Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial

<strong>Objective: </strong>We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes-associated G allele in the melatonin-receptor-1-b gene (<i>MTNR1B</i>).<strong> </strong> <p><strong>Research Design and Methods:</strong> In a Spanish natural late eating population, a randomized, cross-over study design was performed, following an 8-h fast. Each participant <strong>(n=845) </strong>underwent two evening 2-h 75g oral glucose tolerance tests (OGTT): an early condition scheduled 4 hours prior to habitual bedtime <strong>(“early dinner-timing”)</strong>, and a late condition scheduled 1 hour prior to habitual bedtime <strong>(“late dinner-timing”)</strong>, simulating an early and a late dinner timing, respectively.<strong> </strong>Differences in postprandial glucose and insulin responses were determined using incremental area under the curve (AUC) calculated by the trapezoidal method between <strong>early and late dinner-timing.</strong><strong></strong></p> <p><strong>Results:</strong> <strong>Melatonin serum levels were </strong>3.5-fold <strong>higher in the late <i>vs. </i>early condition, with late dinner-timing resulting in </strong>6.7% <strong>lower insulin</strong> <strong>area-under-the-curve (AUC) and </strong>8.3%<strong> higher glucose</strong> <strong>AUC. In the late condition<i> MTNR1B</i> G-allele carriers had lower glucose tolerance than non-carriers. Genotype differences in glucose tolerance were attributed to reductions in </strong>β-cell <strong>function (<i>P_int</i>AUCgluc=0.009, <i>P_int</i>CIR=0.022, <i>P_int</i>DI=0.018).</strong></p> <p><strong>Conclusions:</strong> <strong>Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impair glucose tolerance, especially in <i>MTNR1B</i> G-risk-allele carriers<i>, </i>attributable to insulin secretion defects.</strong></p>

Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial

<strong>Objective: </strong>We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes-associated G allele in the melatonin-receptor-1-b gene (<i>MTNR1B</i>).<strong> </strong> <p><strong>Research Design and Methods:</strong> In a Spanish natural late eating population, a randomized, cross-over study design was performed, following an 8-h fast. Each participant <strong>(n=845) </strong>underwent two evening 2-h 75g oral glucose tolerance tests (OGTT): an early condition scheduled 4 hours prior to habitual bedtime <strong>(“early dinner-timing”)</strong>, and a late condition scheduled 1 hour prior to habitual bedtime <strong>(“late dinner-timing”)</strong>, simulating an early and a late dinner timing, respectively.<strong> </strong>Differences in postprandial glucose and insulin responses were determined using incremental area under the curve (AUC) calculated by the trapezoidal method between <strong>early and late dinner-timing.</strong><strong></strong></p> <p><strong>Results:</strong> <strong>Melatonin serum levels were </strong>3.5-fold <strong>higher in the late <i>vs. </i>early condition, with late dinner-timing resulting in </strong>6.7% <strong>lower insulin</strong> <strong>area-under-the-curve (AUC) and </strong>8.3%<strong> higher glucose</strong> <strong>AUC. In the late condition<i> MTNR1B</i> G-allele carriers had lower glucose tolerance than non-carriers. Genotype differences in glucose tolerance were attributed to reductions in </strong>β-cell <strong>function (<i>P_int</i>AUCgluc=0.009, <i>P_int</i>CIR=0.022, <i>P_int</i>DI=0.018).</strong></p> <p><strong>Conclusions:</strong> <strong>Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impair glucose tolerance, especially in <i>MTNR1B</i> G-risk-allele carriers<i>, </i>attributable to insulin secretion defects.</strong></p>

Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial

OBJECTIVE We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes–associated G allele in the melatonin receptor-1b gene (MTNR1B). RESEARCH DESIGN AND METHODS In a Spanish natural late-eating population, a randomized, crossover study was performed. Each participant (n = 845) underwent two evening 2-h 75-g oral glucose tolerance tests following an 8-h fast: an early condition scheduled 4 h prior to habitual bedtime (“early dinner timing”) and a late condition scheduled 1 h prior to habitual bedtime (“late dinner timing”), simulating an early and a late dinner timing, respectively. Differences in postprandial glucose and insulin responsesbetween early and late dinner timing were determined using incremental area under the curve (AUC) calculated by the trapezoidal method. RESULTS Melatonin serum levels were 3.5-fold higher in the late versus early condition, with late dinner timing resulting in 6.7% lower insulin AUC and 8.3% higher glucose AUC. In the late condition, MTNR1B G-allele carriers had lower glucose tolerance than noncarriers. Genotype differences in glucose tolerance were attributed to reductions in β-cell function (P for interaction, Pint glucose area under the curve = 0.009, Pint corrected insulin response = 0.022, and Pint Disposition Index = 0.018). CONCLUSIONS Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impairs glucose tolerance, especially in MTNR1B G-risk allele carriers, attributable to insulin secretion defects.

“Endogenous Melatonin Concentration Along with the Expression of Mitochondrial Regulator Genes is Elevated by the Serum Shock Process in the U87-MG Cell Line”

According to the World Health Organization, glioblastoma, also known as the fourth grade in the development of astrocytoma, is a glial tumor limited to the central nervous system with a strong ability to invade the brain parenchyma. Melatonin can be generated outside of the pineal gland tissue, according to new research. Melatonin is produced by mitochondria independently but in concert with cell demands, and it plays an important function in cell cycle and metabolism regulation. As a result, we set out to investigate the association between cell metabolism and the serum shock-induced increase in endogenous melatonin, as well as the percentage of cell proliferation.Background: Melatonin can be produced in the mitochondria organelle of glioblastoma cells without the involvement of the pineal gland, according to new research. Regarding the physiological function of melatonin secreted by the pineal gland in the regulation of rhythmicity, the goal of this study was to see if the glioblastoma cell's melatonin production ability could be influenced using a typical serum shock technique established for cellular rhythm regulator.Material and methods: First, U87-MG glioblastoma cells were cultured in a DMEM medium containing 10% FBS and then cells were treated with a standard serum shock process (no FBS, 8h). The concentration of melatonin was measured using ELISA method in supernatant and cell extracts of Shock and control groups. The cell proliferation was measured by using BrdU staining and flow cytometry assessment. The gene expression levels of some mitochondria or circadian related genes including TFAM, BMAL1, PPARGC1A(PGC1-α), and DNM1L(DRP1) were measured, using qRT-PCR method.Results: In comparison to the control group, serum shock treated U87-MG glioblastoma cells had higher concentrations of cellular and released endogenous melatonin (two times). At the mRNA level, we discovered considerable upregulation of mitochondrial or circadian regulator genes (TFAM, BMAL1, PPARGC1A, and DNM1L); in the shock group compared to the control group (P <0.0002). Furthermore, although the percentage of proliferative cells (Brdu positive) was higher in the shock group, it was not statistically significant.Conclusion: The serum shock procedure has a significant impact on the U87-MG cell line's cellular activity. In terms of the study's findings, it's worth noting that an increase in endogenous melatonin concentration influences several signaling pathways within the U87-MG cell line, as seen by the increased expression of candidate genes.In light of the findings of this study, it's worth noting that further research into the role of endogenous melatonin and its effects on cancer cells is critical, and that comparing the results of normal and cancer cells can reveal the hotspots of the signaling pathways involved, which could facilitate in better understanding the biology of glioblastoma.

Melatonin Participates in Selenium-Enhanced Cold Tolerance of Cucumber Seedlings

Melatonin is an important and widespread plant hormone. However, the underlying physiological and molecular mechanisms of melatonin as a secondary messenger in improving cold tolerance by selenium are limited. This study investigated the effects of selenite on the cold stress of cucumber seedlings. The results showed that exogenous application of selenite improved the cold tolerance of cucumber seedlings, which was dependent on the concentration effect. In the present experiment, 1 μM of selenite showed the best effect on alleviating cold stress. Interestingly, we found that in the process of alleviating cold stress, selenite increased the content of endogenous melatonin by regulating the expression of melatonin biosynthesis genes (TDC, T5H, SNAT, and COMT). To determine the interrelation between selenite and melatonin in alleviating cold stress, melatonin synthesis inhibitor p-chlorophenylalanine and melatonin were used for in-depth study. This study provides a theoretical basis for cucumber cultivation and breeding.

