N6‑Methyladenosine Modification and Circadian Regulation: Their

Impact on Diabetes and Underlying Mechanisms

Qinhan Liu

Aquinas International Academy, Ontario, CA, U.S.A.

Keywords: N6‑Methyladenosine, Circadian Rhythm, Insulin Resistance.

Abstract: m6A RNA methylation and circadian rhythms both affect how the body manages blood sugar, influencing

diabetes development. Recent studies show that clock genes such as BMAL1 and CLOCK interact closely

with m6A regulators, affecting insulin signaling in cells. When natural rhythms are disrupted—like staying

up late, shift work, or irregular eating—this balance breaks down, worsening insulin resistance. Therapies

targeting this connection, including timed nutritional strategies or treatments affecting m6A enzymes, may

help improve blood glucose control. More research is needed to clearly understand how these mechanisms

work together, potentially leading to better personalized diabetes treatments.

1 INTRODUCTION

Metabolic disorders, particularly type 2 diabetes

mellitus (T2D), have become a significant global

health burden due to the complex interplay of genetic,

environmental, and epigenetic factors. Among these

modifications, the most notable one is N6-

methyladenosine (m6A) RNA modification, which

has been found to be an important epigenetic

regulator determining the genes' expression in the

post-transcriptional process. However, it is essential

to highlight the circadian rhythms and their function

in metabolic regulation, which is related to the

glucose homeostasis, insulin secretion, and lipid

metabolism. The recent evidence demonstrates that a

complex interaction exists between circadian

regulation and m6A modification and that there is a

possibility of implications involving metabolic

disorders, although the exact mechanisms are

currently unresolved. Research findings indicate that

m6A modification is associated with the involvement

of insulin sensitivity and glucose metabolism, which

occurs through the stabilization of mRNA and

translation of important metabolic genes (Li et al.

2023). In addition to that, circadian rhythms interfere

with the insulin release and hepatic glucose

production, whereas the disruptions of this rhythm

caused by shift work, sleep disturbances, or irregular

feeding schedules have been found to increase

chances of insulin resistance and metabolic

syndrome. This investigation deals with the role of

m6A methylation as an intermediary between

circadian disruption and metabolic dysregulation,

which is a new and developing area.

Additionally, the role of m6A modification is

well-known in the diabetic complications,

especially in diabetic peripheral neuropathy (DPN).

According to the previous findings, the decrease of

m6A modification of Schwann cells as a result of

high glucose concentration leads to a drop in the

expression level of neuroprotective genes and the

dysfunction of autophagic process, which

eventually contributes to aggravation of nerve

damage in the case of diabetes. These findings

imply that m6A modification has an important role

in diabetes-associated complications, but not

merely in glucose metabolism. This paper aims to

review the connection between m6A RNA

modifications and their effect on transcriptional

activities governed by circadian regulation in

metabolic disorders, mainly involving insulin

resistance, diabetes, and obesity. These are going to

be useful as tools for identifying more advanced

therapeutic alternatives to address epigenetic

effects and circadian processes to improve

metabolic wellness outcomes.

Liu, Q.

N6-Methyladenosine Modiﬁcation and Circadian Regulation: Their Impact on Diabetes and Underlying Mechanisms.

DOI: 10.5220/0014486400004933

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 273-280

ISBN: 978-989-758-789-4

273

2 M6A MODIFICATION AND

CIRCADIAN RHYTHM:

EXPLORING THE

MECHANISTIC

CONNECTIONS

2.1 Chronical Stability and Translation

of m6A in Gene Activity

The main function of circadian clock is accomplished

by the transcriptional and translational feedback loop

(TTFL), which is formed through the recognition of

transcription of PER and CRY genes by BMAL1 and

CLOCK proteins. With PER and CRY proteins

snowballing, the next steps will inhibit

BMAL1/CLOCK activity, which subsequently will

be degraded to bring the cycle to an end. The process

of gene expression requires proper regulation which

is often achieved by inserting m6A methylation

(Chen et al. 2023). A number of circumstances come

together in the process of m6A modification, which

takes place while the mRNA is being transcribed and

which has an impact on all three areas of mRNA,

namely stability, translation efficiency, and

degradation. Methylated sites on BMAL1, CLOCK,

PER, and CRY transcripts also exist and are

maintained in state dependent inverse relation to

specific m6A regulatory proteins (De Jesus et al.

