Sweet Nothing

ALLULOSE (‘all you lose’) may be the perfect match of sweetness and calories that will finally allow us to have that cake, eat it and stay slim. It is the latest in a long line of sugar replacements, and it might be the one that everyone has been waiting for. 

It’s not exactly new – preclinical studies started around 2000 (ie 1), and it was first launched commercially in Japan in 2013 – but it has been keeping a low profile. So far.

The original name of this molecule was d-psicose. D-psicose / D-allulose is one of around 50 ‘rare sugars’ (2), and occurs in trace amounts in such foods as wheat, jackfruit, figs, raisins and tamarind. 

Allulose has the basic hexose chemical formula (C6-H12-O6), and a near-identical structure to fructose. A tiny enzymatic re-arrangement of the fructose molecule cuts its sweetness in half. As fructose is one and a half times sweeter than table sugar you end up with a molecule which has 70% of the sweetness of sugar and, because we cannot metabolise allulose, near zero calories (1).  

Sweet!

Applied R&D involving Rats (3) and Dogs (4) showed a clean safety profile, with the bulk of allulose being absorbed and excreted unchanged in the urine. The FDA allowed GRAS status in 2013 and in 2019 start-up Magic Spoon launched their over-priced, allulose-sweetened breakfast cereals for keto-centric adults who still feel the need to eat baby food. EFSA and Health Canada remain, at the time of writing, typically costive.

While we cannot metabolise allulose it does interfere with sugars which we do metabolise, and this has both positive and negative side effects. Let’s start by eliminating the negative.

The main adverse effects are gastrointestinal, and include flatulence, abdominal discomfort and diarrhoea at high doses (5). These are common side effects of many non- or poorly digestible carbohydrates, and likely to occur with single doses of 75 g and daily doses of 150 g of allulose respectively (6). To put this in context, the commonly used sweetener sorbitol starts to trigger these same reactions at 15 g and 30 g respectively (7). 

Potentially more seriously, allulose is an aggressive glycator, with reactivity D-allulose > fructose > glucose (8). This means that it might, if consumed in significant amounts, increase protein cross-linkage and thus induce signalling changes and inflammatory stress. This does not occur to any measurable extent in humans taking food’ish doses (5), but might become an issue if used excessively.

Now let’s accentuate the positive, going back to the humble rat. 

Allulose has a range of integrated and favorable biological effects which include lowering blood glucose (9, 10), protection of pancreatic β-cells (11), improved plasma lipid and insulin levels (12, 13), inhibition of body fat synthesis (12, 13) and accumulation (14, 15), and the prevention of diabetes in diabetes-prone animals (16). It also prevents or at least slows the cognitive decline typically seen in such animals (17).

In humans, allulose does much the same things.

Single doses of allulose improve glucose tolerance in normal and diabetic subjects (18-20), lower serum insulin and leptin levels (20) and increase post-prandial fat burning (21). Used longer-term, allulose was found to help with weight loss; after 3 months, subjects with BMI within normal range exhibited reduced body fat mass including abdominal and subcutaneous fat (22).

There is evidence that allulose may be acting at least in part via microbiomal modification (23) with subsequent up-regulation (24, 25) of Glucagon-like peptide-1 in the gut (26). GLP-1R agonists are effective anti-obesity drugs (ie 27, 28) but their use has been limited by side effects. Allulose, by boosting endogenous GLP-1 synthesis and then modulating vagal activity back into the brain reduces appetite (26), which adds to its already appealing spectrum of effects.

Based on these results, it was proposed that allulose might be helpful in type 2 diabetes (5). A recent semi-acute study in non-diabetics showed promising results in terms of improved glycemic control (29), and set the stage for longer-term clinical trials in diabetic subjects.  

I am informed that these are currently underway in Kagawa Prefecture, due to the long-standing involvement of Kagawa University in rare sugar research and the Prefecture’s huge numbers of diabetics.

I’m not convinced, however, that we need to wait for those results.  Given the negative aspects of fructose, which is implicated in non-alcoholic fatty liver disease, and sucrose, which is both cariogenic and diabetogenic, incorporating allulose into ultra-processed foods looks like an easy win for Big Phood. 

But there are other candidates, and allulose is not the only rare sugar in the bowl. Tagatose offers a better sweetness profile (30, 31), and waiting in the wings is allose, yet another variant on the C6-H12-O6 theme and an epimer of glucose which is even more interesting.

Slightly sweeter than allulose (32), allose is a zero-calorie sugar you can use to sweeten your coffee and fight cancer at the same time (32). It has been shown to be effective against human cancers including ovarian (33), cervical and skin (34), liver (35, 36), prostate (37, 38), pancreas (39) and lung cancer (40). It also enhances the effects of a range of anti-cancer treatments (40, 41).

As if that weren’t enough, allose has anti-inflammatory activity (42), which probably explains its protective effect against reperfusion injury (43, 44), hypertension and stroke (32, 45). But wait – there’s more! This minor variant of glucose also inhibits osteoclast differentiation (46), making it a potentially valuable element in anti-osteoporosis nutrition; and it is reported to have anti-obesity, anti-hypertensive and anti-oxidant effects too (32).

The protective effects of allose in models of neurodegenerative disease are said to be mediated by its antioxidant activity (47, 48), but I suspect there is more to this story.

Some of the other effects of allose are probably mediated by its ability to modify glycolysis and mimic calorific restriction (ie 32, 49, 50), thereby inducing specific epigenetic changes (48-52). It may also influence cell signalling and signal transduction via post-translational glycation of proteins and/or Redox modulation, and it might even act by substituting for pentoses in the sugar-phosphate backbone of DNA and RNA (51, maybe!); but these are, I think, less likely. 

If you like the idea of putting allose in your tea and scones you could cultivate Protea rubropilosa, aka the Transvaal Mountain sugar bush (53), and extract allose from the leaves. Alternatively, thanks to a biochemistry team at Kagawa University (54), you could order Rare Sugar Sweet from the Japanese company Matsutani Chemical Industry Co. This futuristic product, which combines allulose and allose, recently became available on Amazon (55).

The manufacturing process that makes these rare sugars common is called Izumoring, a tribute to Professor Ken Izumori. Based at Kagawa University, Ken discovered an enzyme from bacteria in the soil behind the Faculty of Agriculture cafeteria which converts fructose to allulose. He is also interested in l-gulose. This mystery sugar occurs in the extremophile Thermoplasma acidophilum, and has not yet emerged into the literature. I look forward to the first publications!

Trehalose, a cryoprotectant which occurs in tiny amounts in fungi (yeast and mushrooms) and shellfish, is another fascinating rare sugar. It triggers autophagy (56), and in cell cultures accelerates the removal of degraded proteins including denatured huntingtin and alpha-synuclein, hallmarks of Huntington’s and Parkinson’s respectively (56).

There are a dozen or so clinical trials underway in the muscular dystrophies, as well as vascular inflammation / atherosclerosis, macular edema and, oddly, depression. It is also being proposed as an early treatment for Covid (57) and if proven effective will undoubtedly be taken off the market.

In the meantime, Rare Sugar Sweet is being subtly promoted for preventing caries and promoting weight loss (58-60). These formerly rare sugars will also offer protection against cancer, diabetes and NAFLD (see previous post ‘Foie Gras’), and likely have anti-ageing effects (61, 62) besides. 

More tea, vicar?

Next week: heterochronic fecal parabiosis, the gut / brain connection and shit for brains.

REFERENCES

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