A Complex Relationship

GINA BROWN 

RICK BHIM, ND, CCNM 

Type 2 diabetes (T2DM) is a global health concern, affecting over 462 million individuals worldwide.¹ It is a widely common condition in clinical practice and is a significant burden on the healthcare system.² Current research has identified an interaction between glucose homeostasis – a system that is dysregulated in T2DM pathology – and the sleep-regulating neurotransmitter, melatonin.³ Proper glucose control is the most important aspect of T2DM management, and the importance of sleep in proper metabolic functioning is well-understood.³ Research continues to explore the relationship between these phenomena. An emerging field in nutritional science, known as chrononutrition, aims to understand the complex relationship between the timing of food intake, alterations in circadian rhythms, and their combined impact on overall health.⁴ Chrononutrition may become a new tool for reducing the risk of patient progression to T2DM, establishing an additional method for glycemic control, and improving outcomes for those with clinical disease. 

The Circadian System 

The human body houses a circadian system that regulates a variety of biological processes.⁵ Based on environmental cues, it acts in a cyclical manner, producing diurnal rhythms of activity to anticipate and adapt to changes throughout the 24-hour day.⁶ Levels of light exposure serve as the primary cue, picked up by retinal ganglion cells and relayed to the brain via the retinohypothalamic tract. The primary circadian pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus, sends signals received through this tract to peripheral cells, modifying a wide array of metabolic processes.³ 

The circadian system affects hormonal fluctuations,³ indicating that its role extends beyond the sleep-wake cycle.⁵ Such fluctuations have been observed in normal secretion of plasma lipids, cortisol, growth hormone, and insulin, and these changes may have downstream effects on metabolism.⁵ Communication between the SCN and peripheral oscillators is primarily regulated though the hormonal signaling molecules, melatonin and cortisol.⁴ Melatonin, a peptide hormone produced in the pineal gland of the brain,⁷ acts via binding to designated receptors (MT₁ and MT₂) on target cells.⁸ Pineal secretion of melatonin fluctuates throughout the day, rising 1 to 2 hours prior to sleep onset, remaining elevated throughout the duration of sleep, and decreasing 1 to 2 hours before waking.⁹ Melatonin secretion increases in the absence of light, and conversely, is inhibited in its presence.⁵ MT₁ and MT₂ receptors have been discovered in multiple body systems,¹⁰ including the liver, pancreas, adipose tissue, and skeletal muscle.¹¹ Together, these findings support claims that melatonin may play a larger role in energy homeostasis.¹¹ 

Most melatonin research has been conducted in the context of sleep physiology. Recently, the melatonin receptor 1B (MTNR1B) has been discovered to have a genetic variant that has been linked to the development of T2DM.¹⁰ The variant, a single-nucleotide polymorphism, has been associated with increased fasting plasma glucose levels and impaired insulin secretion.¹⁰ As a result, there has been a heightened interest in determining the role that melatonin plays in human metabolism, and potentially, in the pathogenesis of T2DM.¹² 

Pathogenesis of T2DM 

T2DM is a chronic and progressive disease with 2 pathophysiologic mechanisms underpinning its development: peripheral insulin resistance and pancreatic β-cell dysfunction. Both mechanisms precipitate a persistent hyperglycemic state, the hallmark feature of the disease.^13,14  

Insulin is necessary to remove excess glucose from the bloodstream.¹⁵ In response to high levels of circulating glucose, the pancreas triggers insulin release that facilitates glucose uptake into cells.¹⁶ Any loss of sensitivity from target cells to insulin signalling – defined as insulin resistance – results in elevated blood glucose concentrations and causes a hyperglycemic state with downstream compensatory insulin secretion from the pancreas.¹⁷  

β-cell dysfunction has 2 defining characteristics: decreased secretory function and a loss of cell mass.^18,19 The inability of β-cells to sense and respond to a hyperglycemic environment yields a blunted insulin response and as a result, blood glucose concentrations remain elevated. This catalyzes atrophy of these insulin-secreting cells, resulting in an overall decreased cell mass over time.²⁰ 

