Undercarboxylated osteocalcin reverts insulin resistance induced by endoplasmic reticulum stress in human umbilical vein endothelial cells

Qinyue Guo,Huixia Li,Shufang Wu,Bo Zhou,Lin Xu,Hongzhi Sun

doi:10.1038/s41598-017-00163-2

Abstract

Osteocalcin has been considered to be an important regulator of energy metabolism in type 2 diabetes mellitus (T2DM). However, the mechanism underlying the involvement of uncarboxylated osteocalcin in the vascular complications of T2DM is not fully understood. In the present study, we analyzed the potential correlations between uncarboxylated osteocalcin and macro- or microangiopathic complications in subjects with T2DM and tested the impact of uncarboxylated osteocalcin on insulin resistance in human umbilical vein endothelial cells (HUVECs). The results showed that the serum levels of uncarboxylated osteocalcin were lower in subjects with vascular complications of T2DM. Univariate correlation analyses revealed negative correlations between uncarboxylated osteocalcin and waist-to-hip ratio, HbA1c, and HOMA-IR. In in vitro experiments, insulin resistance was induced by applying tunicamycin to HUVECs. Uncarboxylated osteocalcin not only markedly reduced the phosphorylations of PERK and eIF2α, but also elevated the phosphorylations of IRS-1 and Akt, resulting in improvement of insulin signal transduction via PI3K/Akt/NF-κB signaling in HUVECs. Therefore, there is a possible relationship between uncarboxylated osteocalcin and the vascular complications of T2DM. Uncarboxylated osteocalcin partially improves insulin signal transduction via PI3K/Akt/NF-κB signaling in tunicamycin-induced HUVECs, suggesting osteocalcin as a potential treatment for the vascular complications of T2DM.

Highlights

Reduced OCN levels were involved in all-cause mortality and cardiovascular disease (CVD)-related deaths in older men[12], adding more evidence for the correlation between OCN and CVD
We provide evidence that uncarboxylated osteocalcin (ucOCN) reverses ER stress and restores insulin signaling via PI3K/Akt/NF-κB signaling in human umbilical vein endothelial cells (HUVECs), adding credence to the emerging notion that ucOCN could be used in treatments for the vascular complications of type 2 diabetes mellitus (T2DM)
Subjects diagnosed with T2DM with or without vascular complications exhibited higher FPG, FINS, haemoglobin A1c (HbA1c), total cholesterol (TC), TG, low density lipoprotein cholesterol (LDL-c) and Homeostasis model assessment index for insulin resistance (HOMA-IR) compared with Normal glucose tolerance (NGT)

Summary

Introduction

Reduced OCN levels were involved in all-cause mortality and cardiovascular disease (CVD)-related deaths in older men[12], adding more evidence for the correlation between OCN and CVD. There are recent results showing that NF-κB—as a important signaling molecular in cardiovascular system—is associated with a reduced responsiveness to insulin, and exerts a regulatory role via PI3K/Akt/NF-κB signaling[15]. In light of these observations, we postulated that ucOCN plays a critical role in the vascular complications of T2DM via PI3K/Akt/NF-κB signaling. We evaluated the correlations between ucOCN and macro- or microangiopathic complications in the progression of T2DM. We provide evidence that ucOCN reverses ER stress and restores insulin signaling via PI3K/Akt/NF-κB signaling in HUVECs, adding credence to the emerging notion that ucOCN could be used in treatments for the vascular complications of T2DM

Methods

Results

Conclusion