Can ketones lower blood sugar, and thus help diabetes?

By Jonathan Little (@DrJonLittle) and Étienne Myette-Côté, University of British Columbia

Low-carbohydrate, high-fat ketogenic diets are gaining popularity as a treatment option for type 2 diabetes because when someone eats less carbohydrates their blood sugar remain low. The diet is named after ketone bodies, compounds that the body produces when someone restricts their carbohydrate intake to very low levels.

Now, new ketone supplements that come in liquid or powder form claim to offer some of the benefits of a ketogenic diet without having to follow such a strict diet. Essentially, they allow you to drink ketones instead of relying on your body to produce them naturally. The appeal is obvious: lifestyle interventions like a ketogenic diet are hard to stick to over the long term. However, these supplements are also interesting for us physiologists because when someone eats a ketogenic diet, so many metabolic changes happen at the same time that it’s difficult to pinpoint which change caused which effect. Using ketone supplements can allow us to study the effects of ketones specifically.

Unfortunately there is very little research on ketone supplements, particularly their impact on blood sugar or outcomes relevant to diabetes. To begin to fill this gap in knowledge, our recent research in The Journal of Physiology studied the effect of ketone supplements in healthy adults.

Introducing the ketone star: β-OHB

The most abundant and important ketone body produced by the liver during a ketogenic diet is called beta-hydroxybutyrate (β-OHB). β-OHB can be used as an alternative fuel to carbohydrates by some parts of the body including the brain, heart and muscles. In recent years, β-OHB has garnered substantial media and research attention: studies in cells and animals have shown that β-OHB has glucose lowering, anti-inflammatory, anti-oxidant, and even lifespan-extending effects (1, 2, 3, 4).

In humans, it is difficult to determine the effects of β-OHB itself due to the myriad of physiological and hormonal changes that occur when somebody follows a restrictive ketogenic diet. The first answers come from studies where researchers have infused ketones directly into the blood of participants – like with a drip feed. Several of these studies conducted over the last few decades have consistently observed that when you infuse β-OHB directly into the bloodstream of humans, their blood sugar drops (5, 6).

Although the infusion method provides insight, it lacks therapeutic application: it would be impractical to keep patients with diabetes on a ketone drip in an attempt to lower their glucose. With the blood sugar-lowering effects of β-OHB infusion having been consistently observed in the past, we became interested in studying whether the newly-developed ketone supplements might lower blood sugar levels in humans.

Do ketone supplements lower blood sugar in humans?

Given that this was the first study (to our knowledge) to directly test this, we started by studying young healthy individuals. We recruited 20 healthy participants (10 males and 10 females, aged between 21 and 29 years) who underwent two oral glucose tolerance tests. This test involves drinking a large quantity of sugar (pure glucose) and measuring blood sugar at several time points afterwards to assess changes in blood sugar level. This test can also be used to diagnose diabetes.

One oral glucose tolerance test was performed 30 minutes following the consumption of the ketone supplement and one was performed after consuming a masked placebo. The order was random – some took the ketone supplement first and some the placebo first – and both the participants and study personnel performing the laboratory analyses were blinded, meaning that they did not know whether the participant had taken the ketone supplement or placebo.

The ketone supplement raised blood β-OHB to just over 3 mM within 30 min, levels normally seen after many weeks on a ketogenic diet or several days of fasting. This suggests that the supplements might be a good method to get β-OHB into the blood, without the hassle of a drip. When we then looked at the spike in blood sugar in response to the oral glucose tolerance test, it was much lower after drinking the ketone supplement compared to the placebo condition. Specifically, when plotted on a graph the area under the curve was decreased by ~16% when participants had the ketone supplement. Additional metabolic benefits of the ketone supplement were a reduction in levels of fatty acids circulating in the blood and an improvement in insulin sensitivity. Thus, consuming a ketone supplement was able to improve aspects of glucose regulation in healthy humans.

This study in healthy humans raises the obvious question of whether the same effects could be seen in individuals with elevated blood sugar, such as individuals with type 2 diabetes, prediabetes, or obesity.

It is not clear if our results will carry over to people with these diseases. However, a major reason for high blood glucose in type 2 diabetes is that the liver is constantly “leaking” too much glucose into the circulation. If the ketone supplement prevents this, which is what we think happens, then ketone supplements might indeed be helpful for diabetes; it’s now up to future studies to build on our findings and hopefully find the answer!

References:

1. Madison, L. L., Mebane, D., Unger, R. H., & Lochner, A. (1964). The hypoglycemic action of ketones. II. Evidence for a stimulatory feedback of ketones on the pancreatic beta cells. The Journal of clinical investigation, 43(3), 408-415.
2. Youm, Y. H., Nguyen, K. Y., Grant, R. W., Goldberg, E. L., Bodogai, M., Kim, D., … & Kang, S. (2015). The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nature medicine, 21(3), 263.
3. Shimazu, T., Hirschey, M. D., Newman, J., He, W., Shirakawa, K., Le Moan, N., … & Newgard, C. B. (2013). Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science, 339(6116), 211-214.
4. Edwards, C., Canfield, J., Copes, N., Rehan, M., Lipps, D., & Bradshaw, P. C. (2014). D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging (Albany NY), 6(8), 621.
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