2019). It has been documented that m6A modification

of both BMAL1 and CLOCK transcripts increases the

stability of those two mRNAs, thereby enabling these

mRNAs to be expressed properly. At the opposite end

of the spectrum, transcripts for PER2 and CRY1 go

through degradation, which is dependent on m6A and

ensures that BMAL1/CLOCK is not repressed to the

extent of preventing the transition from activation to

repression (Gibo & Kurosawa 2020). The

downregulation with METTL3 (the primary m6A

methyltransferase) has been shown to disrupt the

circadian clock, implying that the period of mper2

mRNA stability has been extended. The consequence

of this event is the postponement of the suppression

of BMAL1 /CLOCK (Robinson et al. 2019).

YTHDF2, an important m6A reader, was also

removed, leading to its accumulation, which is not

caused by m6A, and which also leads to the

prolongation of the circadian cycle (Yu et al. 2025).

These findings indicate that the precision of circadian

feedback loops in timing depends on m6A.

2.2 The Chronotherapy of m6A

Modifiers and Removers

There is not only the effect of circadian clocks on

m6A, but there is also the feedback regulating m6A

modifying molecules from circadian oscillators,

which are reciprocated by the above-mentioned

modulating variable, providing a way to synchronize

patterns in gene expressions (Yang et al. 2018).

BMAL1 and CLOCK are both in charge of the

activation of METTL3 transcription, which interacts

with the mRNA lock, bringing about METTL3

oscillatory output, leading to rhythmic disposition of

m6A marks on circadian transcripts (Gibo &

Kurosawa 2020). The clock is thus capable of

bringing together the m6A marks to the expected

extent and in due time by telling the clock what's

where to be disposed of as m6A. PDHDNs

involvement in the physiology of metabolic disorder

and sleep disorder was probably because of the

misalignment of m6A modifications and circadian

gene expression (De Jesus et al. 2019). Besides, m6A

erasers that are present in the family of FTO and

ALKBH5 also show circadian variations and their

expression patterns are variably opposite to those of

METTL3 to keep the cycle of methylation and

demethylation unbroken (Robinson et al. 2019). Via

example, the gene ALKBH5 is known to be

upregulated during the early active phase, which

counteracts the accumulation of extra m6A and

provides sufficient time for the stabilization of the

transcripts which are important for circadian function

(Chen et al. 2023). These data provide further support

to the view that circadian rhythms may directly

control both m6A deposition and erasure of some

transcript components and intermittuate the gene

expressions in a time-dependent manner.

Abnormalities in METTL3, FTO, or YTHDF proteins

can result in changes in circadian rhythms of the cells,

which represent the importance of m6A-circadian

interactions (Yu et al. 2025).

2.3 The Circadian Corse Effect on

m6A Periodicity and Amplitude

Circadian processes oscillate with a change or rising

of cycles (cycle length) and amplitude (oscillation

strength), and adjust m6A methylation in both

(Robinson et al. 2019). Scientific observation has

shown that circadian period is elongated when the

level of m6A decreases due to longer persistence of

the PER2 and CRY1 because their decrease is not

proportionalities with that of the m6A (Gibo &

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274

Kurosawa 2020). Literally, mathematical modeling

studies have demonstrated that m6A-deficient cells

display lengthened cycles due to prolonged mRNA

stability (De Jesus et al. 2019). Furthermore, m6A

controls the advertisement of casein kinase 1δ

(CK1δ), which is a critical kinase required to

phosphorylate and degrade PER proteins. Impairing

CK1δ activity leads to alteration of the periodicity

and the binding of the mRNA specified by m6A;

hence, it is possible to conclude that m6A plays a role

in the proper ticking of circadian clock (Yang et al.

