Melatonin Secretion and the Incidence of Type 2 Diabetes

Abstract

Importance Loss-of-function mutations in the melatonin receptor are associated with insulin resistance and type 2 diabetes. Additionally, in a cross-sectional analysis of persons without diabetes, lower nocturnal melatonin secretion was associated with increased insulin resistance.Objective To study the association between melatonin secretion and the risk of developing type 2 diabetes. Design, Setting, and Participants Case-control study nested within the Nurses' Health Study cohort. Among participants without diabetes who provided urine and blood samples at baseline in 2000, we identified 370 women who developed type 2 diabetes from 2000-2012 and matched 370 controls using risk-set sampling.Main Outcome Measures Associations between melatonin secretion at baseline and incidence of type 2 diabetes were evaluated with multivariable conditional logistic regression controlling for demographic characteristics, lifestyle habits, measures of sleep quality, and biomarkers of inflammation and endothelial dysfunction. ResultsThe median urinary ratios of 6-sulfatoxymelatonin to creatinine were 28.2 ng/mg (5%-95% range, 5.5-84.2 ng/mg) among cases and 36.3 ng/mg (5%-95% range, 6.9-110.8 ng/mg) among controls. Women with lower ratios of 6-sulfatoxymelatonin to creatinine had increased risk of diabetes (multivariable odds ratio, 1.48 [95% CI, 1.11-1.98] per unit decrease in the estimated log ratio of 6-sulfatoxymelatonin to creatinine). Compared with women in the highest ratio category of 6-sulfatoxymelatonin to creatinine, those in the lowest category had a multivariable odds ratio of 2.17 (95% CI, 1.18-3.98) of developing type 2 diabetes. Women in the highest category of melatonin secretion had an estimated diabetes incidence rate of 4.27 cases/ 1000 person-years compared with 9.27 cases/1000 person-years in the lowest category. Conclusions and RelevanceLower melatonin secretion was independently associated with a higher risk of developing type 2 diabetes. Further research is warranted to assess if melatonin secretion is a modifiable risk factor for diabetes within the general population.

The case for too little melatonin signalling in increased diabetes risk

“…Our data suggested that decreased melatonin signalling through deleterious MT2 receptor activity increases type 2 diabetes risk. These conclusions were in line with various studies done in rodents, beta cells and human cohorts, which showed that high melatonin levels, or the administration of melatonin or of melatonergic agonists, lead to decreased (and not augmented) risk of diabetes [9,13,14]. Indeed, for instance, a 12 year prospective study including 370 women who developed type 2 diabetes and 370 matched control participants showed that decreased levels of melatonin secretion during the night is independently associated with a higher risk of developing type 2 diabetes [13].…”

“…These conclusions were in line with various studies done in rodents, beta cells and human cohorts, which showed that high melatonin levels, or the administration of melatonin or of melatonergic agonists, lead to decreased (and not augmented) risk of diabetes [9,13,14]. Indeed, for instance, a 12 year prospective study including 370 women who developed type 2 diabetes and 370 matched control participants showed that decreased levels of melatonin secretion during the night is independently associated with a higher risk of developing type 2 diabetes [13]. However, Tuomi et al showed in 45 individuals that 3 month exposure to a high dose of melatonin (4 mg per day) is associated with higher glucose values 90 min post glucose load [1].…”

Chronomedicine and type 2 diabetes: shining some light on melatonin

“…Similar decrements in plasma melatonin levels during the night were also reported in diabetic patients with proliferative retinopathy relative to individuals without diabetes and diabetic individuals without retinopathy [149]. Though considerable evidence supports a positive correlation between lower night-time melatonin and increased risk of type 2 diabetes [50,139], not all data fully support this claim. Mantele and colleagues demonstrated that night-time melatonin levels were, in fact, elevated in obese individuals (compared with lean non-diabetic individuals) and unaffected in type 2 diabetic participants [150].…”

“…Strikingly, a reduced level of night-time melatonin, as assessed by 6-sulfatoxymelatonin in morning urinary void, is positively associated with an increased risk of type 2 diabetes (Fig. 2) [50]. There is an emerging link between melatonin secretion, insulin secretion and abnormal glucose metabolism, and, thus, it is reasonable to hypothesise that altered/reduced melatonin levels may contribute to the development and severity of both metabolic and sleep disturbances in patients with type 2 diabetes.…”

Molecularly imprinted electrochemical sensing of urinary melatonin in a microfluidic system

“…Numerous investigations have suggested that low melatonin levels may be associated with risks of breast cancer, 16 prostate cancer, 17 and type 2 diabetes. 18 Melatonin supplements may help sufferers of insomnia 19 and menopause. 20 The measurement of urinary melatonin 21 is also useful for monitoring levels of serum melatonin following oral administration.…”