Melatonin Receptors Involvement In The Regulation Of Glucose Metabolism
Figure 2. Loss of MT2 does not induce systemic insulin resistance in male mice. Hyperinsulinemic-euglycemic clamp in awake mice. Glucose infusion rate was not different between WT and MT2 KO mice, whereas hepatic glucose production was significantly lower in MT2 KO mice. However, since negative HGP rates are not physiologically possible, the values observed in MT2 KO mice likely arise from a slight underestimation of glucose disposal rates. Insulin-stimulated glucose uptake in skeletal muscle and white adipose tissue is higher in MT2 KO with respect to WT and MT1 KO. Whole body glycolysis and glycogen synthesis. Glycolysis was lower in MT2 KO mice while glycogen synthesis was not different between MT2 KO and WT. Taken together these data suggest that while male MT1KO mice show systemic insulin resistance with respect to WT, MT2 KO do not exhibit insulin resistance. Results are expressed as mean ± SEM . Hyperinsulinemic-euglycemic clamp was performed as described in Owino et al. .
It is worth noting that a series of recent studies have reported that melatonin synthesis occurs in the mitochondria of neurons where MT1 receptors are also present . Since mitochondria are key regulators of cellular metabolism, it would be interesting to see how dysfunction of melatonin synthesis and signaling within the mitochondria may contribute to the regulation of energy metabolism and expenditure.
How Do Variants Of Your Mtnr1b Gene Affect Insulin Secretion
Your MTNR1B gene codes for your MT1B melatonin receptor, which is found on the surface of beta cells in your pancreas. When melatonin binds to this receptor, it inhibits the release of insulin into the bloodstream.
Different variants of your MTNR1B gene affect how many MT1B melatonin receptors your beta cells produce . In turn, this alters the extent to which insulin release is suppressed by melatonin.
One allele of the MTNR1B gene, the G allele*, increases the amount of MT1B receptors expressed on the surface of your pancreatic beta cells. As a result, carriers of the G allele are more responsive to the effects of melatonin.
When melatonin binds to these greater number of receptors, it more strongly inhibits the secretion of insulin. Consequently, people with one or more copies of the G allele have lower circulating levels of insulin during night time.
* – the G allele that results from one particular variation , rs10830963, of the MTNR1B gene.
KEY POINTS
How To Increase Melatonin Levels Naturally
You can increase your melatonin levels without supplementing.
A few hours before bedtime, dim all lights at home and avoid watching TV and using your computer or smartphone.
Too much artificial light can reduce the production of melatonin in your brain, making it harder for you to fall asleep .
You can also strengthen your sleep-wake cycle by exposing yourself to plenty of natural light during the day, especially in the morning (
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The Role Of Melatonin In Diabetes: Therapeutic Implications
Melatonin referred as the hormone of darkness is mainly secreted by pineal gland, its levels being elevated during night and low during the day. The effects of melatonin on insulin secretion are mediated through the melatonin receptors . It decreases insulin secretion by inhibiting cAMP and cGMP pathways but activates the phospholipaseC/IP3 pathway, which mobilizes Ca2+from organelles and, consequently increases insulin secretion. Both in vivo and in vitro, insulin secretion by the pancreatic islets in a circadian manner, is due to the melatonin action on the melatonin receptors inducing a phase shift in the cells. Melatonin may be involved in the genesis of diabetes as a reduction in melatonin levels and a functional interrelationship between melatonin and insulin was observed in diabetic patients. Evidences from experimental studies proved that melatonin induces production of insulin growth factor and promotes insulin receptor tyrosine phosphorylation. The disturbance of internal circadian system induces glucose intolerance and insulin resistance, which could be restored by melatonin supplementation. Therefore, the presence of melatonin receptors on human pancreatic islets may have an impact on pharmacotherapy of type 2 diabetes. Key words: Melatonin diabetes insulin beta cells calcium circadian rhythmContinue reading > >
Why Can Keto Cause Higher Fasting Glucose
First, some people get more insulin resistance with a higher fat diet, and this is highly dependent on genetics. People can have genetic variants that are more susceptible to high fat diets.
