Understanding Circadian Clock Disruption

This is part two of a series on optimizing sleep. If you haven’t already ready Sleep Basics, you can check it out in the Articles section.

Picking up where we left off last, let’s look again at the significance of circadian clock disruption.

Circadian clock disruption refers to a misalignment of the body’s internal 24-hour biological rhythms with external environmental cues, primarily the light-dark cycle. When this rhythm is interrupted or broken, it affects various physiological processes, including hormone production, body temperature regulation, cell regeneration, and most importantly, the body’s ability to rest and restore itself, absorb nutrients, and stay in homeostasis. Shift work, travel across time zones, and exposure to artificial light at night can all undermine your circadian clock.

On the other hand, sleep cycle disruptions specifically relate to disturbances in the pattern of sleep stages throughout the night.

Common sleep problems, including:

• frequent awakenings
• difficulty falling asleep or
• problems maintaining sleep

are all indications of sleep cycle disruptions that can be caused by any number of factors:

• stress
• illness
• alcohol or substance use
• hormonal changes
• environmental disturbances

When it comes to trying to achieve high-quality sleep on a regular basis as a foundation to optimal metabolic functioning, it can help to understand the mechanisms and adverse effects of circadian clock disruption.

Impact of Circadian Clock Disruption on Cell Metabolism

Circadian clock disruption significantly impacts cell metabolism through various mechanisms including glucose and fat metabolism, overall energy homeostasis, and overall circadian gene expression.

In terms of glucose metabolism, a disruption in the circadian clock reduces insulin sensitivity and increases insulin resistance; impairs glucose tolerance; and leads to hyperglycemia and hypoinsulinemia.

Disruption of this sleep mechanism also alters lipid metabolism by causing hyperlipidemia (i.e., elevated triglycerides) and disrupts phospholipid metabolism, including phosphatidylcholine and circadian gene expression.

Further circadian clock disruption promotes hyperphagia, accelerates weight gain, and alters metabolic hormone levels. At the genetic level, such disruptions also affect the rhythmic expression of clock-controlled genes. Collectively, these metabolic disruptions further increase the risk of metabolic disorders such as obesity, type 2 diabetes, and metabolic syndrome.

Specifically, type 2 diabetes is closely associated with this loss of circadian rhythmicity because of the related impairment of glucose metabolism; pancreatic beta cell dysfunction that creates more oxidative stress; disruption of glucose and lipid metabolism in the liver; and dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis that then leads to the dysregulation of glucocorticoid levels.

These disruptions collectively impact overall homeostasis and downregulate redox balance.

There’s one intervention that can help restore the body’s clock: exercise!

How GLP-1s Affect the Circadian Clock

GLP-1 has a circadian secretion pattern, with peaks in the morning and declines in the afternoon. This rhythmic release is crucial for maintaining metabolic homeostasis. Studies have shown that GLP-1 RAs can modulate the expression of clock genes in peripheral tissues, such as the liver and adipose tissue, synchronizing metabolic processes with the light-dark cycle. Further, these powerful peptides can affect the expression of core clock genes, such as Bmal1, Clock, Per1, and Per2, which are essential for maintaining the circadian rhythm and thereby improve sleep patterns. Specifically, the extended half-life of semaglutide provides more consistent activation of GLP-1 receptors over time, potentially leading to a more stable influence on circadian rhythms and metabolic processes. The daily dosing schedule of liraglutide aligns more closely with the natural circadian rhythm of GLP-1 secretion, potentially helping to maintain or restore normal circadian rhythms.

What to Do

Not surprisingly, the quality and duration of sleep affect homeostasis. The good news is that a lot of research is being conducted in this field, and we are learning more and more about how sleep works and why it’s so important. For now, I want to leave with you some basic but powerful guidelines that your patients can use for creating healthy sleep habits and achieving sufficient high-quality sleep:

• Go to bed at around the same time each night. Current research says that the sweet spot is between 10 p.m. and 11 p.m.
• Wake up at around the same time each morning so that you approximate between seven and eight hours of sleep each night.
• Stop eating and drinking at least three hours before going to bed; this includes alcohol. And remember, alcohol will wake you up in the middle of the night when your body tries to metabolize it.
• Keep caffeine consumption to the early part of the day, avoiding it after 3 p.m. or so. Note that some people are more sensitive to caffeine than others. For instance, I can keep drinking coffee until 6 p.m. when I am working long days (and nights!), and it does not interfere with my falling asleep or staying asleep. But for some, a cup of tea or coffee after 2 p.m. can interfere with their sleep.
• Be conscious of the timing of your exercise. Again, this varies. Many people find that exercising later in the day is relaxing, and others find it too stimulating. You be the judge.
• In extreme cases of sleep dysregulation, some of my patients have benefitted from CBD creams or tinctures.
  Melatonin (3 to 10 mg) can help people fall asleep, starting slowly with .3 to 3mg so pineal gland is not adversely affected.
• Consider mouth taping for sleep apnea.

In extreme cases of sleep dysregulation, electromagnetic interventions such as pulsed electromagnetic field (PEMF) therapy (which is based on NASA technology) can regulate the interaction between the sleep drive and circadian rhythm. This technology can literally put you into stage 4 sleep. I have had great success with this type of intervention. Though it is still an emerging field, preliminary studies suggest PEMF exposure may positively impact sleep through its effects on melatonin and mitochondrial function. Specifically, small trials show that PEMF applied before bedtime can increase endogenous melatonin levels, which regulates circadian rhythms. Animal research also indicates PEMF may enhance mitochondrial ATP production and membrane potential, improving cellular bioenergetics that influence sleep cycles. Thus, PEMF may modulate hormones and optimize energy pathways involved in sleep regulation.

