Melatonin and Diabetes | Diabetes Qualified

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Article by Donna Itzstein Pharmacist, CDE

Last year, melatonin in modified-release tablets containing 2 mg became available at pharmacies under schedule 3. The indication is for monotherapy for the short-term treatment of primary insomnia, characterised by poor sleep quality for adults aged 55 or over, in packs containing not more than 30 tablets. (1)  Schedule 3 allows a pharmacist to dispense medication with direction on appropriate use and identification of need of the medication.

Circadian rhythms structure our day/night-related activities and anticipate physiological requirements to come a few hours ahead. They are beneficial with regard to health and, thus, healthy aging.

In many, but not all individuals, nocturnal melatonin levels decrease considerably with age, and the rhythm may almost disappear at an advanced age.  These changes are even more pronounced in several chronic conditions, especially neurodegenerative pathologies.  Sleep disturbances are a frequent complaint associated with aging and can have several secondary consequences, for example nutrition, insulin resistance, and changes in the immune system. This is also a similar circumstance with shift workers with the disruption in circadian rhythm.  (2)

Metabolic syndrome is more prevalent in shift workers, with the disturbances of circadian rhythm, and sleep deprivation has been associated with both obesity and types 2 diabetes. When the circadian rhythm is experimentally misaligned in humans, changes in plasma insulin and glucose levels, promoting glucose intolerance, are observed.  Melatonin is primarily secreted by endocrine cells (pinealocytes) in the pineal gland, located in the brain’s midline. Light exposure and absence of light instructs the circadian clock, with melatonin production occurring at night. Because the clock controls the onset and offset of melatonin secretion, the cycles move closer together in the summer and further apart in winter.

Nocturnal levels of insulin are low—since humans are programmed not to eat during the night, there is less need for insulin. An excess of insulin could have detrimental effects on the central nervous system if hypoglycaemia occurs. Because melatonin is a biological signal of darkness and, consequently, reduced metabolism, it has been proposed that melatonin could contribute to the nocturnal lowering of insulin in humans.

Circadian mechanisms controlling insulin secretion is supported by studies of humans with circadian misalignment. Circadian misalignment produces disturbance of plasma glucose and insulin levels.

There are indications that the diurnal secretion of melatonin is altered in diabetes, particularly when neuropathy is evident. Studies report reduced circulating levels of melatonin are associated with elevated insulin levels in people living with type 2 diabetes not supplementing with exogenous insulin.  If melatonin directly affects insulin secretion, its receptors (MTNR1A, MTNR1B) should be present in islets of Langerhans, preferably beta cells. This appears to be the case. (3) MTNR1B (Melatonin Receptor 1B) is a protein coding gene. Conditions associated with MTNR1B alteration include type 2 diabetes mellitus and gestational diabetes. (4) (5)

A study in Finland where the amount of daylight follows an annual variation ranging from 4 hours 44 min to 20 hours 17 min showed that individuals, who participated in the study on lighter days at the follow-up than at the baseline, displayed to a greater extent worse glycaemic profiles across the follow-up. Findings from the current study show that in the longitudinal analyses, each variation of the MTNR1B rs10830963 was associated with worsening of fasting glucose values, insulin secretion and insulin sensitivity. Taken together, the risk of glycaemic excursions increases with the mutation of the MTNR1B gene when daylight is longer. (6)

What does this all mean for people living with diabetes? There is a possibility of using this link between MTNR1B and type 2 diabetes to create new therapeutic agents. This link emphasises the importance of biological rhythm for metabolic regulation. There is a possibility that melatonin supplementation in older people living with type 2 diabetes and sleep disturbances could be beneficial for glycaemia and health outcomes.  The Pharmaceutical Benefits Scheme (PBS) does not subsidise melatonin supplements at the current time making this unaffordable to concessional clients. Further direct studies may support addition to the PBS for this indication.

References

  1. Australian Government, Department of Health, Therapeutic Goods Administration. Proposed changes to required advisory statements for medicine labels (RASML): Melatonin consultation paper. July 2021.
  2. Hardeland, R. Melatonin and Circadian Oscillators in Aging – A Dynamic Approach to the Multiply Connected Players. [book auth.] Yashin A. and Jazwinski S. Aging and health: a systems biology perspective. New York: Basel, 2015.
  3. Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene. Mulder, H., Nagorny, C.L.F., Lyssenko, V. et al. 2009, Diabetologia, Vol. 52, pp. 1240-1249.
  4. Relationship between melatonin receptor 1B (rs10830963 and rs1387153) with gestational diabetes mellitus: a case-control study and meta-analysis. Liu, Qiong, et al. 1, November 12th, 2015, Archives of gynecology and obstetrics, Vol. 29, pp. 55-61.
  5. Rare MTNR1B variants impairing receptor 1B function contribute to type 2 diabetes. Bonnefond, Amélie, et al. 3, March 2012, Nature genetics, Vol. 44, pp. 297-301.
  6. The associations of daylight and melatonin receptor 1B gene rs10830963 variant with glycemic traits: the prospective PPP-Botnia study. Haljas, Kadri, et al. 1, Helsinki : s.n., 2019, Annals of medicine, Vol. 51, pp. 58-67.