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The deletion of Mecp2, the gene encoding methyl-CpG-binding protein 2, causes severe breathing defects and developmental anomalies in mammals. In Mecp2-null mice, impaired GABAergic neurotransmission is demonstrated at the early stage of life. GABAergic dysfunction in neurons in the rostral ventrolateral medulla (RVLM) is considered as a primary cause of breathing abnormality in Mecp2-null mice, but its molecular mechanism is unclear. Here, we report that mRNA expression levels of Gad1, which encodes glutamate decarboxylase 67 (GAD67), in the RVLM of Mecp2-null (Mecp2-/y, B6.129P2(C)-Mecp2tm1.1Bird/J) mice is closely related to the methylation status of its promoter, and valproate (VPA) can upregulate transcription from Gad1 through epigenetic mechanisms. The administration of VPA (300 mg/kg/day) together with L-carnitine (30 mg/kg/day) from day 8 to day 14 after birth increased Gad1 mRNA expression in the RVLM and reduced apnea counts in Mecp2-/y mice on postnatal day 15. Cytosine methylation levels in the Gad1 promoter were higher in the RVLM of Mecp2-/y mice compared to wild-type mice born to C57BL/6J females, while VPA treatment decreased the methylation levels in Mecp2-/y mice. Chromatin immunoprecipitation assay revealed that the VPA treatment reduced the binding of methyl-CpG binding domain protein 1 (MBD1) to the Gad1 promoter in Mecp2-/y mice. These results suggest that VPA improves breathing of Mecp2-/y mice by reducing the Gad1 promoter methylation, which potentially leads to the enhancement of GABAergic neurotransmission in the RVLM.

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Introduction and Aims: New onset diabetes mellitus (DM) in hemodialysis (HD) patients has been reported to affect mortality; however, the prevalence of diabetes in HD patients is unclear. HD patients have several risk factors for onset of DM including insufficient exercise, and highly glycated, high lipid and high energy intake. As a diagnostic tool, the validity of haemoglobin A1c (HbA1c) or glycoalbumin (GA) measurement is still controversial in HD patients. Indeed, some HD patients exhibit low HbA1c or GA level despite impaired fasting blood glucose (FBG) levels. HbA1c is affected by anemia, using erythropoietin stimulating agents and the shortening red blood cell cycling; in addition, GA is affected by hypoalbuminemia, nephrotic syndrome, cirrhosis and thyroidal dysfunction. Nonetheless, FBG test for HD patients are not popular because many HD management doctors believe that HbA1c or GA are golden diagnostic and management marker for DM. In this study, we examined the more correct prevalence of new onset DM and the validity of HbA1c and GA measurement for diagnosis of DM in HD patients. Methods: This is a single center cross-sectional study. Patients who received hemodialysis in Ohno memorial hospital in 2012 (n=335), were enrolled in this study for a routine monthly blood test and checked up their back ground as past diagnosed DM. Patients with malignancy and unstable condition due to complications were excluded. Patients exhibited FBG level equal to or more than 126 mg/dl, have received a 75g oral glucose tolerance test (75gOGTT). Results: 135 patients had already been diagnosed with DM, 169 had not been examined for DM and 31 denied consent. 3 patients were diagnosed by casual glucose≧200mg/dl at least 2 times. 95 patients out of 166 were suspected to be DM by high FBG level. 75gOGTT revealed that 46 patients were DM (Age 70.5±9.7year, median 70.5, range 44-89year; HD duration 7.8±6.9year, median 5.5year, range 2-32year; Sex male31, female15) and 31 were borderline DM (Age 64.5±11.7year, median 65, range 42-88year; HD duration 9.1±9.8year, median 4year, range 2-35year; Sex male26, female5) . These findings showed that we newly diagnosed DM in 49 out of undiagnosed 169 subjects; that is, we revealed that at least 54.9% ([135+49]/335) HD patients in this hospital were DM. Interestingly, in patients newly diagnosed with DM, the level of both HbA1c and GA were inadequate for the diagnosis of DM (HbA1c, median 5.3%, range 4.6-6.9%; GA, median 14.6%, range 10.9-20.5%). Conclusions: We found high prevalence of DM in HD patients, while there was a pitfall in using HbA1c or GA for the diagnosis of DM in HD patients. Therefore, we strongly recommend routine FBG test and subsequent 75gOGTT for the diagnosis of DM in HD patients who exhibit high FBG.