Relationship Between Chronic Kidney Disease, Glucose Homeostasis, and Plasma Osteocalcin Carboxylation and Fragmentation

Objective: Chronic kidney disease (CKD) is associated with reduced insulin sensitivity, through mechanisms that are not well under-stood. Low vitamin K intake and incomplete carboxylation of the vitamin K-dependent protein osteocalcin may promote insulin resistance. We assessed relationships of osteocalcin concentration, carboxylation, and fragmentation with CKD and glucose homeostasis in a cross-sectional study. Methods: We included 87 participants without diabetes: 50 (27 female) with moderate to severe CKD (estimated glomerular filtration rate <60 mL/min/1.73 m(2) not treated with dialysis) and 37 (17 female) healthy controls. Total osteocalcin was measured by immuno-assay, and osteocalcin carboxylation and fragmentation status by liquid chromatography-electrospray ionization-based mass spectro-metric immunoassay. Endpoints included glucose tolerance (based on 2-hour oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), and pancreatic beta-cell function (intravenous glucose tolerance test). Results: The total plasma osteocalcin concentration was higher in the CKD group (mean [standard deviation] 102.9 [147.5]) than that in the control group (53.6 [51.1] ng/mL, P = .03), and more osteocalcin was circulating as fragments. The extent of osteocalcin carbocylation did not differ between individuals with and without CKD. Osteocalcin concentration, carboxylation, and fragmentation were not associated with any measure of glucose homeostasis in multivariable-adjusted analyses. Conclusions: In CKD, circulating osteocalcin concentrations are elevated, in part due to larger proportions of fragmented forms. However, osteocalcin carboxylation status is not significantly different between individuals with and without CKD. Our data also do not provide support for the hypothesis that differences in osteocalcin carboxylation may explain reduced insulin sensitivity in individuals with CKD. (C) 2020 by the National Kidney Foundation, Inc. All rights reserved

Automated summary

In chronic kidney disease (CKD) patients, circulating osteocalcin concentrations are elevated, partly due to increased proportions of fragmented forms. However, osteocalcin carboxylation status does not significantly differ between individuals with and without CKD. The data also do not support the hypothesis that differences in osteocalcin carboxylation may explain reduced insulin sensitivity in individuals with CKD.