Hidden metabolic crisis in lean youth: Waist-to-height ratio uncovers endoplasmic reticulum stress-driven insulin resistance in platelets

Figure 1 The hidden metabolic crisis in lean youth. Waist-to-height ratio > 0.5 identifies high visceral adiposity risk, even in normal-weight individuals. Platelets serve as early biosensors of endoplasmic reticulum stress-driven insulin resistance, enabling precision prevention through routine screening, lifestyle intervention, and future targeted therapies. WtHR: Waist-to-height ratio; BMI: Body mass index; ER: Endoplasmic reticulum; FFAs: Free fatty acids; p-PERK: Phosphorylated protein kinase R-like endoplasmic reticulum kinase; p-JNK: Phosphorylated c-Jun N-terminal kinase; SERCA: Sarco-endoplasmic reticulum Ca-ATPase.

Figure 2 Endoplasmic reticulum stress acts as the molecular bridge linking visceral adiposity to systemic insulin resistance. Visceral fat releases free fatty acids and cytokines into circulation, inducing endoplasmic reticulum dysfunction in liver, muscle, and platelets. This activates the unfolded protein response pathway, leading to c-Jun N-terminal kinase-mediated insulin-receptor substrate 1 inhibition and impaired insulin signaling, forming a self-perpetuating feed-forward loop. Endoplasmic reticulum; FFAs: Free fatty acids; TNF-α: Tumor necrosis factor α; IL: Interleukin; PERK: Protein kinase R-like endoplasmic reticulum kinase; p-PERK: Phosphorylated protein kinase R-like endoplasmic reticulum kinase; p-JNK: Phosphorylated c-Jun N-terminal kinase; IRS-1: Insulin-receptor substrate 1; UPR: Unfolded protein response; ATF4: Activating transcription factor 4; CHOP: C/EBP homologous protein; PI3K: Phosphoinositide 3-kinases; Akt: Protein kinase B; SERCA: Sarco-endoplasmic reticulum Ca-ATPase; p-eIF2α: Phosphorylated eukaryotic translation initiation factor 2 alpha.