Melato Cola™ or What? Fructose for Improved Glucose Metabolism and Melatonin to Counter Fructose Overload

There was a time, when Coke still contained "coke"... so why not add some melatonin for health benefits? I am obviously just kidding here, but a combination of fructose + melatonin may actually make sense.
The title of today's SuppVersity article is confusing, I know. Firstly, it contains the almost heretical notion that fructose could actually improve instead of impair your glucose metabolism and secondly it does not appear to make sense that you would have to use melatonin to counter the pro-diabetic effects of fructose, if the latter is in fact so good for you.

Before you are getting totally confused, let me clarify how the improvements in glucose metabolism and the melatonin-powered diabesity protection go together: Both have been observed in a recent study from the Pontificia Universidad Católica Argentina in Buenos Aires, Argentina (Cardinali. 2013), in the course of which the improved glucose metabolism was nothing but a side-finding of a study Cardinali et al. conducted to  examine the effect of melatonin when it is administered to rodents simultaneously with fructose in the drinking water.

This is the Coke + sufficient sleep study ;-)

Obviously this is not as the subheading would suggest the "coke + sufficient sleep study", but in light of the fact melatonin is after all the "sleep" hormone and in view of the results of a recent study by Senador et al. who observed that fructose had a negative effect on glucose management only, when it was available during the light phase (which is the inactive phase for a rodent; cf. Senador. 2012), it comes close; and that despite the fact that fructose timing was yet not an issue in the study at hand. Instead of modifying the timing, Cardinali et al. used different amounts of fructose with half of the rodents in the experimental arm of the study having a 5% and the other half having a 10% fructose solution as their main water supply.

Figure 1: Glycemia (mg/dL) 0-140min after 2g/kg body weight  glucose tolerance test (Cardinali. 2013)
If we trust the information about the average fructose content of a "carbonated beverage, cola, with higher caffeine" ...
  • the rodents in the 10% fructose group were consuming the total carbohydrate equivalent of coke, but with a 100% instead of ~50% fructose content, while
  • the rodents in the 5% fructose group were consuming less total carbohydrates, but roughly the same amount of fructose someone would ingest if he drank nothing but coke.
A direct comparison of either of the groups to the "coke only"-drinking human being is thus not warranted.

It is nevertheless intriguing that the 5% fructose group showed a significantly higher glucose tolerance - not just compared to the 10% fructose group, but also compared to the control group that was fed with water, only (see figure 1).
"Meta-Analysis: Lower Glucose, Insulin and HbA1c Levels From 'Catalytic' Dose of 36g Fructose" | read more
"But isn't fructose the reason you develop diabetes?" Before we get on to the effects of melatonin, I want to emphasize that this is by no means an outlier, in fact, I have written about the catalytic effects of 36g of fructose in a previous post "6x Bananas a Day!? Meta-Analysis: Lower Glucose, Insulin and HbA1c Levels From 'Catalytic' Dose of 36g Fructose" (learn more).

Previous studies have also shown that a 2:1 mixture of glucose + fructose is at least up to the regular glucose only drinks in terms of post-workout glycogen repletion (learn more) - partly because the fructose will keep the liver occupied, while the muscles suck up the glucose.
As previously mentioned the main research interest of the Argentinian scientists was not the effect of fructose on the glucose sensitivity of their rodents, but rather if the administration of 25 μg/mL of melatonin in the tapwater the rodents received would lead to significant changes in the study outcomes.
Figure 2: Effects of melatonin in drinking water with or without 5% [left] and 10% [right] fructose on body weight, systolic blood pressure and glucose response to glucose tolerance test (Cardinali. 2013)
As you can see in figure 1 it did: Melatonin did ameliorate the weight gain, and the increase in blood pressure that was observed even with only 5% fructose in the drinking water. It did not improve the glycemic response of the rats in the 5% fructose group even more, though, but it bulnted the negative effects of the 10% fructose solution had on the glycemic response in the glucose tolerance (figure 2, right).
SuppVersity Suggested Read: "Circadian Rhythmicity - Sunlight, Bluelight, Backlight & Co Mess Learn How THey W/ Your Internal Clock. Plus: Tips & Tricks to Prevent Negative Side-Effects" | read more
Is a melatonin solution the solution? If we also consider the negative effects of 10% fructose feeding on LDL (the rodents on 10% + Mel had even lower LDL than the control), the normalization of triglycerides and the potential therapeutic reduction in uric acid (-30% even vs. control), of which Cardinali et al. point out that it could have therapeutic effects in people with gout and other uric acid related metabolic disorders, it would appear smart that do dissolve the human equivalent dose of 21-35mg melatonin in your drinking water in the morning and keep guzzling it all day long.

Well, as I said, it "would appear to be" smart, but is it really smart? I wouldn't be too sure about that. Despite the fact that that you probably won't die, the chronically increased systemic melatonin levels could have long-term negative consequences on your circadian rhythm that could undo all potential benefits.

Restricting your fructose intake to fructose from fruit, only, getting enough sleep and using melatonin timely, i.e. 20min before bed would thus appear to be a more prudent approach to improve / maintain optimal blood glucose levels and insulin sensitivity. And if you are more into hard facts than "erring on the side of caution", you may consider the acute decrease in glucose tolerance, Cagnacci et al. observed in postmenopausal women, when they participated in a blood glucose test after the administration of 1 mg melatonin more convincing (Cagnacci. 2001).
  • Cagnacci A, Arangino S, Renzi A, Paoletti AM, Melis GB, Cagnacci P, Volpe A. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin Endocrinol (Oxf). 2001 Mar;54(3):339-46. 
  • Cardinali DP, Bernasconi PA, Reynoso R, Toso CF, Scacchi P. Melatonin may curtail the metabolic syndrome: studies on initial and fully established fructose-induced metabolic syndrome in rats. Int J Mol Sci. 2013 Jan 25;14(2):2502-14.
  • Senador D, Shewale S, Irigoyen MC, Elased KM, Morris M. Effects of restricted fructose access on body weight and blood pressure circadian rhythms. Exp Diabetes Res. 2012;2012:459087.
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