Endocrine Abstracts

Introduction

Diabetes, a metabolic disease, is responsible for 1.6 million deaths each year. Type 2 diabetes (T2D) is the most common type (90%) that usually occurs in adults. Type 1 diabetes (T1D) an autoimmune disorder, affects more children and adolescents. Diabetic Ketoacidosis (DKA) is the most common acute cause of morbidity and mortality in youth with T1D. Soluble protein oligomers (SPOs), are a class of misfolded toxic proteins released during endoplasmic reticulum (ER) stress and unfold protein response (UPR). Hyperglycemia leads to ER stress and activate the UPR pathway. We hypothesized that SPOs are increased in the plasma from patients with DKA. Also, ER stress induce SPO release and/or vice versa.

Methods

By using the dot blotting, we measured SPOs in plasma from young (8–18 years old) male (n = 4) and female (n = 6) DKA patients in three different time points: 6–12 hours of treatment; 2–3 weeks; and 3 months post-DKA correction. Mechanistically, we evaluated if vascular smooth muscle cells ( VS MCs) from the tibial artery of a 45-year-old male with T2D in normal glucose, or human aortic endothelial cells (HAEC), from a 33 year old health woman, submitted to high glucose concentrations (35 nmol/l) for 48 hours, presents with ER stress and/or SPOs in the media. Some VS MCs and HAEC were treated with ER stress inhibitor (4-PBA 2 mmol/l), SPOs inhibitor (K01–162, 10 µmol/l), or vehicle (DMSO) for 48 hours.

Results

SPOs were present in plasma from patients with DKA at all-time points. Interestingly, SPOs levels increased in a time-dependent manner in females, but not males. On the other hand, SPOs were not detected in the media of VS MCs or HAEC patients. However, the C/EBP Homologous Protein (CHOP), a marker for ER stress, was expressed in VS MC from patient with T2D, and the treatment with ER stress inhibitor, PBA, but not SPOs inhibitor, decreased its expression (A.U.: Vehicle: 55.3 ± 5 vs . PBA: 40.1 ± 5* vs . K01–162: 64.3 ± 9; *P = 0.04 vs . Vehicle). CHOP was not detected in HAEC after high glucose treatment.

Conclusion:

In diabetes there is an accumulation of SPOs that may contribute to the systemic inflammation observed in young patients with DKA. Although there was ER stress in VS MC from T2D, SPOs were not detected in the supernatant from these cells nor HAEC treated with high glucose. More studies are necessary to evaluate the relation between SPOs, ER stress and vascular dysfunction in diabetes.