TomBAvoider Posted May 13, 2016 Report Share Posted May 13, 2016 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: Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes Tiinamaija Tuomi1, 2, 3, 4, 12, Cecilia L.F. Nagorny5, 12, Pratibha Singh5, 12, Hedvig Bennet6, Qian Yu7, Ida Alenkvist7, Bo Isomaa2, 4, 8, Bjarne Östman2, Johan Söderström2, 4, Anu-Katriina Pesonen9, Silja Martikainen9, Katri Räikkönen9, Tom Forsén2, Liisa Hakaste1, 2, 3, Peter Almgren9, 10, Petter Storm10, Olof Asplund10, Liliya Shcherbina11, Malin Fex6, João Fadista10, Anders Tengholm7, Nils Wierup11, Leif Groop4,10, 13, Hindrik Mulder5, 13, doi:10.1016/j.cmet.2016.04.009 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 SummaryType 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: https://www.sciencedaily.com/releases/2016/05/160512124913.htm Background: PMID: 19060908 (full free text available) Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Lyssenko V1, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spégel P, Bugliani M, Saxena R, Fex M, Pulizzi N, Isomaa B, Tuomi T, Nilsson P, Kuusisto J,Tuomilehto J, Boehnke M, Altshuler D, Sundler F, Eriksson JG, Jackson AU, Laakso M, Marchetti P, Watanabe RM, Mulder H, Groop L. Author information 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 levelsFirst, 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. Koeck T1, Olsson AH, Nitert MD, Sharoyko VV, Ladenvall C, Kotova O, Reiling E, Rönn T, Parikh H, Taneera J, Eriksson JG, Metodiev MD, Larsson NG,Balhuizen A, Luthman H, Stančáková A, Kuusisto J, Laakso M, Poulsen P, Vaag A, Groop L, Lyssenko V, Mulder H, Ling C. Author information 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 Link to comment Share on other sites More sharing options...
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