But I want to dive into one specific factor.
Lower carb diets may cause some insulin resistance as a result of lower melatonin.
Carbs are important for increasing serotonin, and serotonin is what the body uses to create melatonin.
Melatonin is useful for blood glucose balance and insulin sensitivity .
If you have a certain genetic variant in the melatonin gene , you can be even more affected.
Check out your own results for this SNP variation here if you have uploaded your DNA file to a SelfDecode account. I have one of the negative genetic variants, which interferes with melatonin binding to its receptor and results in higher fasting glucose and risk of diabetes .
If youre doing a low carb diet or having blood sugar regulation issues, you should check out this gene.
You should also take a look at your CLOCK gene which has established relationships with both your Circadian Rhythm Cycle and your Insulin levels. You can read about the CLOCK gene and ways to improve both your sleep and blood sugar levels in this SelfDecode Blog Post.
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Insomnia And Intermittent Fasting Why It Happens
Sleep quality and intermittent fasting is a controversial topic. Why? Because youll probably find as many people who say fasting helped them sleep better as those who say it gave them insomnia. Studies are equally contradictory. Youll find research that says fasting regulates the circadian rhythm and research that says the opposite. In other words, were all different, and we have different ways of reacting to fasting.
If youre looking at an article about melatonin, chances are youre in the group that experiences poor sleep due to fasting. This usually happens because your body perceives the abstinence from food as high stress, and it begins making more cortisol. Cortisol is a hormone that keeps you on high alert, ready to fight for your life. Except, in this case, no fight is coming, and youre left with an excess of cortisol that leads to insomnia.
Melatonin helps your body wind down. It is a hormone that humans naturally produce in the evening after the sun sets and it gets dark. Sadly, with the technological advancements, were staring at computers all evening, spending time in artificial light, which means we produce less melatonin. Add to that an excess of cortisol caused by fasting and the results are disastrous.
Supplementing with melatonin can help you regain your natural sleep cycle. Without causing all the side effects of sleeping pills. But thats not the only way in which melatonin helps intermittent fasting.
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Researchers Conducted A Trial To Understand The Connection Between Disturbed Blood Sugar Level Control And The Timing Of Meals Relative To Sleep
Blood sugar level control, which is impaired in individuals with diabetes, is affected by various factors, including the timing of meals relative to sleep and melatonin levels, a hormone primarily released at night that helps control sleep-wake cycles.
Investigators at Massachusetts General Hospital , Brigham and Womens Hospital and the University of Murcia in Spain performed a clinical trial to connect blood sugar level control and meal timings.
Senior author, Richa Saxena, PhD, a principal investigator at the Center for Genomic Medicine at MGH, addressed the study: We decided to test if late eating that usually occurs with elevated melatonin levels results in disturbed blood sugar control.
The research was published in Diabetes Care.
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Taking Melatonin Supplements For Sleep Issues
While most people produce enough melatonin, some people could benefit from taking melatonin as a dietary supplement for short-term use. Taking melatonin may help you fall asleep more quickly and decrease the likelihood of waking up during the night.
If jet lag is an issue for you due to traveling across time zones, research suggests that melatonin supplements can help for reducing jet lag symptoms and improving sleep. Its also thought that melatonin might help shift workers, although results from two 2014 research reviews on whether melatonin supplements might help were inconclusive.
Sleep issues aside, some research indicates that melatonin supplements may improve fasting blood glucose level, hemoglobin A1C levels , and insulin resistance. Melatonin supplements show promise for other issues related to diabetes, according to a 2020 review published in the journal Diabetology & Metabolic Syndrome. The authors mention that melatonin lowers blood pressure, improves glycemic control, and may help prevent or treat complications of diabetes, including cardiomyopathy , retinopathy , wound healing, end-stage renal disease, and neuropathy . However, they state that human clinical trials are needed to demonstrate and support melatonins use for preventing and treating diabetes complications.
Melatonin And Diabetic Complications
As mentioned above, diabetes mellitus causes numerous micro- and macrovascular complications in affected patients. Melatonin is considered as an appropriate candidate for the prevention and treatment of diabetes mellitus complications. Here, we discuss about its therapeutic potentials for cardiomyopathy, retinopathy, central nervous system -related complications of diabetes, neuropathy, and nephropathy.
