Dr. Ron’s Research Review – March 26, 2014

© 2014

This week’s research review focuses on melatonin, insulin and diabetes type 2.

A study published in JAMA showed that lower melatonin secretion was independently associated with a higher risk of developing type 2 diabetes. (McMullan, Schernhammer et al. 2013)

The same authors found higher nocturnal melatonin secretion was inversely associated with insulin levels and insulin resistance in non-diabetic young women. (McMullan, Curhan et al. 2013)

Both studies used the urinary 6-sulfatoxymelatonin:creatinine ratio.

An earlier study published in the Journal of Pineal Research found that melatonin treatment (5 mg/day, 2 hr before bedtime for 2 months) improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome. (Kozirog, Poliwczak et al. 2011)

A summary of melatonin, endocrine pancreas and diabetes was published in the Journal of Pineal Research. (Peschke 2008)

Insulin exhibits a circadian rhythm, which is apparently influenced by melatonin.

Melatonin likely inhibits insulin release via inhibition of the cGMP-pathway.

Beta-cells are very susceptible to oxidative stress, which may be ameliorated by melatonin.

Dr. Ron


Articles

Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome

         (Kozirog, Poliwczak et al. 2011) Download

Experimental studies have proven that melatonin has many beneficial pleiotropic actions. The aim of this study was to assess melatonin efficacy in patients with metabolic syndrome (MS). The study included 33 healthy volunteers (who were not treated with melatonin) and 30 patients with MS, who did not respond to 3-month lifestyle modification. Patients with MS were treated with melatonin (5 mg/day, 2 hr before bedtime) for 2 months. The following parameters were studied: systolic and diastolic blood pressure (SBP, DBP), levels of glucose, serum lipids, C-reactive protein, fibrinogen, activities of antioxidative enzymes: catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), thiobarbituric acid reactive substrates (TBARS). After 2-month therapy in comparison with baseline, the following significant changes were measured: systolic blood pressure (132.8+/-9.8 versus 120.5+/-11.0 mmHg, P<0.001), DBP (81.7+/-8.8 versus 75+/-7.4 mmHg, P<0.01), low-density lipoprotein cholesterol (LDL-C) (149.7+/-26.4 versus 139.9+/-30.2 mg/dL, P<0.05), TBARS (0.5+/-0.2 versus 0.4+/-0.1 mum/gHb, P<0.01), and CAT (245.9+/-46.9 versus 276.8+/-39.4 U/gHb). Melatonin administered for 2 months significantly improved antioxidative defense (increase in CAT activity, decrease in TBARS level) and lipid profile (decrease in LDL-C), and lowered blood pressure. We conclude that melatonin therapy may be of benefit for patients with MS, particularly with arterial hypertension. Further studies with higher doses of melatonin or prolonged supplementation are awaited.

Melatonin secretion and the incidence of type 2 diabetes

         (McMullan, Schernhammer et al. 2013) Download

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. RESULTS: The 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 RELEVANCE: Lower 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.

Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women

         (McMullan, Curhan et al. 2013) Download

Exogenous melatonin ameliorates insulin resistance in animals, while among humans, polymorphisms in the melatonin receptor gene are associated with insulin resistance. We aimed to investigate the association of endogenous nocturnal melatonin secretion with insulin resistance in humans. We analyzed the association between endogenous nocturnal melatonin secretion, estimated by measuring the main melatonin metabolite, 6-sulfatoxymelatonin, from the first morning urinary void, and the prevalence of insulin resistance based on fasting blood samples collected in a cross-sectional study of 1,075 US women (1997-1999) without diabetes, hypertension, or malignancy. Urinary 6-sulfatoxymelatonin level was standardized to urinary creatinine level; insulin resistance was defined as an insulin sensitivity index value (using the McAuley formula) less than 7.85. Logistic regression models included adjustment for age, body mass index, smoking, physical activity, alcohol intake, dietary glycemic index, family history of diabetes mellitus, blood pressure, plasma total cholesterol, uric acid, and estimated glomerular filtration rate. Higher nocturnal melatonin secretion was inversely associated with insulin levels and insulin resistance. In fully adjusted models, the odds ratio for insulin resistance was 0.45 (95% confidence interval: 0.28, 0.74) among women in the highest quartile of urinary 6-sulfatoxymelatonin:creatinine ratio compared with women in the lowest quartile. Nocturnal melatonin secretion is independently and inversely associated with insulin resistance.

Melatonin, endocrine pancreas and diabetes

         (Peschke 2008) Download

Melatonin influences insulin secretion both in vivo and in vitro. (i) The effects are MT(1)-and MT(2)-receptor-mediated. (ii) They are specific, high-affinity, pertussis-toxin-sensitive, G(i)-protein-coupled, leading to inhibition of the cAMP-pathway and decrease of insulin release. [Correction added after online publication 4 December 2007: in the preceding sentence, 'increase of insulin release' was changed to 'decrease of insulin release'.] Furthermore, melatonin inhibits the cGMP-pathway, possibly mediated by MT(2) receptors. In this way, melatonin likely inhibits insulin release. A third system, the IP(3)-pathway, is mediated by G(q)-proteins, phospholipase C and IP(3), which mobilize Ca(2+) from intracellular stores, with a resultant increase in insulin. (iii) Insulin secretion in vivo, as well as from isolated islets, exhibits a circadian rhythm. This rhythm, which is apparently generated within the islets, is influenced by melatonin, which induces a phase shift in insulin secretion. (iv) Observation of the circadian expression of clock genes in the pancreas could possibly be an indication of the generation of circadian rhythms in the pancreatic islets themselves. (v) Melatonin influences diabetes and associated metabolic disturbances. The diabetogens, alloxan and streptozotocin, lead to selective destruction of beta-cells through their accumulation in these cells, where they induce the generation of ROS. Beta-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. Results suggest that melatonin in pharmacological doses provides protection against ROS. (vi) Finally, melatonin levels in plasma, as well as the arylalkylamine-N-acetyltransferase (AANAT) activity, are lower in diabetic than in nondiabetic rats and humans. In contrast, in the pineal gland, the AANAT mRNA is increased and the insulin receptor mRNA is decreased, which indicates a close interrelationship between insulin and melatonin.

References

Kozirog, M., A. R. Poliwczak, et al. (2011). "Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome." J Pineal Res 50(3): 261-6. [PMID: 21138476]

McMullan, C. J., G. C. Curhan, et al. (2013). "Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women." Am J Epidemiol 178(2): 231-8. [PMID: 23813704]

McMullan, C. J., E. S. Schernhammer, et al. (2013). "Melatonin secretion and the incidence of type 2 diabetes." JAMA 309(13): 1388-96. [PMID: 23549584]

Peschke, E. (2008). "Melatonin, endocrine pancreas and diabetes." J Pineal Res 44(1): 26-40. [PMID: 18078445]