Sleep Disruption & T2DM 

Sleep is rarely considered in the context of T2DM,²¹ despite the growing body of evidence that suggests that abnormal sleeping patterns are associated with a greater risk of disease development.^22-24 Specifically, pathological sleep disorders and shift work, which can cause circadian misalignment, have been associated with metabolic consequences that include obesity and T2DM.^23-28 In a 2010 study, sleep restriction of 4-5 hours per night, over the course of 1 week, resulted in poor β-cell responsivity and acute insulin resistance, causing lower glucose tolerance and insulin insensitivity in healthy subjects.²⁶ Another study found that just 4 days of simulated night shift work reduced insulin sensitivity by 25% and resulted in heightened fasting plasma glucose levels.²⁸ 

Insomnia and sleep apnea are 2 conditions that often present along with T2DM in patients that do shift work.²⁹ It is important to note that roughly 90% of patients with T2DM report suffering from at least 1 sleep issue and, in comparison to the general population, have an increased likelihood of reporting multiple issues.²⁹ In a potentially vicious cycle, T2DM can also impact both the quality and the quantity of sleep. Commonly associated symptoms such as nocturia and neuropathic pain can increase the frequency of nighttime awakenings,^27,30 and while the mechanisms remain unclear, the prevalence of restless legs syndrome is heightened in diabetic patient populations.³² Based on these data, it stands to reason that dysfunctions in circadian rhythms may both contribute to disease development and potentially worsen the prognosis in those with an established T2DM diagnosis. 

The Link Between Melatonin & Glucose Homeostasis 

Activation of the melatonin signaling pathway is thought to be primarily to maintain circadian rhythm regularity. A growing body of evidence, however, continues to uncover complex interactions between melatonin and systems that regulate glucose management.³³ For instance, research has implicated melatonin in β-cell functionality,^33,34 and changes in melatonin signalling may also predispose those susceptible to metabolic changes associated with T2DM.¹² Furthermore, impaired melatonin production and secretion have both been observed in studies aimed at establishing a physiologic link between melatonin and glucose homeostasis.^35-38 Using rats as an animal model, findings from a 2010 study support this hypothesis, demonstrating melatonin secretion impairment following induction of a hyperglycemic state.³⁷ 

Other data include in vitro studies that found that when exogenous melatonin is administered, pancreatic β-cells increased production of somatostatin, an insulin-inhibiting hormone, following induction of a hyperglycemic environment.^39,40 In studies with human participants, those with T2DM showed decreased nocturnal melatonin secretion in comparison to healthy controls,³⁶ and exogenous melatonin administration to a female cohort was met with decreased glucose tolerance on oral glucose tolerance testing.^41,42  

Finally, as previously discussed, a variation in the MTNR1B gene that alters downstream receptor signaling, which then leads to abnormal glucose regulation, has been associated with an increased risk for T2DM.⁴³ Interestingly, those with the variant – but without a diagnosis of T2DM – seemed to exhibit a blunted early-phase insulin response. These types of findings may offer clues about mechanisms that underpin the pathogenesis of T2DM in those yet to develop clinical symptoms.⁴⁴ This link was strengthened by an additional study that observed diminished insulin secretion and decreased disposition index values following an oral glucose tolerance test in those carrying the MTNR1B mutation.⁴⁵ 

Potential for Treatment 

Melatonin administration may provide a benefit for insulin control. A potent antioxidant, melatonin has demonstrated the ability to modulate multiple intracellular signaling pathways and exert positive effects on parameters of glucose metabolism by decreasing hyperglycemia, improving insulin resistance, and reducing oxidative stress and inflammation – all of which contribute to T2DM pathophysiology.⁴⁶ Melatonin has shown the ability to restore proper β-cell survival in isolated pancreatic islets, evidencing a protective role against β-cell damage.⁴⁷  

When animal models were subjected to a pinealectomy – a procedure where the pineal gland is removed and results in altered melatonin secretion – GLUT4 receptor expression was decreased. This change in receptor expression resulted in glucose intolerance and both central and peripheral insulin resistance.^48,49 Interestingly, these effects were reversed with exogenous melatonin administration.^48,49 In human trials, researchers also observed an improvement in HbA1c levels over a 5-month trial of nightly dosing in patients with comorbid insomnia and T2DM.⁵⁰ These results suggest that supplementation with exogenous melatonin may have beneficial effects on glycemic control. 

