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TomBAvoider

Insulin - Melatonin - Glucagon axis genetic risk profiles

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Circadian rhythms - the pancreas releases less insulin, insulin levels drop while we are asleep, presumably because the organism evolved not needing to digest food as much while one is asleep. The drop in insulin is mediated by melatonin (melatonin causes the pancreas to release less insulin) - since there is a natural circadian cycle to the peaks and valleys of melatonin released during day/night. Generally, we don't want too much insulin circulating for long (as it's strongly connected with cancer), but we do want it timed to have enough to break down the sugars post-meal, so we don't have elevated BG circulating too long. However, it's easy to see how melatonin release cycle might be mismatched with food/blood sugar for people with atypical sleeping patterns (maybe one reason for elevated cancer in night shift workers?) - and that includes those atypical sleepers who, say, f.ex. go to bed around 8 pm and get up around 2-3 am. Now it transpires that different people are affected by melatonin's signalling differently "up to 30 percent of the population may be predisposed to have a pancreas that's more sensitive to the insulin-inhibiting effects of melatonin. People with this increased sensitivity carry a slightly altered melatonin receptor gene that is a known risk factor for type 2 diabetes." We are talking about rs10830963 and the risk allele is G (fwiw, mine is CG according to 23andme). In any case, during the night another hormone is released - glucagon, which elevates the levels of BG in the absence of food, which if you combine with now insufficient insulin results in higher BG upon awakening... and if you have a fasting BG test first thing in the morning, you as the carrier of G might then show elevated BC levels. The effect is so strong that it might lead to type 2 diabetes. Incidentally, some CR'd folks have odd BG levels, I wonder if it's not due to being G carriers (30% of the population makes this a very popular case). The other interesting thing is that given how popular melatonin supplements are, researchers caution that regular melatonin supplementation can cause some serious diabetes problems down the road - and they actually tested that hypothesis and confirmed that part of it (i.e. indicating caution wrt. melatonin supplementation). If you know your status (through 23andme or otherwise), you can ponder the insulin-cancer-glucagon-diabetes-melatonin axis and adjust your food and sleeping patterns if so inclined. Here in Cell Metabolism:

 

Highlights

 

rs10830963 is an eQTL in human islets conferring increased MTNR1B mRNA expression

Melatonin inhibits cAMP rises in mouse islets and clonal insulin-secreting cells

Melatonin blocks insulin release in mouse islets and clonal insulin-secreting cells

Melatonin’s inhibition of insulin release is stronger in risk allele carriers

 

Summary

Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increasedMTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.

 
There's also a pop writeup:
 
 
Background:

 

PMID: 19060908 (full free text available)

 

Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
 
Abstract

 

Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.

 

The key point I'm citing is:

 

"A variant in the MTNR1B gene increases future risk of T2D and is associated with increased fasting glucose levels

First, we studied whether the MTNR1B rs10830963 SNP predicts future T2D in 16,061 Swedish (from the Malmoe Preventive Project, MPP) and 2,770 Finnish (from the Botnia study) subjects, 2,201 (2063/138) of whom developed diabetes during 400,000 follow-up years (Table 1). The frequency of the risk G-allele of SNP rs10830963 was higher in individuals from the MPP study who converted to T2D compared to non-converters (30.2% vs 28.0%, P=0.002). This yielded a modestly increased risk of 1.12 (95%CI 1.04–1.20, P=0.002). There was no significant difference between converters and non-converters in the Botnia study, but here only 138 individuals developed T2D during a 7 year follow-up period (31.0% vs 29.3%; OR 1.09, 95%CI 0.82–1.43, P=0.56). In the combined analysis of the two cohorts, the risk allele was associated with a 1.11-fold increased risk of future T2D (95% CI 1.03–1.18, P=0.004). This relatively modest risk for future T2D probably explains why this SNP was not identified as being associated with T2D in previous GWAS (OR 1.12 (95% CI 1.04– 1.20), P=0.003 in DIAGRAM). However, the effect on glucose levels seems much stronger; in non-diabetic individuals from the MPP study, risk G-allele carriers displayed a higher fasting plasma glucose concentration at baseline (CC: 5.38±0.54 mmol/l, CG: 5.44±0.55 mmol/l, GG 5.50±0.55 mmol/l, P=3×10−19), which remained elevated throughout the 25-year follow-up period (CC: 5.41±0.54 mmol/l, CG: 5.49±0.54 mmol/l, GG 5.55±0.54 mmol/l, P=2×10−31) (Figure 1E)."