2018). Beside the increase in the cycle length, m6A

increases the amplitude of circadian oscillations by

making sure that the core clock transcripts are

stabilized (Chen et al. 2023). The removal of m6A

methlylation observably shortens the circadian state

of gene expression and causes substandard

oscillations that subsequently modify the circadian

control for the ease of use (Yu et al. 2025). This point

entails the conclusion that m6A activity contrasts

from both increase of the circadian period and the

amplitude which in turn allows steady oscillation on

all the cellular processes (Robinson et al. 2019).

2.4 The Environment Influence on

Interaction of m6A with Circadian

Time

Circadian rhythms are formed by external factors in

the environment, such as light exposure and feeding,

as well as occasional m6A modifications, both of

which are involved in regulating it (Gibo & Kurosawa

2020). Light being a significant environmental sync

factor for circadian rhythm has been implicated in

affecting the level of m6A in clock-associated

transcripts (Yang et al. 2018). Previous studies

indicated that m6A modifications were activated on

both BMAL1 and PER2 transcripts in response to

light signals and their degradation was timeshifted

according to external day-night cycles (De Jesus et al.

2019). Shift workers and people who are exposed to

artificial light during the night all have altered

patterns of m6A methylation, which may eventually

bring about circadian misalignment (Yu et al. 2025).

2.5 Feeding Habit and m6A

Modification

Meal time is also an important regulator of circadian

gene expression, which maintains the rhythm of m6A

activity (Chen et al. 2023). The fasting-feeding

regime has been associated with the alteration of

hepatic m6A patternings among all metabolic genes

in particular REV-ERBα (NR1D1), IGF1R, and AKT

(Robinson et al. 2019). Out-of-time feeding behavior

is ecologic, which enhances the m6A-mediated

circadian entrainment pull together (Gibo &

Kurosawa 2020). These discoveries suggest that m6A

works as a modulator of the exposure of

environmental information into the circadian system

as the surrounding conditions change (Yang et al.

2018).

2.6 The Possible Venue for m6A

Therapy in Circadian Disorders

Because the close connection between m6A

methylation and the circadian process is well known,

the targeting of the m6A axis provides a tool to

develop novel therapeutic approaches for the

circadian disorders. Pharmacological modulation of

m6A writers (METTL3), erasers (FTO, ALKBH5),

and readers (YTHDF proteins) could help restore

disrupted rhythms, particularly in shift workers,

metabolic syndrome patients, and individuals with

sleep disorders (Chen et al. 2023). METTL3

modulation has shown promise in regulating BMAL1

and CLOCK expression, reinforcing circadian

oscillations (De Jesus et al. 2019). Conversely, FTO

and ALKBH5 inhibitors have demonstrated effects in

stabilizing circadian metabolic pathways, potentially

benefiting conditions like type 2 diabetes (Yang et al.

2018). Additionally, nutritional interventions such as

dihydroartemisinin (DHA) supplementation and

chrono-nutrition strategies may help fine-tune m6A-

dependent circadian regulation (Gibo & Kurosawa

2020). Although m6A-targeting therapies remain in

early stages, the potential for correcting circadian

misalignment and mitigating metabolic disorders

warrants further investigation. Future studies should

focus on selective modulators of m6A regulators and

their clinical applications in circadian-related

diseases (Robinson et al. 2019).

3 M6A MODIFICATION AND

CIRCADIAN RHYTHM: THEIR

ROLES IN DIABETES

3.1 Circadian Rhythm and Glucose

Homeostasis in Diabetes

The circadian clock is essential in regulating glucose

and lipid metabolism through its influence on insulin

secretion, glucose uptake, and hepatic

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275

gluconeogenesis. Disruption of this temporal

coordination contributes significantly to the

development of type 2 diabetes mellitus (T2DM).

BMAL1, a core clock transcription factor, plays a

central role in maintaining rhythmic metabolic gene

expression. Mahajan et al. demonstrated that BMAL1

overexpression in the suprachiasmatic nucleus (SCN)

of diabetic mice restored behavioral rhythmicity,

improved glucose tolerance, and reduced hepatic

glucose production, underscoring the link between

circadian regulation and metabolic homeostasis.