Another mechanism that has been gaining traction as a potential treatment for glycemic control is time-restricted feeding (TRF).⁵¹ With the potential to modulate insulin sensitivity, this type of dietary pattern imposes specific time frames for feeding and fasting – typically an 8-9 hour feeding window within a 24h period – and is thought to sustain a healthy diurnal rhythm.³³ In the context of T2DM and melatonin’s role in glucose management, TRF has been shown to improve glucose homeostasis, reduce insulin resistance, and aid in the reversal of previously established glucose intolerance.⁵¹ Among the many benefits associated with TRF, improvements to glucose metabolism are thought to arise primarily from the restoration of proper melatonin signalling, the re-establishment of healthy circadian rhythms, and the resulting promotion of normal metabolic functioning.¹¹ 

Conflicting Evidence 

Despite many recent advancements in the research on the role of melatonin in glucose homeostasis, the underlying mechanisms connecting them remain elusive. While some studies highlight a beneficial role for melatonin in T2DM prevention and treatment, other research has suggested it may have an antagonistic relationship with insulin. Decreased glucose tolerance has been observed with elevated melatonin concentrations and may be attributed to melatonin inhibiting insulin secretion from β-cells. However, conclusions cannot be concretely drawn without considering other mechanisms that may be at play.¹⁰ To what magnitude melatonin may exert an effect in the fasting vs fed state has yet to be determined, as well as what clinical implications this dichotomy may hold. Because high melatonin concentrations have a demonstrated role for facilitating β-cell recovery, using sleep as a pillar to reduce the risk of T2DM is logical, and may be further optimized in a fasted state. Conversely, high melatonin concentrations in the fed state may impair glucose uptake; therefore, a low melatonin environment may be conducive to glycemic control after meals. Garaulet et al established the hypothesis for timing as a central tenet for understanding the conflicting data of melatonin in the context of glucose management and T2DM, and these findings can further be applied to the recommendations for clinical practice outlined below.³ 

Clinical Implications 

There are many avenues to consider in the management of patients presenting with T2DM. In addition to ensuring proper blood glucose control, adopting tailored glycemic targets, and consistent monitoring,⁵² the following should be also considered: 

• Identify and treat individuals with a heightened risk for poor glucose control, such as shift workers, patients who eat late in the evening, patients with disrupted sleep patterns, and patients who supplement exogenous melatonin. 
• Understand that oral glucose tolerance testing results may be impacted when administered early in the morning, while melatonin levels are still elevated. 
• Promote sleep optimization as a priority in all patients, regardless of glucose status, as a preventive strategy for T2DM development. Appreciation of age-related sleep changes and how this may impact glucose control should also be considered. 

• Encourage TRF in those with abnormal glucose parameters or T2DM to optimize glycemic control. Emphasis should be placed on the importance of consuming meals earlier in the day as opposed to late evening, as hyperglycemia is sustained for longer durations following an evening meal. Initiating meals 1-2 hours after waking and ending at least 2 hours before bedtime are good recommendations. 
• In those with poor glycemic control and a comorbid sleep disorder, evaluate the risks and benefits of using exogenous melatonin, and provide proper education on the potential effects the supplement has on glucose homeostasis. If supplementation is indicated, advise dosing away from meals to improve glucose uptake, as insulin release may be blunted while melatonin is elevated. 

The relationship between melatonin and glucose homeostasis remains complex. However, given the high prevalence of T2DM and the consequences of the disease, adopting the strategies proposed above should be considered in patients presenting with the condition. Further studies are needed to assess whether there is clinical benefit to testing for the MTNR1B genetic variant, and to what magnitude these interventions may have in the prevention or management of the disease going forward. 

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Gina Brown is a fourth-year student at the Canadian College of Naturopathic Medicine in Toronto, Ontario. She completed a Bachelor of Science degree in Kinesiology as well as a Bachelor of Science in Human Nutrition at Saint Francis Xavier University in Antigonish, Nova Scotia. She has an interest in understanding the complex mechanisms that underpin human physiology and their application in improving outcomes with her patients. 

Rick Bhim, ND, practices in Toronto and Dundas, Ontario. Dr Bhim is a faculty member at the Canadian College of Naturopathic Medicine, where he graduated and underwent 2 naturopathic residency programs. He holds both a Doctor of Naturopathic Medicine and Doctor of Medicine degree. Combining private practice with being an educator makes him a better doctor for his patients and a better teacher for his students.