Associations between nocturnal urinary 6-sulfatoxymelatonin, obstructive sleep apnea severity and glycemic control in type 2 diabetes

ABSTRACT

Reduced nocturnal secretion of melatonin, a pineal hormone under circadian control, and obstructive sleep apnea have been both identified as risk factors for the development of type 2 diabetes mellitus. Whether they interact to impact glycemic control in patients with existing type 2 diabetes is not known. Therefore, this study explores the relationships between obstructive sleep apnea, melatonin and glycemic control in type 2 diabetes. As diabetic retinopathy may affect melatonin secretion, we also explore the relationship between retinopathy, melatonin and glycemic control. Fifty-six non-shift workers with type 2 diabetes, who were not using beta-blockers, participated. Most recent hemoglobin A1c (HbA1c) levels and the results of ophthalmologic examinations were obtained from medical records. Obstructive sleep apnea was diagnosed using an ambulatory device. Sleep duration and fragmentation were recorded by 7-day wrist actigraphy. The urinary 6-sulfatoxymelatonin/creatinine ratio, an indicator of nocturnal melatonin secretion, was measured in an overnight urine sample. Mediation analyses were applied to explore whether low nocturnal urinary 6-sulfatoxymelatonin/creatinine ratio could be a causal link between increasing obstructive sleep apnea severity [as measured by an Apnea Hypopnea Index (AHI)] and poorer glycemic control, and between the presence of retinopathy and glycemic control. AHI and HbA1c were log-scale (ln) transformed. Obstructive sleep apnea was found in 76.8%, and 25.5% had diabetic retinopathy. The median (interquartile range) of urinary 6-sulfatoxymelatonin/creatinine ratio was 12.3 (6.0, 20.1) ng/mg. Higher lnHbA1c significantly correlated with lower 6-sulfatoxymelatonin/creatinine ratio (p = 0.04) but was not directly associated with OSA severity. More severe obstructive sleep apnea (lnAHI, p = 0.01), longer diabetes duration (p = 0.02), retinopathy (p = 0.01) and insulin use (p = 0.03) correlated with lower urinary 6-sulfatoxymelatonin/creatinine ratio, while habitual sleep duration and fragmentation did not. A mediation analysis revealed that lnAHI negatively correlated with urinary 6-sulfatoxymelatonin/creatinine ratio (coefficient = −2.413, p = 0.03), and urinary 6-sulfatoxymelatonin/creatinine negatively associated with lnHbA1c (coefficient = −0.005, p = 0.02), after adjusting for covariates. Mediation analysis indicated that the effect of lnAHI on lnHbA1c was indirectly mediated by urinary 6-sulfatoxymelatonin/creatinine ratio (B = 0.013, 95% CI: 0.0006, 0.0505). In addition, having retinopathy was significantly associated with reduced nocturnal urinary 6-sulfatoxymelatonin/creatinine ratio, and an increase in HbA1c by 1.013% of its original value (B = −0.013, 95% CI: −0.038, −0.005). In conclusion, the presence and severity of obstructive sleep apnea as well as the presence of diabetic retinopathy were associated with lower nocturnal melatonin secretion, with an indirect adverse effect on glycemic control. Intervention studies are needed to determine whether melatonin supplementation may be beneficial in type 2 diabetes patients with obstructive sleep apnea.

KEYWORDS:

• Type 2 diabetes
• melatonin
• glycemic control
• obstructive sleep apnea

Acknowledgements

We thank Dr. Eve Van Cauter, Ph.D., Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, and Sleep, Metabolism and Health Center, Department of Medicine, The University of Chicago, Chicago, IL, USA, for her guidance and critical input to the manuscript; and Dr. Piyarat Govitrapong, Mahidol University, Bangkok, Thailand, for her assistance in reviewing the manuscript.

Declaration Of Interest

S. Reutrakul received speaker honoraria from Sanofi Aventis, Medtronic, Novo Nordisk and Astra Zeneca; research equipment support from ResMed, Thailand; and a research grant from Merck Sharp and Dohme. There is no financial interest related to the subject matter of this manuscript. Rest of the authors reported no conflicts of interest.

Funding

This study received grant support from Mahidol University, Bangkok, Thailand.

Additional information

Funding

This study received grant support from Mahidol University.

Notes on contributors

Sirimon Reutrakul

S. Reutrakul conceptualized the study, researched and analyzed the data, wrote manuscript, contributed to discussion, reviewed/edited manuscript and is the guarantor of this work and, as such, had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. N. Siwasaranond, H. Nimitphong, S. Saetung, L. Chailurkit researched data and reviewed/edited manuscript; N. Chirakalwasan contributed to discussion and reviewed/edited manuscript; K. Srijaruskul researched data; B. Ongphiphadhanakul analyzed data, contributed to discussion and reviewed/edited manuscript. A. Thakkinstian analyzed data, wrote manuscript, contributed to discussion and reviewed/edited manuscript.