Evidence for a link between the body clock hormone melatonin and type 2 diabetes continues to mount, and lower melatonin secretion in women was independently associated with a higher risk of developing type 2 diabetes.

Note that while the mechanism is not known, the evidence strongly suggests that melatonin has a direct effect on the pancreas and secretion of insulin.

Evidence for a link between the body clock hormone melatonin and type 2 diabetes continues to mount.

In a case-control study nested within the Nurses' Health Study cohort, women in the lowest category of melatonin secretion had more than double the risk of developing type 2 diabetes compared with women in the highest category of melatonin secretion, according to findings reported in the April 3 issue of the Journal of the American Medical Association.

The findings raise the intriguing possibility that increasing melatonin levels in the body may lower the risk of diabetes, although that remains to be tested, lead author Ciaran J. McMullan, MD, of Brigham and Women's Hospital, said in an interview.

Ian Hickie, MD, executive director of the Brain & Mind Research Institute at the University of Sydney in Australia, said in an interview that the study "is an important contribution to the emerging literature that suggests a likely physiological link between nighttime melatonin secretion and risk of diabetes." Hickie was not involved in the study.

Among the lines of evidence pointing to a protective effect of melatonin against diabetes development:

In several large, genome-wide association studies, loss-of-function mutations in the melatonin receptor were associated with insulin resistance and type 2 diabetes.

In a cross-sectional analysis of persons without diabetes, lower nocturnal melatonin secretion was associated with increased insulin resistance.

Diabetes-prone rats fed melatonin supplements were protected against the disease.

Because a prospective association between melatonin secretion and type 2 diabetes has not been previously reported in humans, McMullan and colleagues analyzed data from the Nurses' Health Study cohort.

Among participants without diabetes who provided urine and blood samples at baseline in 2000, the researchers identified 370 women who developed type 2 diabetes from 2000-2012, and matched 370 controls using risk-set sampling.

Melatonin secretion was estimated by measuring the concentration of its major metabolite, 6-sulfatoxymelatonin, in a first morning void urine specimen, and normalized to urinary creatinine.

Results showed:

An inverse association between melatonin secretion and incident type 2 diabetes when the ratio of urinary 6-sulfatoxymelatonin to creatinine was analyzed as a continuous variable (OR, 1.36 per unit decrease in estimated log ratio of 6-sulfatoxymelatonin to creatinine; 95% CI 1.14 to 1.61).

Women in the lowest tertile of melatonin secretion had 2.17 times the risk of developing type 2 diabetes than women in the highest category (95% CI 1.18 to 3.98).

The analysis was adjusted for diabetes confounders, including body mass index and other lifestyle factors, menopausal status, family history of diabetes, history of hypertension, use of beta-blockers or nonsteroidal anti-inflammatory drugs, region of the U.S., and plasma biomarkers of diabetes risk.

The incidence rate of diabetes was estimated to be 4.27 cases/1,000 person-years in the highest category of melatonin secretion and 9.27 cases/1,000 person-years in the lowest category of melatonin secretion, or an absolute rate difference of five cases/1,000 person-years.

While only women were studied, McMullan said he suspects the association will hold up in men as well.

Asked about mechanism, McMullan said the evidence strongly suggests that melatonin has an direct effect on the pancreas and secretion of insulin.

Melatonin secretion may contribute to the previously reported association between poor sleep and diabetes risk, he added.

Pending further study, patients must be discouraged from taking melatonin supplements in an effort to protect themselves against diabetes, McMullan stressed.

For starters, secretion of melatonin follows a diurnal pattern, with almost no production during daylight. "If you take over-the-counter supplements, you may get a very dissimilar pattern and we don't know what effect that would have on the body," McMullan said.

Also, "we still don't know who will benefit," he said. "It may be that only low melatonin secretors benefit."

Finally just because it is natural, doesn't mean it is safe, McMullan said. Melatonin can cause a host of side effects, including daytime sleepiness, dizziness, and headaches.