Research Reveals a Surprising Link Between Melatonin and Type 2 Diabetes

Melatonin, the Sleep Hormone, and the Pancreas

Melatonin is produced by the pineal gland in the brain in response to darkness. Levels are typically very low during the day and reach their peak at night. Like other hormones, melatonin works by binding to compatible receptors – kind of like a lock and key. These receptors are found abundantly in the eyes and the brain, and when melatonin binds to them, they signal that it’s dark outside. For humans, this darkness signal indicates that it is the period when we rest, so this timing signal contributes to and is a part of a cascade of other responses that help initiate and maintain sleep.

Strangely enough, we now know that these receptors are also found in the pancreas – specifically in pancreatic beta cells. By releasing insulin, beta cells regulate glucose levels in the blood. We have also discovered that when melatonin activates these receptors, insulin secretion is decreased.

Circadian Physiology and Glucose Metabolism

Prior research in animals has suggested that there is a relationship between melatonin and glucose metabolism. Mice with mutations that eliminate their melatonin receptors exhibit higher insulin secretion from their islet cells.

We also know that glucose regulation and insulin secretion are naturally subject to daily rises and falls, which are independent of food intake and activity levels. Removal of the pineal gland – which completely eliminates the secretion of melatonin – abolishes these circadian oscillations, which supports the idea that they are regulated by the circadian system via melatonin.

But why?

It is believed that melatonin’s effect on insulin secretion may have evolved as a protective mechanism against low blood sugar (hypoglycemia) during the period when we sleep. We don’t normally eat when we’re asleep, so there’s less need for insulin to store incoming food substrates. Blocking insulin action, in fact, helps keep blood sugar levels stable while sleeping, which provides the brain with glucose throughout the night.

Some new studies have suggested that certain genetic variants may modulate the response of the melatonin receptors in pancreatic beta cells – which may have important implications for your metabolic health over the long term.

Genetics of Melatonin Receptors

Genome-wide association studies have enabled us to scan markers across genomes of many individuals to identify gene variations that may be associated with diseases. This approach has revealed a wide array of gene variations that are associated with the development of diabetes mellitus.

One example of this is a genetic variation in the MTNR1B gene. This gene codes for one of the melatonin receptors. Those who carry a particular alternate form of this gene (the G-allele) experience higher blood sugar levels and are at significantly greater risk of developing type 2 diabetes than those with the C-allele, or wild type.

It is important to note that the G-allele is atypical, but it is not particularly rare. Though its prevalence varies to some degree by ethnicity, it has been estimated to occur in roughly 30% of the human population.

It has been hypothesized, based on animal models and in vitro evidence, that individuals with this risk variant have melatonin receptors that are more sensitive to the hormone, which results in exaggerated inhibition of the beta cells and slower insulin release.

New Experimental Evidence

Researchers at Lund University in Sweden, after studying this effect in mice and in human islet cells, hypothesized that melatonin supplementation would produce different effects on insulin and blood sugar regulation in humans depending on whether they carry the G-allele.

The team tested this hypothesis by looking at 45 healthy individuals, all non-diabetic, and similar age and BMI. Participants were recruited based on their genotype:

23 participants were GG, or carriers of the risk allele
The other 22 participants were CC (wild type), or non-carriers of the risk allele

Subjects were given an oral glucose tolerance test – a test in which patients drink a standard dose of glucose, and their blood sugar levels are measured over the course of two hours to determine how well their body handles carbohydrates.

As expected, baseline glucose concentrations were higher in carriers, and the insulin response to clear that blood glucose was delayed and reduced. The non-carriers experienced rapid insulin response, and insulin secretion (when adjusted for insulin sensitivity) was 3x higher. This no doubt contributed to the difference in glucose metabolism between the two groups.

Next, all of the subjects were told to take 4 mg of melatonin every night for three months. This is a relatively common dose taken by people to assist with sleep onset, and this amount is readily available over the counter at drugstores in the US. Their baseline melatonin levels were measured at 16-25 pg / ml. The study does not indicate at what time these measurements were drawn, but it seems likely that this was at some point during the day.

At the end of the 3-month regimen, melatonin levels were measured in response to the 4 mg of melatonin. As one would expect based on previous research, peak plasma levels vastly exceeded the normal physiological range in both groups.

However, the risk variant carriers had 76% higher levels than non-carriers: 510 pg / ml versus 289 pg / ml, respectively.

As hypothesized, the carriers of the risk allele (GG) did indeed experience higher blood sugar levels than their non-carrier counterparts (CC), and the blood sugar took longer to come back down.

Measurements of plasma insulin levels during this glucose tolerance test showed why this was the case. As you can see below, carriers of the G allele experienced a pronounced delay in first-phase insulin response. The carriers also experienced a decline in overall secretion of insulin after the supplement regimen compared to baseline.

Practical Implications

Melatonin supplementation

The first thing that I want to point out is that this study is gauging the impact of the melatonin receptor gene variant through the administration of melatonin supplements. This is not a problem from a methodological standpoint, but it is important because it is well documented that this results in supraphysiological levels of melatonin, even in those with genetically typical levels of melatonin receptor activity.

Typically in young healthy adults, melatonin levels during the day are very low (~1-10 pg / ml), and rise in the evening in response to darkness to approximately 40-100 pg / ml.

But as we saw in this study, a dose of 4 mg of melatonin, which is commonly found in melatonin supplements, produces much higher levels than you would ever see naturally. Perhaps more importantly, these very high doses take longer to clear. In other words, the absolute intensity of exposure per se may not be the main problem (or even a problem at all) – you also have to consider the duration and timing of the elevated melatonin levels that result from that dose.

