Decreased Melatonin Production Research Articles

The influence of insulin and glucose on norepinephrine stimulated pineal melatonin secretion

Interrelationships between carbohydrate metabolism and melatonin have been discussed for a long time. The melatonin(MT1)-receptor and Gi-mediated decrease of insulin secretion by melatonin is a well known fact. Recently, we found reduced melatonin plasma levels in type 2 diabetic patients and diabetic Goto Kakizaki (GK) rats, a model of non insulin dependent diabetes mellitus (NIDDM). Several mechanisms, such as diabetic neuropathy and oxidative stress were discussed by others to be the basis for this observation. We reported the expression of insulin receptor (InsR)-mRNA in the rat pineal gland. Earlier studies showed the InsR as being located at the cell membrane of the pinealocytes. The aim of this study was to investigate glucose, insulin and melatonin plasma levels by radioimmunoassay, regarding age and metabolic state of metabolic healthy Wistar and diabetic GK rats. Diurnal pineal InsR-mRNA expression was monitored by real-time RT-PCR. The influence of insulin and glucose on norepinephrine (NE) stimulated pineal melatonin secretion. Here we show that GK rats are permanently hyperglycemic and hyperinsulinemic at night-time. Hyperglycemia is stronger in adult than in young animals. The pineal expression level of InsR-mRNA is significantly lower in young, but higher in adult pineal glands of GK rats. No diurnal rhythmicity of expression was observed. Insulin-stimulated pineals from batch culture supernatants of both, GK- and Wistar rats, showed decreased melatonin production. First perifusion experiments revealed a lower melatonin output when stimulating pineals with NE and insulin or NE and glucose than with NE alone. The effects were not cAMP-mediated. Our results suggest that there is an insulin/InsR-mediated interrelationship between beta cells and pinealocytes. A contribution of hyperglycemia and hyperinsulinemia to reduced melatonin plasma levels seems to be likely and should be further investigated.

Headliners: Breast Cancer: Decreased Melatonin Production Linked to Light Exposure

Blask DE, Brainard GC, Dauchy RT, Hanifin JP, Davidson LK, Krause JA, et al. 2005. Cancer Res 65(23):11174–11184. The incidence of breast cancer is up to fives times higher in women living in industrialized nations compared to those living in developing countries, and female night shift workers have particularly high rates of the disease. Given that Western nations have become “24-hour societies,” with more people awake around the clock, one hypothesis holds that nighttime exposure to artificial light suppresses the nocturnal production of melatonin. This hormone, produced by the pineal gland, helps regulate the body’s circadian rhythm and immune function, and also suppresses tumor growth. Now NIEHS grantees David E. Blask and George C. Brainard and their colleagues have confirmed that ocular exposure to bright artificial light at night inhibits the production of melatonin, which in turn may lead to an increased risk of developing breast cancer. The researchers implanted human breast cancer cells into female laboratory mice, then transferred the malignant tumors that formed to female rats for continued development. They then collected blood from several healthy premenopausal volunteers under three different conditions: during the day, during the night following two hours of complete darkness, and during the night following 90 minutes of exposure to bright fluorescent light. Next, they infused the collected blood directly through the developing tumors. Melatonin-rich blood collected following complete darkness slowed the growth of cancer tumors, while melatonin-depleted blood collected from volunteers exposed to both daylight and bright fluorescent light stimulated tumor growth. The team also exposed tumor-bearing rats to varying intensities of light during the darkness phase of an alternating 12-hour light/12-hour dark cycle. They found that the extent to which melatonin production was suppressed depended on the magnitude of the light intensity that the rats were exposed to during the dark phase. The authors say these results establish a role for the natural, nocturnal production of melatonin as a preventive agent in human disease. They also emphasize the risks of extensive exposure to bright artificial light at night, and point to the possibility that preserving the integrity of the circadian melatonin signal could help prevent breast cancer.

Light at Night and Cancer Risk¶

Environmental lighting powerfully suppresses the physiologic release of melatonin, which typically peaks in the middle of the night. This decreased melatonin production has been hypothesized to increase the risk of cancer. Evidence from experimental studies supports a link between melatonin and tumor growth. There is also fairly consistent indirect evidence from observational studies for an association between melatonin suppression, using night work as a surrogate, and breast cancer risk.