Phenylalanine 4-Hydroxylase Contributes to Endophytic Bacterium Pseudomonas fluorescens’ Melatonin Biosynthesis

Melatonin acts both as an antioxidant and as a growth regulatory substance in plants. Pseudomonas fluorescens endophytic bacterium has been shown to produce melatonin and increase plant resistance to abiotic stressors through increasing endogenous melatonin. However, in bacteria, genes are still not known to be melatonin-related. Here, we reported that the bacterial phenylalanine 4-hydroxylase (PAH) may be involved in the 5-hydroxytryptophan (5-HTP) biosynthesis and further influenced the subsequent production of melatonin in P. fluorescens. The purified PAH protein of P. fluorescens not only hydroxylated phenylalanine but also exhibited l-tryptophan (l-Trp) hydroxylase activity by converting l-Trp to 5-HTP in vitro. However, bacterial PAH displayed lower activity and affinity for l-Trp than l-phenylalanine. Notably, the PAH deletion of P. fluorescens blocked melatonin production by causing a significant decline in 5-HTP levels and thus decreased the resistance to abiotic stress. Overall, this study revealed a possible role for bacterial PAH in controlling 5-HTP and melatonin biosynthesis in bacteria, and expanded the current knowledge of melatonin production in microorganisms.

Endogenous Melatonin Concentration Along With the Expression of Mitochondrial Regulator Genes Is Elevated by the Serum Shock Process in the U87-MG Cell Line

Glioblastoma, also known as the fourth grade in the development of astrocytoma according to the World Health Organization, is a tumor in the glial region confined to the central nervous system with high invasion capability to the parenchyma of the brain. Recent findings suggest that melatonin can be synthesized outside the pineal gland tissue. Mitochondria can produce melatonin independently but in coordination with cell demands which plays a critical role in regulating the cell cycle and cell metabolism. hence, we aimed to examine the relationship between cell metabolism and the induction of endogenous melatonin increase induced by the serum shock process, then, determine the percentage of cell proliferation.Background: glioblastoma is a highly invasive tumor of glial cell of brain tissue. Recently it was reported that melatonin can be produced in mitochondria organelle of the glioblastoma cells independent to pineal gland. Regarding the physiological function of melatonin released from pineal gland in regulation of rhythmicity, here we aimed to investigate if serum shock standard protocol known for cellular rhythm regulator can change the melatonin production ability of the glioblastoma cell.Material and methods: First, U87-MG glioblastoma cells were cultured in a DMEM medium containing 10% FBS and then cells were treated with a standard serum shock process (no FBS, 8h). The concentration of melatonin was measured using ELISA method in supernatant and cell extracts of Shock and control groups. The cell proliferation was measured by using BrdU staining and flow cytometry assessment. The gene expression levels of some mitochondria or circadian related genes including TFAM, BMAL1, PGC-1α, and DRP1 were measured, using qRT-PCR method.Results: our findings showed increased (two times) concentration of cellular and released endogenous melatonin in the FBS shock treated U87-MG glioblastoma cells compared to the control group. we found significant up-regulation of the mitochondria or circadian regulator genes (TFAM, BMAL1, PGC-1α, and DRP1) at mRNA level; in the FBS shock group compared to the control group (P <0.0002). Moreover, the percent of proliferative cell (Brdu positive) was also elevated in FBS shock group however it was not statistically significant. Conclusion: the serum shock process has a far effect on the cellular behavior of the U87-MG cell line. regard to the results of the study, it is worth mentioning that an increase in the concentration of endogenous melatonin affects many signaling pathways within the U87-MG cell line, and the elevated expression of the candidate genes was the proof of this fact.by considering the results of this study it also should be noted that detailed investigating the role of endogenous melatonin and its effects on cancer cells is pivotal and by comparing the results of the normal cells with cancer cells we can find the hotspots of the involved signaling pathways that could help better understanding the biology of glioblastoma.