Further evidence suggests that dietary modulation of

circadian gene expression can also influence glucose

regulation. Wang et al. showed that theabrownin, a

tea-derived polyphenol, improved glucose and lipid

profiles in diabetic mice by altering gut microbiota-

derived metabolites and upregulating circadian genes

such as BMAL1 and CLOCK in liver and adipose

tissues (Lu et al. 2025). These changes contributed to

enhanced insulin sensitivity and metabolic balance.

Moreover, environmental cues such as light exposure

modulate sympathetic nervous system activity, which

in turn influences hepatic glucose metabolism. Chen

et al. found that circadian gene expression in

metabolic tissues is partly driven by light-regulated

neuroendocrine signaling, reinforcing the concept

that both intrinsic circadian components and external

factors jointly regulate glucose homeostasis (Le Bras

2025).

3.2 m6A Epitranscriptomic Regulation

in Pancreatic β-cell Function

m6A methylation has emerged as a critical post-

transcriptional regulatory mechanism in maintaining

pancreatic β-cell homeostasis. These cells are central

to insulin production, and their dysfunction is a

hallmark of type 2 diabetes mellitus (T2DM). The

epitranscriptomic regulation mediated by m6A

modulates β-cell maturation, insulin synthesis, and

glucose-stimulated insulin secretion through dynamic

control of mRNA stability and translation efficiency.

METTL3, the major methyltransferase responsible

for m6A deposition, plays a key role in β-cell

development and function. Benak et al. demonstrated

that β-cell-specific deletion of METTL3 impairs

insulin gene transcription, reduces insulin granule

formation, and diminishes glucose-stimulated insulin

secretion, ultimately leading to glucose intolerance in

mice (De Jesus et al. 2019). Additionally, m6A reader

proteins such as YTHDF1 and YTHDF2 influence the

translation and decay of transcripts critical to β-cell

identity and function (Bornaque et al. 2022). On the

other hand, FTO and ALKBH5, the major m6A

demethylases, are also involved in regulating

metabolic genes in β-cells. Elevated FTO expression

has been associated with increased insulin resistance

and hyperglycemia. Zhang et al. reported that FTO

modulates the expression of AKT and FOXO1

pathways, linking m6A dynamics directly to insulin

sensitivity and downstream glucose regulation. These

findings suggest that targeting m6A regulators in β-

cells could be a promising therapeutic strategy for

improving insulin secretion and glycemic control in

diabetes.

3.3 The Disruption of m6A and

Circadian Crosstalk under Diabetic

Conditions

Under diabetic circumstances, the connection

between m6A RNA methylation and circadian

processes, which are normally functional, is gradually

perturbed and is harmful to metabolic homeostasis.

All these mechanisms undergo rhythmic changes,

which interfere with the expression of gene rhythm

that keeps the metabolic balance constant; otherwise,

the disorder may worsen. Last, the enzyme levels

associated with m6A have been found to be

modulated in the diabetic state. For example, in the

course of the hyperglycemic situation, diminished

activity of METTL3 and raised activity of FTO have

been witnessed, leading to disturbances in terms of

mRNA methylation of genes related to metabolism

and circadian rhythm. It exerts its effects by

prolonging the half-life of mRNA and changing the

translation dynamics, which in turn results in a

delayed or changed metabolism cycle. Moreover,

circadian rhythm disturbances that accompany

specific lifestyle habits, such as rotating work

schedules or irregular sleep patterns, have been

shown to alter the expression of circadian-controlled

genes (CCGs). CLOCK and BMAL1, which have

been disturbed in diabetic tissues, are associated with

the development of insulin resistance and chronic

systemic inflammation. Newly accumulating data

show that m6A can also act as a regulatory switch of

the circadian gene expression. To be more precise,

abnormal methylation of m6A involving the PER and

CRY mRNA biosynthesis are responsible for the

disturbance of circadian feedback loops, which in

turn amplify metabolic dysregulation (Hong et al.

