In a study observing 370 women (nurses) who developed
diabetes between 2000 and 2012 and 370 women (also nurses) who did not develop
diabetes during this time frame the major urinary metabolite of melatonin
(6-sulfatoxymelatonin) was measured against urinary creatinine. This was a part
of the Nurses'
Health Study cohort.[1]
This study provides a correlation between the lowest level
of melatonin metabolite secretion and the development of type 2 diabetes. Women
with the highest excretion of 6-sulfatoxymelatonin developed diabetes at a rate
of 4.27 cases per 1000 while women with the lowest excretion of
6-sulfatoxymelatonin developed diabetes at a rate of 9.27 cases per 1000. This
provides 2.17 times the risk for development of type 2 diabetes for those with
low excretion.
Upon the initial publication of these results, two immediate
camps developed. One camp, excited to explore the therapeutic uses of
supplemental melatonin and then another that dismissed the data due to the
nature of the study. It is correct to indicate that this information alone does
not allow for mass medication of those with type 2 diabetes or for use in
prophylaxis. However, researchers did an excellent job of addressing
confounding issues within the scope of known physiologic mechanisms.
With diabetes on the rise, and 1 in 10 American adults
wielding the diagnosis, this information is welcomed if it is interpreted
correctly and cautiously.
The first question that must be addressed is if urinary
excretion of 6-sulfatoxymelatonin is an adequate surrogate for nocturnal
melatonin secretion from the pineal gland. Secretion of melatonin follows a
daily pattern peaking 3-5 hours after sleep onset when it is dark with almost
no production during daylight. Fortunately, the urinary excretion of
6-sulfatoxymelatonin when normalized to urinary creatinine has been used to
estimate overnight melatonin secretion. This is good news since nocturnal
plasma evaluation is impractical in the outpatient setting.[2],[3]
Of interest is that this same biomarker was used to provide evidence for a
statistically significant inverse association between melatonin levels, as
measured in overnight morning urine, and invasive breast cancer risk in
postmenopausal women.[4]
The next question may be in regards to the relationship
between disrupted sleep and type 2 diabetes.[5]
Researchers noted sleep disruption by two factors: snoring and sleep duration.
Both of these factors were self-reported which may lead to limitation of
information.
Another question arises in regards to the mechanism of how
melatonin, a hormone typically associated with sleep directly affect glucose
metabolism. Researchers suggest it may have to do with insulin secretion but human
studies are lacking in this area. Most research is done on rodents and this is potentially
problematic. Rodents are primarily nocturnal creatures and have different
circadian patterns. While rats and mice may derive specific health benefits
from exogenous administration of melatonin, it doesn’t always mean that humans
will derive the same benefit to the same magnitude. However, the work that has
been done so far piques curiosity. Oral consumption of melatonin protected rats
prone to diabetes from developing increased cardiovascular and diabetes risk
markers while being fed a high-calorie diet.[6]
Melatonin administration to insulin-resistant mice reversed insulin resistance
and improved glucose metabolism.[7]
Human in-vitro studies have pointed to a kinase pathway that supports
pancreatic islet cells.[8],[9],[10]
While some may discount summarily the study because it is
done with nurses, all women, mostly (97%) Caucasian, and prone to shift work,
that may be a premature dismissal. Interestingly, the nurses involved in this
nested group of the Nurses’ Health Study reflected very little shift work
perhaps due to age and seniority. It is true though that results can only be
attributed to women and a limited racial heritage.
So while it is too early to suggest the use of melatonin as
adjunctive care to glucose metabolism, it will likely be several years before
type, dose, and timing of administration will be available in the peer-reviewed
literature. One thought in integrative medicine is to normalize levels similar as
how vitamin D is often recommended rather than a set dose. However, no agreed
upon reference range has been established for urinary 6-sulfatoxymelatonin:
creatinine although the highest quartile in this study had a median ratio of
67.0 ng/mg. Because melatonin is a hormone from outside of the body, the
recommendation of lowest effective dose may apply similarly to the
recommendation of hormone therapy.[11]
While melatonin may not be ready for the lime-light in
diabetes, low-dose melatonin is something to keep in mind when caring for those
patients at risk or suffering from the condition.
Natural Health International is the proud manufacturer and distributor of Herbatonin the first plant-based melatonin available in 3 mg and 0.3 mg
[1]
McMullan CJ, Schernhammer ES, Rimm EB, Hu FB, Forman JP. Melatonin secretion and the incidence
of type 2 diabetes. JAMA. 2013 Apr 3;309(13):1388-96.
doi: 10.1001/jama.2013.2710.
[2]
Lang U, Kornemark
M, Aubert ML, Paunier L, Sizonenko PC. Radioimmunological determination of
urinary melatonin in humans: correlation with
plasma levels and typical 24-hour rhythmicity. J Clin Endocrinol Metab. 1981;53(3):645-650.
[3]
Baskett JJ,
Cockrem JF, Antunovich TA. Sulphatoxymelatonin excretion in older people:
relationship
to plasma melatonin and renal function. J Pineal Res. 1998;24(1):58-61.
[4] Schernhammer ES, Berrino F, Krogh V, Secreto G,
Micheli A, Venturelli E, Sieri S, Sempos CT, Cavalleri A, Schünemann HJ, Strano
S, Muti P. Urinary 6-sulfatoxymelatonin levels and risk of breast cancer in
postmenopausal women.J Natl Cancer Inst. 2008 Jun 18;100(12):898-905. doi:
10.1093/jnci/djn171. Epub 2008 Jun 10.
[5] Wagner, Kelly. "Sleep Laboratory Finds Insomnia
With Short Sleep Duration Is A Risk Factor For Diabetes." Medical News
Today. MediLexicon, Intl., 11 Jun. 2009. Web.
13 May. 2013. <http://www.medicalnewstoday.com/releases/153361.php>
[6]
Prunet-Marcassus
B, Desbazeille M, Bros A, et al. Melatonin reduces body weight gain in Sprague
Dawley rats with diet-induced obesity. Endocrinology. 2003; 144(12):5347-5352.
[7]
Cuesta S, Kireev
R, Garcı´a C, Rancan L, Vara E,
Tresguerres JA. Melatonin can improve insulin resistance and aging-induced
pancreas alterations in senescence-
accelerated prone male mice (SAMP8). Age (Dordr). 2012.
[8]
Kemp DM, Ubeda M,
Habener JF. Identification and functional characterization of melatonin Mel 1a
receptors in pancreatic beta cells: potential role
in incretin-mediated cell function by sensitization of cAMP signaling. Mol Cell Endocrinol. 2002;191(2):157-166.
[9]
Ramracheya RD,
Muller DS, Squires PE, et al. Function and expression of melatonin receptors on
human pancreatic islets. J Pineal Res. 2008;44(3): 273-279.
[10]
Picinato MC,
Hirata AE, Cipolla-Neto J, et al. Activation of insulin and IGF-1 signaling
pathways
by melatonin through MT1 receptor in isolated rat
pancreatic islets. J Pineal Res. 2008;44(1):88-94.
[11]
http://www.fda.gov/forconsumers/byaudience/forwomen/ucm118624.htm
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