In a study comparing two different doses of melatonin (4 mg versus 0.4 mg), participants who were assigned the 4 mg dose saw their melatonin levels rise 65-fold higher than normal peak levels! And those levels remained elevated (above 50 pg / ml) for approximately ten hours after oral administration. This means that if you took 4 mg of melatonin at midnight, you would still have higher-than-normal levels through the morning – and with that comes the suppression of insulin and disturbed glucose metabolism. One would assume that this effect would be significantly amplified in people with the risk gene variant.

This suggests that if you have inherited the risk variant of MTNR1B, you would want to be cautious with melatonin supplementation. If you do use them, you would want to stick to small doses.

Feeding Patterns

This brings us to another potential problem.

One might reasonably speculate, from these findings, that eating when melatonin levels are relatively high – while your pancreatic beta cells are functionally “sleeping” – could result in even more pronounced disturbance of blood glucose regulation.

This may partially explain why late night eating has been found to be associated with high blood sugar (hyperglycemia), and why feeding a person a meal at 10:30pm results in prolonged high blood sugar and elevated 24 hr blood glucose levels.

However, this effect may also extend beyond just eating late at night – if you are using melatonin supplements. As we established above, elevated melatonin levels (and consequently inhibited insulin response) that result from melatonin supplementation can linger for ten hours. This could interfere with appropriate insulin response during breakfast the next morning.

This means that if you have the diabetes risk allele, you might consider eating dinner early. And, if you supplement with melatonin, you may want to ensure that you take the supplement a couple of hours after your last meal.

Shift Work

Finally, carriers of the risk allele may be more vulnerable to the deleterious metabolic effects of shift work. Previous research has shown that nocturnal shift workers exhibit high post meal (postprandial) glucose responses; one might reasonably speculate that having this gene variant would only exacerbate this response.

Presently there is no research that specifically examines the impact of MTNR1B genotype on shift work, but until such studies are conducted, I think we can surmise that it would be best to avoid night shifts if you carry this risk variant, or be extra mindful of eating timing and melatonin supplementation.

How do you know whether or not you have this diabetes risk variant?

Fortunately, you don’t have to enroll in a study to find out your MTNR1B genotype. DNA analysis through 23andme can easily tell you your melatonin receptor genetics.

(I have no relationship with the company by the way – it’s just a handy tool)

Here’s how you figure it out, once you get your 23andme report:

At the home screen, look up at the right-hand corner and click on your name. You’ll see a drop-down menu under your name. Scroll down and select “browse raw data.”
You’ll be brought to a new page. In the middle of the page, you’ll a text box that says, “Jump to an SNP.”
In this text box, enter rs10830963, and press “Go.”
You should see another page now that displays chromosome 11 (where this polymorphism is situated). Below it, you will see MTNR1B, and your genotype.
If you have GG, you have the at-risk genotype – and are consequently more sensitive to the effects of melatonin on blood sugar regulation.

6 Key Takeaways

Melatonin binds to receptors on pancreatic cells to suppress insulin secretion. This occurs in order to keep blood glucose levels steady during the overnight fast.
Approximately 30% of people carry a variant in the MTNR1B gene which causes them to exhibit greater melatonin signaling in pancreatic islet cells.
This causes them to be more sensitive to the effects of melatonin, which results in an exaggerated inhibition of insulin secretion. That makes their bodies less effective at regulating blood sugar levels.
These individuals experience higher blood glucose levels over the course of the day, and insulin does not respond as quickly after a meal to get blood sugar levels back to normal.
Epidemiological evidence suggests that people with this trait, subjected to periods of elevated blood sugar levels, may be at greater risk of developing type 2 diabetes.
You can’t control whether or not you were born with this particular genetic predisposition. However, there are some relevant lifestyle factors that you may want to consider if you have the risk variant and want to minimize its negative impact:

Avoid melatonin supplementation, especially in doses significantly greater than ~0.3-0.5mg. You can find a bottle of 0.3 mg tablets super cheap right here.
Avoid eating when melatonin levels are high (i.e. late in the evening or whenever you might be exposed to exogenous melatonin via supplementation)
Avoid working night shifts (if possible).

References

Mühlbauer E, Gross E, Labucay K, Wolgast S, Peschke E. Loss of melatonin signaling and its impact on circadian rhythms in mouse organs regulating blood glucose. 2009. European Journal of Pharmacology 606(1-3):61-71.

Picinato MC, Haber EP, Carpinelli AR, Cipolla-Neto J. Daily rhythm of glucose-induced insulin secretion by isolated islets from intact and pinealectomized rat. 2002. Journal of Pineal Research 33(3):172-7.Lyssenko V, Nagorny CL, Erdos MR, Wierup N, et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. 2009. Nature Genetics 41(1):82-8.

Tuomi T, Nagorny CL, Singh P, Bennet H, et al. Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes. 2016. Cell Metabolism doi: 10.1016/j.cmet.2016.04.009.

Gooneratne NS, Edwards AY, Zhou C, Cuellar N, Grandner MA, Barrett JS. Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults. 2012. Journal of Pineal Research 52(4):437-445.

Nakajima K, Suwa K. Association of hyperglycemia in a general Japanese population with late-night-dinner eating alone, but not breakfast skipping alone. 2015. Journal of Diabetes & Metabolic Disorders 14:16.

Sato M, Nakamura K, Ogata H, Miyashita A, et al. Acute effect of late evening meal on diurnal variation of blood glucose and energy metabolism. 2011. Obesity Research and Clinical Practice 5(3):e169-266.

Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. 2009. Proceedings of the National Academy of Science of the United States of America 106(11):4453-8.