title: 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.
authors.affiliation: a Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital , Mahidol University , Bangkok , Thailand.
authors.forename: Sirimon
authors.initials: S
authors.lastname: Reutrakul
authors.affiliation: a Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital , Mahidol University , Bangkok , Thailand.
authors.forename: Nantaporn
authors.initials: N
authors.lastname: Siwasaranond
authors.affiliation: a Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital , Mahidol University , Bangkok , Thailand.
authors.forename: Hataikarn
authors.initials: H
authors.lastname: Nimitphong
authors.affiliation: a Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital , Mahidol University , Bangkok , Thailand.
authors.forename: Sunee
authors.initials: S
authors.lastname: Saetung
authors.affiliation: b Division of Pulmonary and Critical Care Medicine, Department of Medicine, Faculty of Medicine , Chulalongkorn University , Bangkok , Thailand.|c Excellence Center for Sleep Disorders , King Chulalongkorn Memorial Hospital, Thai Red Cross Society , Bangkok , Thailand.
authors.forename: Naricha
authors.initials: N
authors.lastname: Chirakalwasan
authors.affiliation: a Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital , Mahidol University , Bangkok , Thailand.
authors.forename: La-Or
authors.initials: LO
authors.lastname: Chailurkit
authors.affiliation: a Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital , Mahidol University , Bangkok , Thailand.
authors.forename: Kriangsuk
authors.initials: K
authors.lastname: Srijaruskul
authors.affiliation: a Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital , Mahidol University , Bangkok , Thailand.
authors.forename: Boonsong
authors.initials: B
authors.lastname: Ongphiphadhanakul
authors.affiliation: d Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine , Ramathibodi Hospital, Mahidol University , Bangkok , Thailand.
authors.forename: Ammarin
authors.initials: A
authors.lastname: Thakkinstian
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology*; D003404:Creatinine / Q000652:urine*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives* / Q000652:urine; D008875:Middle Aged; D012307:Risk Factors; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; C054513:6-sulfatoxymelatonin; D003404:Creatinine; D008550:Melatonin
keywords: Type 2 diabetes; glycemic control; melatonin; obstructive sleep apnea