Association between high waist-height ratio and endoplasmic reticulum stress of young adults with insulin resistance

BACKGROUND In our search to unravel the pathophysiological mechanisms underlying the development of insulin resistance (IR) in the young population, we evaluated the waist-to-height ratio (WtHR) in 39 participants, setting 0.5 as the cut-off value. A high WtHR has been associated with metabolic alterations and increased risk of developing IR. AIM To explore the relationship between WtHR and IR in young individuals with endoplasmic reticulum (ER) stress molecular mechanisms. METHODS This was a cross-sectional study conducted at the Faculty of Medicine of the Autonomous University of Baja California (Mexico). A total of 39 young participants (18-25 years old, both sexes) were recruited from the general community. All measurements and sample analyses were performed in a single study visit per participant. According to their WtHR, 0.5 is used as the threshold to define high or low WtHR. The degree of IR was estimated using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index. Additionally, we analyzed ER stress markers in platelets, including SERCA protein expression and phosphorylation levels of PERK and JNK. Data were analyzed using one-way ANOVA followed by Dunn’s post-hoc test. RESULTS Young individuals with high WtHR showed greater body weight, body mass index, and visceral fat area percentage; additionally, high-density lipoprotein cholesterol (HDL-C) levels were lower, and the triglyceride/HDL-C ratio was higher (P < 0.05). Fasting insulin was higher in the high-WtHR group (18.76 ± 2.35 µU/mL vs 13.54 ± 1.5 µU/mL; P < 0.05), resulting in elevated HOMA-IR (4.34 ± 0.54 vs 2.90 ± 0.3; P < 0.05). Moreover, platelets from participants with high WtHR exhibited elevated SERCA protein expression (297.3 ± 39.4 vs 98.8 ± 14.9; P < 0.0002) and increased PERK phosphorylation (532.0 ± 98.9 vs 127.8 ± 29.6; P < 0.001), indicating activation of the unfolded protein response. These platelets also showed greater JNK phosphorylation than those from individuals with low WtHR (604.9 ± 216.3 vs 126.7 ± 25; P < 0.04), confirming JNK activation, a negative regulator of the insulin signaling pathway. CONCLUSION High-WtHR in young people is associated with IR and ER stress, driven by JNK activation in platelets, suggesting molecular alterations in early metabolic dysfunction.