancy of the many mechanistic links between physical exercise and health benefits (100), it seems implausible that any mimetic could duplicate all the effects and health benefits of exercise. Having said that, the emergence of synthetic and natural AMP-kinase up-regulators is a good start. These compounds exert positive effects resembling those of exercise, and via the same mechanisms as exercise, on blood chemistry (101, 102), liver health (103–105) and many aspects of muscle function (104–106). Like exercise also, they help to lose deep intra-abdominal adipose tissue (107).

Exercise is also linked to improved sleep, mood, and chemoprevention. How do the AMP-K up-regulators score here?

In pre-clinical models, loss of AMP-K causes sleep fragmentation (108) but there is no evidence that AMP-K up–regulators improve sleep in any way. Nor is there any evidence that they improve mood; and the cancer story is a cautionary one. While strengthening and to a lesser extent aerobic exercise appear to reduce the risk of cancer (ie 109), the case for AMP-Kup–regulators is less clear. The available evidence suggests that while they are also probably chemo-preventive, they may actually promote some existing cancers (110).

These data indicate that while AMP-K up-regulators act in parallel with physical exercise, they are not identical. And there are other areas of differentiation. It seems unlikely, for example, that AMP–K up-regulators improve endothelial function by modulating circulatory sheer forces, as exercise does.

That doesn’t really matter. There are other pharmaco-nutritional tools that achieve those desired end-points.

Vascular health can be restored and maintained using a blend of omega 3 HUFA’s and amphiphile polyphenols (ie 110). Mood can be improved and sleep enhanced with saffron extract (ie112-114).

Natural chemo-prevention is real, but is more complex and deserves its own post, which is due next month.

Pharmaco-nutrition can provide the health benefits generated by optimizing diet and activity levels. They also provide a safer and more ethical alternative to polypills, and an antidote to the terrible damage wreaked upon us by the industrial diet. In light of current public health projections, which envisage the numbers of young Americans with type 2 diabetes increasing up to 700 percent by 2060 (115), this is the road that society must take.

I predict that wearable blood glucose monitors will be in smartwatches before the end of 2023. I also predict they will be mostly worn by young folk who need to show how ahead of the curve they are, but will do little for the thundering herd who will continue to eat the health-destroying destructive industrial diet sold in retail outlets everywhere.

Given the idiotic food policy currently emanating from the White House (116), Big Phood has no incentive to change. You will have to step up to the plate yourself, and cut down on those foods which combine excessive amounts of sugars and fats with effectively zero phytoprotection (117). Give Ben and Jerry the cold shoulder and leave Hershey and Cadbury in your wake – orthey will be at yours (118).

Next week: Keep your hair on.

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