Relationship between chronic kidney disease, glucose homeostasis, and plasma osteocalcin carboxylation and fragmentation

Authors: KRATZ, MARIO - Fred Hutchinson Cancer Research Center; ZELNICK, LEILA - University Of Washington; TRENCHEVSKA, OLGICA - Arizona State University; JEFFS, JOSHUA - Arizona State University; BORGES, CHAD - Arizona State University; TSENG, HSIN-HUI - Fred Hutchinson Cancer Research Center; BOOTH, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KESTENBAUM, BRYAN - University Of Washington; UTZSCHNEIDER, KRISTINA - University Of Washington; DE BOER, IAN - University Of Washington

Submitted to: Journal of Renal Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/18/2020
Publication Date: 7/18/2020
Citation: Kratz, M., Zelnick, L.R., Trenchevska, O., Jeffs, J.W., Borges, C.R., Tseng, H., Booth, S.L., Kestenbaum, B.R., Utzschneider, K.M., De Boer, I.H. 2020. Relationship between chronic kidney disease, glucose homeostasis, and plasma osteocalcin carboxylation and fragmentation. Journal of Renal Nutrition. 31(3):248-256. https://doi.org/10.1053/j.jrn.2020.05.013.
DOI: https://doi.org/10.1053/j.jrn.2020.05.013

Interpretive Summary: Chronic kidney disease (CKD) is associated with reduced insulin sensitivity through mechanisms that are not well understood. Low vitamin K intake and incomplete carboxylation of the vitamin K-dependent protein osteocalcin may promote insulin resistance. We assessed relationships of osteocalcin concentration and the carboxylation of osteocalcin with CKD and glucose metabolism in men and women with and without moderate to severe CKD. The total plasma osteocalcin concentration was higher in the CKD group. However, the extent of osteocalcin carboxylation did not differ between individuals with and without CKD. Osteocalcin concentration and carboxylation were not associated with any measure of glucose metabolism. Our data do not provide support for the hypothesis that differences in osteocalcin carboxylation may explain reduced insulin sensitivity in individuals with CKD.

Technical Abstract: Chronic kidney disease (CKD) is associated with reduced insulin sensitivity, through mechanisms that are not well understood. 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. We included 87 participants without diabetes: 50 (27 female) with moderate to severe CKD (estimated GFR <60 mL/min/1.73m^2 not treated with dialysis) and 37 (17 female) healthy controls. Total osteocalcin was measured by immunoassay, and osteocalcin carboxylation and fragmentation status by LC-ESI based mass spectrometric 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). The total plasma osteocalcin concentration was higher in the CKD group [mean (SD) 102.9 (147.5)] vs. controls [53.6 (51.1) ng/mL, p=0.03], 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. 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.