 

The other interesting study is this:
 
PMID: 21195351 (full free text available)
 
A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.
 
Abstract

 

Type 2 diabetes (T2D) evolves when insulin secretion fails. Insulin release from the pancreatic β cell is controlled by mitochondrial metabolism, which translates fluctuations in blood glucose into metabolic coupling signals. We identified a common variant (rs950994) in the human transcription factor B1 mitochondrial (TFB1M) gene associated with reduced insulin secretion, elevated postprandial glucose levels, and future risk of T2D. Because islet TFB1M mRNA levels were lower in carriers of the risk allele and correlated with insulin secretion, we examined mice heterozygous for Tfb1m deficiency. These mice displayed lower expression of TFB1M in islets and impaired mitochondrial function and released less insulin in response to glucose in vivo and in vitro. Reducing TFB1M mRNA and protein in clonal β cells by RNA interference impaired complexes of the mitochondrial oxidative phosphorylation system. Consequently, nutrient-stimulated ATP generation was reduced, leading to perturbed insulin secretion. We conclude that a deficiency in TFB1M and impaired mitochondrial function contribute to the pathogenesis of T2D.

 

Here are talking about rs950994 and the risk allele is A (available to check through 23andme - fwiw, mine is GG

 

 
 

 

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Thanks Tom - very interesting group of papers!

 

Generally, we don't want too much insulin circulating for long (as it's strongly connected with cancer), but we do want it timed to have enough to break down the sugars post-meal, so we don't have elevated BG circulating too long. However, it's easy to see how melatonin release cycle might be mismatched with food/blood sugar for people with atypical sleeping patterns (maybe one reason for elevated cancer in night shift workers?) - and that includes those atypical sleepers who, say, f.ex. go to bed around 8 pm and get up around 2-3 am. 

 

Boy, I wonder who you might be referring to in that last statement...☺ 

 

I agree with you that an odd sleep pattern (e.g. shift workers) coupled with eating at times that don't align well with the melatonin / insulin circadian rhythm could be bad news for glucose control and risk of diabetes. That's why I'm a strong advocate for eating one's calories early in the day (when insulin sensitivity is highest [1]), and leaving a long period between one's last meal and bedtime.

 

Despite the fact that I go to bed at 8pm, by that time of night (or day - depending on your perspective...), I've been fasting for 12+ hours. So while I totally agree with the first part of your statement (i.e. "we do want it [insulin production capacity] timed to have enough to break down the sugars post-meal, so we don't have elevated BG circulating too long."), the problem of such timing seems irrelevant to my situation, since I've aligned my eating pattern with my sleep pattern to a greater degree than virtually anyone else on the planet .

 

BTW, 23andMe says I've got the same profile as you for the two SNPs involved - I'm CG for rs10830963 and GG for rs950994. 

 

Regarding the particular study of melatonin, insulin and glucose you posted, if you read the full text the results look rather equivocal. In fact I'm really confused where the authors came up with the title of their paper "Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes" based on their own data reported in this paper. Perhaps they wanted headlines...