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Interplay Between Melatonin And Leptin
Leptin is an adipose-derived hormone that is released in a circadian manner by adipose tissue. Plasma leptin levels peak late within the dark cycle and subsequently decrease during the light cycle . Because of the circadian nature of melatonin’s secretionpeaking at nightmelatonin has been thought to be a circadian timing cue for leptin secretion. Indeed, melatonin has been shown to drive the daily rhythm of plasma leptin, and when it is absent the leptin rhythm is severely blunted in Syrian hamsters . Moreover, Buonfiglio et al. demonstrated that the long-term absence of circulating melatonin leads to impairments in leptin signaling and leptin resistance within the hypothalamus. Obese individuals have high levels of leptin, however due to leptin resistance their regulation of food intakeand consequently body weight regulationis impaired. Therefore, leptin resistance, which is induced either by pinealectomy or genetic removal of melatonin receptors, increases the expression of a number of orexigenic genes such as Agouti-related protein and Neuropeptide Y , which are modulated by leptin signaling.
Can Sleep Raise Or Lower Glucose Levels
Although it sounds contradictory, sleep can both raise and lower glucose levels. Our bodies experience a cycle of changes every daycalled a circadian rhythmwhich naturally raises blood sugar levels at night and when a person sleeps. These natural blood sugar elevations are not a cause for concern.
Restorative sleep might also lower unhealthy blood sugar levels by promoting healthy systems. levels. Even partial sleep deprivation over one night increases insulin resistance, which can in turn increase blood sugar levels. As a result, a lack of sleep has been associated with diabetes, a blood sugar disorder.
More research is needed to better understand the connection between sleep and blood sugar. So far, the following factors have been found to influence the relationship between sleep and blood sugar levels:
- Inflammatory markers IL-6 and TNF-alpha are increased by sleep deprivation and can cause insulin resistance, which impacts glucose
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Melatonin As A Regulator Of Metabolism And Body Weight
Within recent decades, a large number of animal studies using both pinealectomized rats and melatonin receptor knock out mice have begun to establish a rather unexpected role for melatonin in the regulation of glucose metabolism and energy balance. Early pinealectomy studies demonstrated that abolishing melatonin levels produces glucose intolerance and insulin resistance . Interestingly, reintroducing exogenous melatonin into this system restored metabolic parameters to levels observed within control animals. Similarly, in mice fed a high fat diet , exogenous melatonin administration was sufficient to restore diminished insulin sensitivity and glucose tolerance . Consequently, another study demonstrated that daily melatonin administration was sufficient to decrease the bodyweight gain of HFD fed rats by 54% compared to HFD rats not treated with melatonin .
Figure 1. Removal of MT1 alters the metabolic response of C3H mice to DIO. Male mice were fed ad libitum with a HFD from weaning at 4 weeks of age until 20 weeks of age. MT1 KO mice showed a small, but significant cumulative weight gain with respect to control . Fasting glucose levels were significantly higher in MT1 KO mice after 10 weeks of HFD. Data are presented as mean ± SEM *p< 0.05, **p< 0.01 WT vs. MT1 KO Two-Way ANOVA .
Previous studies have established a potential role for melatonin in the regulation of body fat by demonstrating that melatonin administration leads to a reduction in body fat content .
Is Melatonin Beneficial For T2d
Several lines of evidence support a beneficial role of melatonin in glucose tolerance, including human epidemiologic studies, clinical trials and genetic studies . Furthermore, prolonged melatonin treatment enhances post-exposure glucose-stimulated insulin secretion from cultured non-diabetic human islets . It has been also suggested melatonin stimulates both glucagon and insulin release from cultured human islets . Low urinary levels of the primary metabolite of melatonin, 6-sulfatoxy melatonin, have been prospectively associated with increased insulin resistance and risk of T2D . Also, in patients with T2D and insomnia, a significant decrease in glycated hemoglobin levels was found after a 5-month open label trial of repeated nighttime melatonin administration, although HbA1c levels were not affected in the preceding 3-week randomized, double blind, crossover trial . Moreover, a genetic study together with a recent functional genomics study has reported that rare coding variants in the melatonin receptor gene MTNR1B, that inhibit melatonin binding or signaling, are collectively associated with increased risk of T2D although recent well-powered analysis of coding variants from exome and genome sequencing studies do not support these initial findings .