2025). Furthermore, gut microbiota byproducts,

which are altered in diabetes, are reported to

contribute to m6A modification and alter clock genes,

implying a possible circadian epigenetic-metabolic

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cross talk (Pelczyńska et al. 2025). These discoveries

bring to light the fact that the reciprocally controlling

cycle between m6A and circadian rhythm is

susceptible to disturbance under diabetic conditions,

which in turn might be a modifiable axis and striking

foundation for treating diabetes.

3.4 Therapeutic Strategies Targeting

the m6A-circadian Axis in Diabetes

Management

Treating diabetes by harnessing the m6A-RNA

methylation-chronobiology relationship comes as

an alternative now that the evidence is mounting

that both control glucose metabolism. A decrease in

the activity of METTL3, FTO, as well as the

circadian regulators such as BMAL1 and CLOCK

in diabetic conditions implies that restoring their

balance would provide a potential impetus to

improving metabolic outcomes. Targeting

therapeutic to fewer disturbances of m6A enzymes

is becoming an attractive option. FTO inhibitors

have displayed encouraging signs in terms of

insulin sensitivity and eventually lowering

hyperglycemia in preclinical trials (Zhu et al. 2025).

These medicines have the potential to correct m6A

monomethylation levels, most notably when they

bind to mRNA controlling insulin signaling and

circadian rhythms. Moreover, chrono-nutrition, a

concept which involves maintaining food intake

also in harmony with the biological clock, has been

promulgated as a starting point without invasive

treatment that could help improve metabolic

control. Dietary interventions timed according to

circadian cycles have shown benefits in improving

glucose tolerance and reducing insulin resistance

(Reinke & Asher 2016). Similarly, light therapy has

been studied as an external cue to reset circadian

rhythms and indirectly influence metabolic

pathways (Panda 2016). Emerging studies also

point toward the gut microbiota–m6A–circadian

axis. Modulation of microbial metabolites such as

short-chain fatty acids may influence both m6A

methylation and circadian gene expression, offering

a multi-layered therapeutic approach (Romaní-

Pérez et al. 2021). Taken together, integrating

pharmacological, nutritional, and behavioral

interventions targeting the m6A–circadian interface

may offer more precise and effective strategies for

preventing and managing diabetes.

4 THE INTERPLAY BETWEEN

M6A, CIRCADIAN RHYTHM,

AND INSULIN RESISTANCE

4.1 Molecular Mechanisms of Insulin

Resistance in the Context of

Circadian Disruption

Circadian rhythm is tightly coupled with metabolic

homeostasis, and its disruption has been increasingly

associated with the development of insulin resistance.

Core clock components such as BMAL1 and CLOCK

orchestrate temporal gene expression that regulates

key metabolic pathways, including glucose transport,

insulin signaling, and lipid metabolism (Kimura et al.

2025). Under physiological conditions, this rhythmic

regulation ensures insulin sensitivity in peripheral

tissues at specific times of the day. Disruption of

circadian genes affects insulin signaling cascades.

Notably, Kimura et al. reported that the circadian

metabolite D-alanine plays a regulatory role in

maintaining glucose metabolism via its interaction

with BMAL1 and CLOCK. Dysregulation of this

loop, whether by genetic perturbations or

environmental desynchronization, disrupts insulin

receptor expression and Akt phosphorylation,

contributing to decreased glucose uptake in hepatic

and muscle tissues (Kimura et al. 2025). In addition,

the role of sleep-related circadian misalignment in

impairing glucose tolerance has been emphasized.

Hong et al. showed that insufficient sleep affects

AMPK signaling and reduces GLUT4 translocation,

thus exacerbating insulin resistance (Hong et al.

2025). This was supported by evidence that sleep

deprivation alters appetite hormones and promotes

inflammatory cytokine release, further impairing

insulin action (Hong et al. 2025). Furthermore,

Pelczynska et al. highlighted the chronotype-specific

differences in insulin sensitivity, noting that

individuals with evening chronotype exhibit impaired

glucose regulation, elevated HbA1c levels, and

altered adipokine secretion (Pelczyńska et al. 2025).

