ORF33-05 - Effects of Insulin Resistance in Different Insulin Signaling Pathways on Vascular Function : Lipodystrophy Compared to Pathogenic Variants of the Insulin Receptor

Insulin resistance (IR) in obesity and type 2 diabetes cause endothelial dysfunction, an early marker of cardiovascular disease (CVD). Rare, syndromic forms of severe IR (SIR) exist. SIR is classified as pathway selective IR, where insulin signaling is increased in some signal transduction pathways and decreased in others (i.e. lipodystrophy, LD), or total IR, where all insulin signal transduction is blocked at the insulin receptor (i.e. insulin receptor pathogenic variants, INSR). To determine effects of selective IR (LD) and total IR (INSR) on vascular function, we used CD34+ hematopoietic progenitor cells as biomarkers of endothelial health and in vivo measures of vascular stiffness. We hypothesized that LD causes more vascular dysfunction than INSR due to a combination of deficient and excess insulin signal transduction in LD.

This is a prospective, cross-sectional study of four groups: insulin sensitive controls, INSR, LD with SIR (LD-SIR), and LD on metreleptin with well-controlled IR (LD-M). Fasting (8-12 hrs) blood samples were obtained to measure insulin and HbA1c and harvest CD34+ from mononuclear cells (MNC). CD34+ to MNC number ratio, colony formation units (CFU), migratory function (in response to a chemotactic factor), and gene expression (TNF-⍺, CASP3, and SOD2, expressed as mRNA fold change normalized to 18S) were evaluated. Pulse wave velocity (PWV) was measured by SphygmoCor XCEL®. Patient groups were compared to controls by Kruskal-Wallis test and correlations by Spearman.

We studied 10 controls (34±12 years; 80% female), 9 INSR (30±7 years; 60% female), 13 LD-SIR (40±15 years; 92% female), and 6 LD-M (34±12 years; 83% female). Insulin (mcU/mL) in controls (4±2) was lower than INSR (199±253) and LD-SIR (44±44) but not LD-M (13±10) (P= < 0.0001). HbA1c (%) in controls (5.1±0.1) was lower than INSR (8.5±2.9) but not LD-SIR (6.6±2.2) or LD-M (6.1±1.5) (P=0.04). PWV (m/s) in controls (4.9±0.4) was lower than INSR (6.0±1.1) and LD-SIR (6.1±0.9) but not LD-M (5.1±0.8) (P=0.03). TNF-⍺ in controls (0.6±1.4) was lower than LD-SIR (7.6±6.6) but not INSR (3.4±2.2) or LD-M (1.1±3.8) (P=0.05). CASP3 and SOD2 were higher in INSR and LD-SIR vs controls but differences did not reach significance. No significant between-group differences were detected for cellular measures. In the combined cohort, PWV correlated negatively with CD34+: MNC ratio (r=-0.6, P=0.002) and positively with fasting insulin (r=0.6, P=0.0002) and HbA1c (r=0.6, P=0.001).

Counter to our hypothesis, patients with both total (INSR) and selective IR (LD-SIR) had elevated PWV vs controls, suggesting increased CVD risk. Inverse correlations between PWV and CD34+: MNC ratio support this ratio as a predictor of CVD risk. By investigating pro- and anti-atherogenic vascular actions of insulin, this study enhances understanding of CVD mechanisms in the general population. Larger sample sizes are needed to confirm our findings.