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Melatonin: A Boost For Mitochondrial Biogenesis And Dynamics
Mitochondrial dynamics are crucial in T2D and its vascular complications. Mitochondrial dynamics involve fusion and fission processes critical for preserving essential cellular functions such as mitochondrial respiratory activity, mitochondrial DNA distribution, cell survival, apoptosis, or calcium signalling . Hyperglycemia in T2D increases ROS production leading to increased mitochondrial fragmentation and fission. Alteration in dynamics can lead to mitochondrial dysfunction, such as
Safety Of Melatonin Supplements
Short-term use of melatonin supplements appears to be safe, says the NCCIH, but there isnt enough information to support its long-term use, especially at doses higher than what the body normally produces.
If youre thinking about taking a melatonin supplement, the NCCIH states that its important to keep in mind the following:
- Melatonin might interact with some medicines, and if you take blood thinners or have epilepsy, you should be under medical supervision.
- Theres no research on the safety of using melatonin in pregnant or breastfeeding women.
- Melatonin shouldnt be used in people with dementia also, melatonin use in older people can cause daytime drowsiness.
- It may not be appropriate to take if you have an autoimmune disorder or depression.
- Melatonin in the U.S. is not regulated as strictly as an over-the-counter or prescription medicine.
- Some melatonin supplements may not contain whats listed on the label.
Melatonin can interact with other medicines, too, such as blood pressure medicine, diabetes medicines, contraceptives, and immunosuppressants. Always talk with your provider before taking melatonin to ensure that its safe for you.
Be aware of possible side effects from taking melatonin supplements. These include:
- Headache
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Melatonin And Energy Expenditure
In addition to the modulatory role of melatonin on energy intake, it seems that melatonin may also play an important role in modulating energy expenditure. In an experimental model of obesity and type 2 diabetes mellitus, using Zücker diabetic fatty rats, melatonin treatment induced browning of inguinal white adipose tissue and increased Brown adipose tissue weight with thermogenic properties . Buonfiglio et al. has demonstrated that pinealectomy decreased the amount of uncoupling protein 1 in BAT, thereby indicating lower thermogenic activity after cold exposure . Tan et al. suggested that there is a correlation between light exposure at night and bodyweight gain in humans, and if melatonin recruits BAT in humansas it does in other speciesindividuals who have their endogenous melatonin decreased by experiencing long daily photoperiods should have less functional BAT and may gain more bodyweight.
Eating Dinner Late Ups Diabetes Risk Melatonin Involved
Eating dinner close to bedtime when endogenous melatonin levels are high is associated with decreased insulin secretion and decreased glucose tolerance, which increase the risk of type 2 diabetes.
And people who are carriers of the G allele of the melatonin receptor-1b gene have greater impairment in glucose tolerance after eating a late dinner.
“In natural late eaters , we simulated early and late dinner timing by administering a glucose drink and compared effects on blood sugar control over 2 hours,” said senior author Richa Saxena, PhD, a principal investigator at the Center for Genomic Medicine at Massachusetts General Hospital, Boston.
The study also compared outcomes in carriers and noncarriers of the G allele variant of the melatonin receptor gene, Saxena pointed out, in a press release from the hospital.
“We found that late eating disturbed blood sugar control in the whole group,” added lead author Marta Garaulet, PhD.
“This impaired glucose control was predominantly seen in genetic risk variant carriers, representing about half of the cohort,” said Garaulet, professor of physiology and nutrition, University of Murcia, Spain.
The study results “may be important in the effort towards prevention of type 2 diabetes,” according to co-senior author Frank A.J.L. Scheer, PhD.
The results suggest people should not eat within 2 hours of bedtime, say the researchers.
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