These observations underscore the multifactorial

mechanisms through which circadian disturbance

contributes to insulin resistance. Taken together,

these findings suggest that insulin resistance is not

solely a result of metabolic overload but also a

consequence of disrupted circadian timing, mediated

by alterations in clock gene expression, metabolite

oscillations, and hormonal imbalance.

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277

4.2 m6A Modification in Key Insulin

Signaling Pathways

m6A RNA methylation is a dynamic regulatory

mechanism essential for proper insulin signaling. Its

dysregulation significantly impacts glucose

metabolism, influencing the progression of insulin

resistance. Recent evidence highlights how specific

m6A enzymes modulate the insulin signaling cascade

and metabolic gene expression, emphasizing their

potential therapeutic relevance in diabetes. FTO, a

major RNA demethylase, influences metabolic

homeostasis by regulating m6A modifications on

critical transcripts involved in insulin signaling

pathways. Zhang et al. demonstrated that

pharmacological inhibition of FTO improves insulin

sensitivity, glucose tolerance, and energy

expenditure, primarily through increasing m6A

methylation of key metabolic mRNAs involved in

hepatic gluconeogenesis and lipid metabolism

pathways (Huang et al. 2023). Further supporting

these findings, betaine supplementation modulates

hepatic m6A patterns, specifically increasing the

m6A methylation of metabolic genes, consequently

reducing insulin resistance and hepatic lipid

accumulation. This occurs primarily through the

METTL3-mediated methylation of Trub2, a critical

regulator in metabolic control (Reinke & Asher

2016). Additionally, circadian misalignment disrupts

m6A modifications in insulin-responsive tissues.

Misalignment, induced by lifestyle factors such as

shift work or abnormal feeding times, significantly

alters rhythmic m6A patterns in clock-controlled

metabolic genes. This further exacerbates insulin

resistance by disrupting normal circadian-driven

metabolic homeostasis (Wu et al. 2025). Therefore,

targeting m6A methylation pathways represents a

promising therapeutic strategy to improve insulin

signaling in metabolic diseases, particularly when

circadian rhythms are concurrently disrupted (Wu et

al. 2025).

4.3 The Crosstalk between m6A and

Circadian Clock in Regulating

Insulin Sensitivity

Recent studies have revealed a functional

interdependence between m6A RNA methylation and

the circadian clock in the regulation of insulin

sensitivity. Core clock genes such as BMAL1 and

CLOCK not only maintain rhythmic metabolic

homeostasis but are also regulated by m6A

modifications at the post-transcriptional level.

Conversely, circadian oscillations can influence the

expression and activity of m6A regulatory enzymes,

suggesting a bidirectional interaction. For instance,

rhythmic expression of METTL3 and FTO, the m6A

writer and eraser enzymes, has been observed in

insulin-responsive tissues, with peak activity aligning

to metabolic gene expression cycles. Disruption of

circadian regulators alters the timing of m6A

deposition, leading to aberrant stabilization or

degradation of insulin signaling-related mRNAs,

including IRS1 and FOXO1 (Reinke & Asher 2016).

Moreover, m6A marks on transcripts such as PER and

CRY genes modulate their mRNA turnover and

translation efficiency, directly influencing circadian

feedback loops and thereby indirectly affecting

insulin sensitivity (Yang et al. 2018). Theabrownin

has also been shown to enhance insulin sensitivity by

restoring rhythmic expression of both m6A regulators

and core clock genes in diabetic models (Lu et al.

2025). In parallel, gut microbiota-derived short-chain

fatty acids (SCFAs) may act as upstream modulators

of both m6A methylation and circadian gene

expression. Romaní et al. proposed a gut–m6A–

circadian axis that synchronizes metabolic rhythms,

contributing to improved insulin responsiveness

(Romaní-Pérez et al. 2021). These findings highlight

a mechanistic bridge between m6A and circadian

timing in maintaining insulin action, offering new

targets for metabolic disease interventions.