 

In particular, in the human part of their study, they gave rs10830963 purebreed folks (i.e. CC or GG, not mutts like you and me with CG) 4mg/day of melatonin for 3 months and then tested their post-meal glucose, insulin and insulin sensitivity. Here are the graphs of the results before (left) and after (right) the melatonin treatment:

 

N50eREX.png

 

As you can see from A, at baseline the risk allele folks (GG) had higher postprandial glucose spikes than the CC folks. But 3 months of melatonin didn't make much difference in this relationship or the post-meal glucose levels of either group (graph B). From graphs C and E, it appears the reason for the higher post-meal glucose spike in the GG folks at baseline was lesser & later release of glucose-clearing insulin. After three months of melatonin supplements, the early post-meal insulin release in both the CC and GG folks went down (graph E), but their insulin sensitivity went up (graph F) to compensate. As a result, the post-meal glucose spike and amount of insulin released was virtually unchanged for both CC and GG folks after 3 months of melatonin (A vs B and C vs D). 

 

So what exactly is the concern Tom?

 

Sure, it appears to be a mixed blessing to be a carrier of the G allele for this SNP - reducing insulin exposure on the one hand (a good thing) but increasing the postprandial glucose spike on the other (a bad thing). But regarding melatonin supplements, if anything it appears from the human data that both the CC and GG folks people achieved the same glucose control using less insulin (i.e. exhibited greater insulin sensitivity) after three months on melatonin. As you mentioned, keeping insulin levels low is good for cancer and a host of other health-related effects, as long as it doesn't result in increased glucose levels, which appears to be the case with melatonin supplements at least based on this study.

 

The second study you posted (PMID 19060908) followed 16K Swedes for 25 years to see how diabetes risk varied with whether or not they were carriers of the risky G allele for this same SNP (rs10830963). It appears the G folks were a bit more likely to become diabetic, but only very modestly so (~12% greater risk in this population, but no statistically significant increased risk in two other studies the authors cite). And this is in people who were likely eating a pretty crappy diet, so it's relevance and significance for us is even more dubious. Yes, as you point out, the G carriers had higher fasting glucose, but likely as a result of having lower fasting insulin. So pick your poison.

 

In short, the fact that the G carriers had only a very modestly higher risk of diabetes in this one study (and no higher risk in several others), makes it appear the so-called "insulin-cancer-glucagon-diabetes-melatonin axis" is pretty tenuous, at least the part of it involving melatonin signalling. 

 

I personally don't take melatonin myself - I'm sleeping like a baby lately. But if I needed to, I wouldn't lose sleep over taking melatonin to avoid losing sleep based on this data.

 

Am I missing something?

 

--Dean 

 

 

-------

[1] Diabetologia December 1969, Volume 5, Issue 6, pp 397-404

 
Circadian variations of blood sugar and plasma insulin levels in man
 
C. Malherbe, M. de Gasparo, R. de Hertogh, J. J. Hoem
 
Summary
 
Blood sugar, plasma insulin, non-esterified fatty acids (NEFA), plasma cortisol, and urinary catecholamines were measured for 24 h in seven normal subjects receiving a standard diet. During the night, blood sugar and plasma insulin remained low, NEFA decreased progressively, and the excretion of catecholamines diminished. During the day, the insulin response appeared particularly important after the morning meal. This last observation was also made when normal subjects were given three identical meals at intervals of four and a half hours. Under these conditions, the postprandial elevations of blood sugar were not statistically different, but the plasma insulin rose significantly higher after the morning meal. These observations may be explained by the existence of a periodicity which would regulate the insulin secretion. It is also possible that the insulin liberated postprandially conserves a certain activity at the moment of the next meal, and still intervenes in the maintaining of blood sugar homeostasis. Later in the day, however, blood sugar homeostasis would necessitate a new synthesis of insulin, which would explain the delayed plasma insulin response to the evening meal.
 
Key-words
Plasma insulin blood sugar non-esterified fatty acids urinary catecholamines circadian variations meals

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First of all, yes, if you are a risk allele carrier, indeed, you would benefit from keeping your meals well away from peak melatonin - in practical terms (unless you're a shift worker), this means "don't have late dinners", and don't snack in the evening. So you are in the clear :) - but this might be good info for those who have a different pattern (say, the Spanish who love late dinners that start 10.00 pm and later).

