title: Timed Inhibition of Orexin System by Suvorexant Improved Sleep and Glucose Metabolism in Type 2 Diabetic db/db Mice.
abstract: Sleep disturbances are associated with type 2 diabetes; therefore, the amelioration of sleep may improve metabolic disorders. To investigate this possibility, we here examined the effects of suvorexant, an antiinsomnia drug targeting the orexin system, on sleep and glucose metabolism in type 2 diabetic mice. Diabetic db/db mice had a longer wakefulness time during the resting period, as compared with nondiabetic db/m+ control mice. The single or 7-day administration of suvorexant at lights-on (ie, the beginning of the resting phase) increased nonrapid eye movement sleep time during the resting phase and, as a consequence, reduced awake time. The daily resting-phase administration of suvorexant for 2-4 weeks improved impaired glucose tolerance in db/db mice without affecting body weight gain, food intake, systemic insulin sensitivity, or serum insulin, and glucagon levels. No changes were detected in the markers of lipid metabolism and inflammation, such as the hepatic triglyceride content and Tnf-α mRNA levels in liver and adipose tissues. The improving effect of suvorexant on glucose tolerance was associated with a reduction in the expression levels of hepatic gluconeogenic factors, including phosphoenolpyruvate carboxykinase and peroxisome proliferator-activated receptor-γ coactivator-1α in the liver in the resting phase. In contrast, the daily awake-phase administration of suvorexant had no beneficial effect on glucose metabolism. These results suggest that the suvorexant-induced increase of sleep time at the resting phase improved hepatic glucose metabolism in db/db mice. Our results provide insight into the development of novel pharmacological interventions for type 2 diabetes that target the orexin-operated sleep/wake regulatory system.
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuneki
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Kanta
authors.initials: K
authors.lastname: Kon
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Hisakatsu
authors.initials: H
authors.lastname: Ito
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Satoyuki
authors.initials: S
authors.lastname: Takahara
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Toyooka
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sasahara
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Wada
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Departments of Clinical Pharmacology (H.T., K.K., T.W., T.Sas.) and Anesthesiology (H.I., M.Yam.), Graduate School of Science and Technology, and Graduate School of Innovative Life Science (S.T., N.T.), and Department of Pathology (Y.I., M.S.), University of Toyama, Toyama 930-0194, Japan; and International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Yan., T.Sak.), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sasaoka
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001381:Azepines / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000068796:Orexin Receptor Antagonists / Q000627:therapeutic use*; D000068797:Orexins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D012890:Sleep / Q000187:drug effects*; D014230:Triazoles / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood; D014851:Wakefulness / Q000187:drug effects
chemical_list: D001381:Azepines; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000068796:Orexin Receptor Antagonists; D000068797:Orexins; D054411:Receptors, Leptin; D014230:Triazoles; D014280:Triglycerides; C515447:leptin receptor, mouse; C551624:suvorexant; D005934:Glucagon; D005947:Glucose