Correlations of Carboxylated and un(der)Carboxylated Osteocalcin with Parameters of Energy Metabolism in Subjects with and without Type 2 Diabetes View PDF

^*Silvia Gancheva
Department Of Pharmacology And Clinical Pharmacology And Therapeutics, Faculty Of Medicine, Medical University Of Varna, 55 Marin Drinov Str, Varna 9002, Bulgaria

^*Corresponding Author:

Silvia Gancheva
Department Of Pharmacology And Clinical Pharmacology And Therapeutics, Faculty Of Medicine, Medical University Of Varna, 55 Marin Drinov Str, Varna 9002, Bulgaria
Email:silvi_gancheva@abv.bg

Published on: 2021-12-20

Abstract

Background: Osteocalcin is a vitamin K-dependent protein produced by osteoblasts. In systemic circulation, it is found in both carboxylated and un- or undercarboxylated forms. Experimental studies have revealed that un(der)carboxylated osteocalcin affects beneficially the energy metabolism in mice and rats. Clinical trials have confirmed the endocrine activity of osteocalcin in humans. However, it remains controversial as to which form of the protein is the one possessing hormonal function.
Aim: In an attempt to clarify the above question, we searched for associations of un(der)carboxylated and carboxylated osteocalcin with anthropometric and biochemical parameters in subjects with and without type 2 diabetes.
Methods: The current cross-sectional study included 46 diabetics and 19 non-diabetic participants. Circulating levels of carboxylated and un(der)carboxylated osteocalcin were measured through high-sensitive enzyme immunoassay kits. The energy metabolism was characterized by anthropometric measures, lipid profile, fasting blood glucose and glycated hemoglobin level. The level of lipid peroxidation was determined to assess oxidative stress.
Results: Carboxylated osteocalcin was negatively correlated with body mass index, waist circumference and waist-to-height ratio and positively associated with HDL-cholesterol in the entire sample and in the non-diabetic group. In the diabetic group carboxylated osteocalcin was associated with waist circumference and HDL-cholesterol. Un(der)carboxylated osteocalcin was negatively correlated with fasting blood glucose in the non-diabetic group.
Conclusion: Our study confirmed the connection of osteocalcin with parameters of metabolic disorders in humans. We found associations indicating beneficial metabolic effects for both forms of osteocalcin, the carboxylated one being more active.

Keywords

Osteocalcin; Vitamin K; HbA1c; Un(der)carboxylated Osteocalcin; Carboxylated Osteocalcin

Introduction

Osteocalcin (OC) is a bone-derived protein, containing three gamma-glutamic acid residues. After its synthesis in osteoblasts, it undergoes posttranslational vitamin K-dependent carboxylation of all three gamma-glutamic acid residues [1]. The traditional understanding of OC role postulates that the carboxylated form of the protein (cOC) is essential for normal bone structure and function. Circulating levels of OC are measured to predict the fracture risk and to assess the effectiveness of antiresorptive therapy [2]. In the process of bone resorption, one or more of the carboxylated residues are decarboxylated due to the acidification of the environment, and the protein is released in the systemic circulation as un- or undercarboxylated OC (ucOC) [3].
A number of experimental studies conducted on wild type and OCdeficient mice over the past 20 years have shown that ucOC plays an important role in the regulation of energy metabolism by stimulating insulin release and increasing peripheral insulin sensitivity [4,5]. In our previous work, we have shown that ucOC is hormonally active also in rats [6]. We found that ucOC level was reduced in rats with diet-induced metabolic syndrome, while cOC remained unchanged. In addition, there was a negative correlation between ucOC concentration and fasting blood glucose level [6]. We next showed that the pharmacological reduction of ucOC, achieved by alendronate administration, was associated with impairment of glucose metabolism [7]. In this study, ucOC level was negatively correlated with the fat index of the experimental animals as an indicator of visceral obesity. Our findings in rats confirmed that similarly to mice, the un(der) carboxylated form of OC appeared to possess hormonal activity, while the carboxylated form was inactive.