 

Re: differences - I do see some difference in those graphs. As to how meaningful those differences are, I can't tell, maybe someone studying diabetes could say "this amount of extra time BC is circulating will eventually lead to problems" - but as the authors hinted in the paper, this is just one of many things that go wrong when you develop DMT2, it is one factor, not the only factor, and perhaps not even the most important.

 

I just thought this might be interesting info here, because generally we're obsessed by insulin-glucose, and some of us have considered melatonin. I personally have considered it too, but there is still too little we know for me to take melatonin regularly. 

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I'm CC for rs10830963 and my Hemoglobin A1c is 4.1. But I attribute that low number (if it's even a relevant number to this conversation) to a vegan diet, a silly crazy active lifestyle, and to not one simple gene. I've been flirting with the idea of eating my one and only daily meal in the evening, say, a few hours before zzzz. But now I don't know. My reasoning for eating in the pm might be because anecdotally I feel sleepy after feasting like nutrition royalty. So perhaps giving my body the time and space it wants to digest the feast is smart. By resting after pigging out, do I donate more blood to the digestion process, as we hippies might say? Spend resources digesting all those greens, onions, beans, broccoli sprouts and all of the feast (rather than devoting full bellied energy to running around leaping during daylight hours) is a good idea? Eat, rest, dream?

 

Since we've no playbooks to guide our choreographies through the mess of life -- how best to eat, what best to eat, when best to move, when best to stop -- it seems intuitive to eat, then rest. Follow the body: listen with inward wisdom that borders on sounding woo. And although I've read -- no no no this is wrong, Sthira, you should eat, then go burn off that feast in order to keep BG down low -- this advice doesn't feel maternally inspired to me. No swimming until an hour after lunch, my mom wags her sunburned hand. Is mom wrong? My hba1c hints nope mom might be right: eat, then relax, take rest, go siesta. But eat one big meal, then go to nightly sleep a few hours later? I dunno. What's Watson have to tell us?

Edited by Sthira

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Not sure where to post this, but since Time Restricted Feeding was discussed here this is probably ok. A new Dr. Rhonda Patrick interview, this time with Dr. Satchin Panda, an expert on TRF:

 

https://www.youtube.com/watch?v=-R-eqJDQ2nU

 

The first half hour or so is kind of intro fluff. Around 56 minutes he talks about a very recent finding in past few weeks that melatonin receptors have been found on pancreatic beta islet cells, and when these receptors are triggered they inhibit insulin secretion... leading to the well known differences in day/night insulin sensitivity.

 

There was a very brief BAT mention in the video, but no significant time spent on that during this interview.

 

Dr. Panda is using an app to gather crowdsourced TRF data, you can participate at www.mycircadianclock.org

 

In the last 10 minutes he talks a bit about another TRF finding which is that the bacteria types/quantities in your gut microbiome actually change through the day on their own daily cycle. And a brief mention of how TRF modifies uptake of simple carbs, and bile acids.

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BrianA,

 

I finally got around to listening to the Rhonda Patrick interview with Dr. Panda on the benefits of time restricted feeding (TRF). Fascinating stuff. I too especially liked the apparently recently uncovered link between melatonin and insulin secretion (i.e. melatonin blocks insulin production by the pancreas). 

 

Dr. Panda's website (http://www.mycircadianclock.org/) and is iPhone/Android app, by which random people like us can participate in a "citizen science" study of TRF by simply taking a picture of what we eat (w/ timestamp for when) is really cool!

 

Thanks for bringing it to our attention. I've embedded the interview below.

 

--Dean

 

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I used the MyCircadianClock app for several months and even had some interaction with its developers.  It's a nice way to track sleep and tRF patterns as well as BG & BMI.  The Android version had quite a few bugs, they fixed many of them but eventually I had to remove the app because it was never freeing up its internal memory usage, every time you take a pic of the food you are eating the app was using more memory.  Maybe they have since fixed that, I don't know.  Reinstalling the app temporarily fixes the problem but that got annoying after a while. There are a bunch of popular press articles explaining these researchers' findings and how the app has been used to help some typical Americans who were eating pretty much around the clock.

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