ACTIGRAPHIC SLEEP-WAKE PATTERNS AND URINARY 6-SULFATOXYMELATONIN EXCRETION IN PATIENTS WITH ALZHEIMER'S DISEASE

Recent studies suggest melatonin, due to its antioxidant and free-radical- scavenging actions, may play a role in the neuroprotection against amyloid, which is implicated in the pathogenesis of Alzheimer's disease (AD). In this study, we determined urinary 6-sulfatoxymelatonin (aMT6s) excretion together with actigraphic sleep-wake patterns of untreated male patients with AD who lived at home. Results were compared with those obtained from normal age-matched elderly and normal young male subjects. Similar measurements were also performed in another group of patients with AD who were treated with a cholinesterase inhibitor (Donepezil, Aricept). Total 24h aMT6s values were significantly reduced in elderly controls (19.9h ± 5.2 μg/24h), in those with untreated AD (12.7 ± 4.4 μg/24h), and in patients treated for AD (12.4 ± 4.4 μ g/24h) compared with normal young men (32.8 ± 3.1 μ g/24h). A day-night difference in aMT6s was evident in all young controls, in 50% of elderly controls, in only 20% of patients with untreated AD, and in 67% of those with AD receiving Aricept. Sleep quality (expressed as sleep efficiency, wake time, and long undisturbed sleep duration) was better in young and elderly controls compared with the two groups of patients with AD. There was no significant correlation between aMT6s values or sleep patterns and the severity of cognitive impairment in patients with AD. Taken together, these data suggest that disrupted sleep, decreased melatonin production, and partial lack of day-night difference in melatonin secretion were observed equally in normal elderly and in patients with AD. Our results do not permit drawing any conclusion as to whether changes in urinary aMT6s excretion is correlated with disturbed sleep in patients with AD. (Chronobiology International, 18(3), 513–524, 2001)

A preliminary understanding of mania: roles for melatonin, vasotocin and rapid-eye-movement sleep

Speculation about mania links melatonin, vasotocin and rapid-eye-movement (REM) sleep. Normal REM sleep can have the loss of reality testing and this feature intruding into the wake period could be the cause of the distorted reality present in manic delusions. REM sleep has a role in memory formation. Abnormal levels and/or rhythms of melatonin are thought to be involved in mania. Decreased melatonin production with malfunction of REM sleep is proposed to be a cause of sudden infant death syndrome and Alzheimer's disease, because the loss of the antioxidant function of melatonin allows brain injury to occur.

The relationship between electromagnetic field and light exposures to melatonin and breast cancer risk: a review of the relevant literature.

Worldwide, breast cancer is the most common malignancy accounting for 20-32% of all female cancers. This review summarizes the peer-reviewed, published data pertinent to the hypothesis that increased breast cancer in industrialized countries is related to the increased use of electricity [Stevens, R.G., S. Davis 1996]. That hypothesis specifically proposes that increased exposure to light at night and electromagnetic fields (EMF) reduce melatonin production. Because some studies have shown that melatonin suppresses mammary tumorigenesis in rats and blocks estrogen-induced proliferation of human breast cancer cells in vitro, it is reasoned that decreased melatonin production leads to increased risk of breast cancer. To evaluate this hypothesis, the paper reviews epidemiological data on associations between electricity and breast cancer, and assesses the data on the effects of EMF exposure on melatonin physiology in both laboratory animals and humans. In addition, the results on the effects of melatonin on in vivo carcinogenesis in animals are detailed along with the controlled in vitro studies on melatonin's effects on human breast cancer cell lines. The literature is evaluated for strength of evidence, inter-relationships between various lines of evidence, and gaps in our knowledge. Based on the published data, it is currently unclear if EMF and electric light exposure are significant risk factors for breast cancer, but further study appears warranted. Given the ubiquitous nature of EMF and artificial light exposure along with the high incidence of breast cancer, even a small risk would have a substantial public health impact.

Docosahexaenoic Acid Reduces Both Cyclic Nucleotide and Melatonin Synthesis in Rat Pinealocytes

The effect of docosahexaenoic acid (22:6n-3) on melatonin (MT) production in rat pinealocytes was measured. In pinealocytes, supplementation with 50 μM 22:6n-3 for 48 h decreased MT production after a norepinephrine (NE)-stimulation (1 and 10 μM). Using co-treatment with IBMX (1 mM), a cyclic nucleotide phosphodiesterase inhibitor known to increase NE-stimulated cAMP and prazosin (1 μM), an α1 antagonist, the results indicate that a) 22:6n-3 did not act on cyclic nucleotide phosphodiesterase activities to decrease both cAMP (−64%) and cGMP (−45%) levels and b) the inhibition of cGMP was higher (−70%) in presence of prazosin. These results confirm that in rat pinealocytes the lowering effect of 22:6n-3 supplementation on cAMP is likely to be dependent on α1-adrenoceptor modulation whereas the decrease of cGMP seems to involve other intracellular mechanisms. The absence of 22:6n-3 effect on serotonin metabolites suggest that the lowering effect on MT may be also correlated with alterations of O-methylation step.