Therapeutic potentials of nonpeptidic V2R agonists for partial cNDI-causing V2R mutants.

Loss-of-function mutations in the type 2 vasopressin receptor (V2R) are a major cause of congenital nephrogenic diabetes insipidus (cNDI). In the context of partial cNDI, the response to desmopressin (dDAVP) is partially, but not entirely, diminished. For those with the partial cNDI, restoration of V2R function would offer a prospective therapeutic approach. In this study, we revealed that OPC-51803 (OPC5) and its structurally related V2R agonists could functionally restore V2R mutants causing partial cNDI by inducing prolonged signal activation. The OPC5-related agonists exhibited functional selectivity by inducing signaling through the Gs-cAMP pathway while not recruiting ß-arrestin1/2. We found that six cNDI-related V2R partial mutants (V882.53M, Y1283.41S, L1614.47P, T2736.37M, S3298.47R and S3338.51del) displayed varying degrees of plasma membrane expression levels and exhibited moderately impaired signaling function. Several OPC5-related agonists induced higher cAMP responses than AVP at V2R mutants after prolonged agonist stimulation, suggesting their potential effectiveness in compensating impaired V2R-mediated function. Furthermore, docking analysis revealed that the differential interaction of agonists with L3127.40 caused altered coordination of TM7, potentially contributing to the functional selectivity of signaling. These findings suggest that nonpeptide V2R agonists could hold promise as potential drug candidates for addressing partial cNDI.

HbA1c levels Measured by Enzymatic Assay and Immunoassay during Off-Site Health Checkups Are Both Lower than Those Measured by On-Site HPLC Assay.

It has already been reported that HbA1c levels measured by immunoassay (IA) (IA-HbA1c) during off-site health checkups present falsely lower results. We also reported that HbA1c levels measured by enzymatic assay (EA) (EA-HbA1c) during off-site health checkups are lower. In the present study, we compared IA-HbA1c levels or EA-HbA1c levels during off-site health checkups with on-site high-performance liquid chromatography (HPLC)-HbA1c levels using the same samples. Subjects were 88 non-diabetic individuals who had health checkups in Nishinomiya Municipal Central Hospital. Subjects with a history of diabetes mellitus and those with HPLC-HbA1c ≥ 6.5% were excluded. IA-HbA1c levels (Study 1) or EA-HbA1c levels (Study 2) in the health checkups were compared with on-site HPLC-HbA1c levels using the same samples. Both IA-HbA1c levels and EA-HbA1c levels had positive correlations with HPLC-HbA1c levels (p <0.0001 for both), although both were significantly lower than HPLC-HbA1c levels (p <0.0001 for both). The degrees of reductions in the IA-HbA1c levels and EA-HbA1c levels compared with HPLC-HbA1c levels were almost same to each other. Similarly to IA-HbA1c levels, EA-HbA1c levels during the health checkups were lower than HPLC-HbA1c levels. It was demonstrated that HbA1c levels decrease similarly if measured by either EA or IA during off-site health checkups.