# Iatrogenic Hypoglycemia in Type 2 Diabetes Affects Endothelial Proteins Involved in Cardiovascular Dysfunction

## TL;DR

This study shows that hypoglycemia in type 2 diabetes affects endothelial proteins linked to cardiovascular issues, worsening vascular function.

## Contribution

The study reveals how hypoglycemia alters endothelial proteins in type 2 diabetes, contributing to cardiovascular dysfunction.

## Key findings

- Baseline levels of P-selectin, PAI-1, E-selectin, and ANGPT1 were higher in T2D patients.
- Hypoglycemia caused decreases in cadherin-5 and sTie-2, and increases in P-selectin, ICAM3, ANGPT1, and PAI-1.
- Post-hypoglycemia, T2D patients showed reduced levels of E-selectin, P-selectin, and ICAM3 compared to controls.

## Abstract

Hypoglycemia is associated with cardiovascular events reflected by platelet abnormalities. We hypothesized that sequential endothelial changes may occur during hypoglycemia that may enhance cardiovascular risk. In type 2 diabetes (T2D) (n = 23) and controls (n = 23), blood SOMAscan proteomic analysis of endothelial proteins at baseline, insulin-induced hypoglycemia and post hypoglycemia to 24 h were examined using repeated-measures linear mixed modeling with a prospective parallel study design. Most endothelial proteins that changed over time did not differ between groups. Baseline levels of P-selectin, plasminogen activator inhibitor-1 (PAI-1; serpine-1), E-selectin and angiopoietin-1 (ANGPT1) were significantly higher, whilst cadherin-5 was lower in T2D. Several proteins exhibited changes versus baseline in both T2D and controls. Under hypoglycemia, decreases in cadherin-5 and soluble angiopoietin-1 receptor (sTie-2) were observed, with increased P-selectin, intercellular adhesion molecule-3 (ICAM3), ANGPT1 and PAI-1. Post hypoglycemia, decreased cadherin-5 and ICAM5 were observed at 2 h and PAI-1 at 4 h, as well as increases in P-selectin at 30 min, 1 h and 24 h and ICAM3 at 24 h. Post hypoglycemia, E-selectin, P-selectin and ICAM3 were significantly lower in T2D patients at 2 h, while PAI-1 was significantly lower at 4 h and ICAM3 was significantly lower at 24 h. Baseline endothelial proteins differed between T2D and controls, which may suggest local endothelial inflammatory activation leading to a pro-thrombotic, destabilized vascular phenotype characteristic of diabetic vasculopathy. Hypoglycemia may exacerbate this towards a pro-adhesive and pro-thrombotic phenotype, worsening endothelial dysfunction.