However, current evidence has limitations, including small sample sizes and lack of controlled trials in humans. High-quality randomized studies are still needed to establish clear efficacy, optimal treatment parameters, and underlying mechanisms of how PEMF may improve sleep. But the initial findings are promising. With further rigorous research, PEMF could emerge as an innovative, nonpharmacological approach to managing sleep disorders and improving sleep quality through effects on melatonin signaling, mitochondrial function optimization, and other cellular processes. The potential of PEMF warrants continued investigation in this area.

A final recommendation: try napping. Studies have shown that taking a nap during the day can lead to improvements in glucose metabolism and insulin sensitivity, both of which are important for maintaining overall metabolic health. For example, a study published in Diabetes Care found that taking a 30-minute nap after lunch improved glucose metabolism in healthy adults. Another study, published in the Journal of Clinical Endocrinology and Metabolism, found that taking a nap during the day improved insulin sensitivity in healthy individuals. In addition, a study published in Sleep Medicine found that taking a 30-minute nap during the day led to changes in the expression of genes involved in metabolism and energy regulation. And a study published in Neurobiology of Aging found that taking a one-hour nap in the afternoon was associated with better cognitive performance in older adults.

Overall, while the precise mechanisms by which napping affects cell metabolism are not fully understood, there is growing evidence to suggest that napping can have important effects on metabolic health.

Peptides for Sleep Dysregulation

As we know, getting a consistent amount of sleep, including REM and deep sleep (stage 4) is an important predictor of overall immunity and well being. Delta sleep-inducing peptide (DSIP) is a peptide that not only addresses sleep disturbance but also helps in cellular repair.

• Sequence: N-Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-C
  Molar Weight: [MF1] 849
• Half Life: 7-8 min
• Induces alpha waves
• Improves REM
• Suppresses paradoxical sleep
• Does not induce tolerance
• Degraded in blood, the pathway involving the amino-peptidases
• No significant side-effects have so far been reported with DSIP
• In some human studies, transient headache, nausea and vertigo have been reported
• Naturally occurring
• First isolated in rabbits
• Similar peptide found in high concentrations Human milk
• DSIP show Diurnal Pattern
• Cross blood Brain Barrier

In order to use DSIP effectively, it’s important to keep in mind the sleep cycle

• Five Sleep stages: 1, 2, 3, 4 and REM (rapid eye movement) sleep
• Stages 3 and 4 are referred to as deep sleep, slow wave sleep, or delta sleep.
• The first sleep cycle takes about 90 minutes. After that, they average between 100 to 120 minutes

SWS Disruptors

• Sleep deprivation
• Parkinson’s disease
• Diabetes and insulin resistance
• Fibromyalgia
• Alcoholism
• Narcolepsy
• Depression
• Anxiety
• OCD
• ADHD

Delta-waves are the predominant wave forms of infants

• Delta waves have been shown to decrease across the lifespan
• 75 yrs of age stage four sleep and delta waves may be absent
• Disruptions in Slow wave sleep

Applications

• Treatment in insomnia clinically varied success
• Treatment of narcolepsy restoring circadian rhythms
• Sleep-promoting substance rather than a sedative
• Modulating effect on sleep and wake functions with a greater activity in circumstances where sleep is disturbed
• Not a sedation drug

DSIP Research Findings

Controlled double-blind study showed that use of DSIP normalized disturbed sleep, and improved performance and increased alertness during awake cycles together with improved stress tolerance and coping behavior.

Source: Schneider-Helmert, D. (1986). Efficacy of DSIP to normalize sleep in middle-aged and elderly chronic insomniacs. European neurology, 25(6), 448-453.

Non-sleep applications for DSIP

• Anticonvulsant action
• Neuroprotective effect
• Attenuates emotional and psychological responses to stress
• Corticotrophin releasing factor on the pituitary gland attenuated
• Anti-oxidant benefits -slow down cell damage
• Decreases exitotoxicity owing to its influence on the NMDA-subtype of neuronal glutamate receptors
• Modulates neurotransmitter balance

Endocrine functions

• Reduction in plasma ACTH
• Stimulates release of luteinizing hormone (LH)
• GHRH secretion and inhibits somatostatin secretion
• The release of thyroid stimulating hormone (TSH) 2nd to increase SWS signaling
• Endorphin, increased in centrally to cope with pain

Clinical Uses

• Restore Disrupted Sleep
• Alcohol and opioid withdrawal
• Antihypertensive effect
• Antimetastatic activity
• Chronic pain
• Direct or indirect effect on body temperature and alleviating
• Hypothermia
• Neurocognition

Dosage

• 100 mcg SubQ at night, 3 hours before bedtime
• Frequency varies based on clinical response
• Could be daily, Q3 days, Q week
• When patient stabilizes, may decrease to 50 mcg doses
• May disrupt sleep

Potential Side Effects and/or Contraindications

• DSIP peptide given subcutaneously is reported safe and efficacious in recommended dosages.
• As with all injections, redness and pain at the site of injection may be present
• Transient Headache, Nausea,Vertigo

NOTE: Naloxone is reported to block the effects of DSIP