4.4 Clinical Evidences and Implications

in Metabolic Disease Management

Emerging clinical and translational studies suggest

that the interplay between m6A modification and

circadian regulation has tangible implications in the

management of metabolic diseases such as type 2

diabetes. Evidence from human cohorts indicates that

circadian misalignment—resulting from shift work,

social jet lag, or irregular sleep patterns—is

associated with reduced insulin sensitivity and

elevated HbA1c levels, particularly in individuals

with evening chronotypes (Pelczyńska et al. 2025).

These clinical observations support mechanistic data

from experimental models linking disrupted circadian

gene expression to altered insulin signaling pathways.

Moreover, variations in m6A-related gene expression

have been observed in metabolic tissues of patients

with obesity and diabetes. Clinical studies have found

upregulation of FTO and decreased METTL3 activity

in diabetic individuals, correlating with impaired

glucose tolerance and elevated hepatic

gluconeogenesis (Huang et al. 2023). Such findings

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278

reinforce the role of epitranscriptomic regulation in

the metabolic phenotype of insulin resistance.

Intervention studies also highlight the therapeutic

potential of targeting this axis. Chrono-nutritional

approaches that epidemiologically exactly match

food intake with circadian rhythms have shown

improvement in glycemic control and lipid profile in

clinical trials. Conversely, pharmacological blocking

of the FTO has showed promising effect in preclinical

trials, which could directly correlate the translational

potential for epigenetic changes of m6A methylation.

These findings emphasize the clinical relevance of

integrating circadian rhythm alignment and m6A-

directed therapies together as a crowded and

comprehensive strategy in preventing and treating

metabolic disorders.

4.5 Integrative Therapeutic

Approaches and Future

Perspectives

The concert of circadian modulation with m6A

epitranscriptomic control creates a new framework

for treatment of metabolic disorders. Since both

networks significantly intersect the control of insulin

signaling cascades and metabolism-associated genes,

targeting the m6A-circadian axis together holds

optimism for greater insulin sensitivity and better

glycemic control than the therapies based on the m6A

or circadian modulation alone. Recently proposed

strategies of dual intervention might consist of

chronotherapy combined with FTO inhibitors or

applying FTO inhibitors in an environment with light

and mealtime (Reinke & Asher 2016, Huang et al.

2023). Such methods aim at restoring the normal

levels of clock and epitranscriptomic genes' activity

while concurrently overcoming the underlying

metabolic disease. The progress in the creation of

circadian–m6A concentration-based predictors can

result in personalized physical activities protocols

intended for those with high chronotype risks.

However, a few problems remain unresolved, in

particular, m6A–clock discrepancies for particular

tissues, the effect of potential off-targets caused by

epigenetic drugs, and the lack of long-term safety

data. The development of bioinformatics, including

multi-omics profiling, will provide greater favor to

specifying therapeutic targets and finding the best

moment for treatment for maximum performance.

Thus, m6A-circadian connection should particularly

be regarded as a core interdisciplinary target in

metabolic diseases research that crosses the

boundaries of molecular regulation and system-wide

rhythm towards precision treatment.

5 CONCLUSION

The interplay between m6A modification and

circadian rhythm significantly impacts diabetes

progression by modulating insulin sensitivity and

metabolic balance. Circadian disruptions, such as

those induced by altered BMAL1 and CLOCK

activity, impair insulin signaling pathways, including

Akt phosphorylation and GLUT4-mediated glucose

uptake, exacerbating insulin resistance.

Simultaneously, dysregulated m6A RNA

methylation—particularly through altered activity of

METTL3 and FTO—further disrupts the expression

and stability of insulin-related transcripts like IRS-1,

contributing to metabolic dysfunction.

Therapeutically, aligning dietary patterns with

circadian rhythms, employing FTO inhibition

strategies, and manipulating gut microbiota

metabolites have demonstrated effectiveness in

restoring insulin responsiveness and glucose

metabolism. Future research must address

individualized therapeutic responses and long-term

safety of combined circadian and m6A-targeted

interventions, ultimately enhancing personalized

treatment strategies for diabetes management.

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