Letter to the Editor: Dynamic SERCA regulation and early metabolic dysfunction in young adults with high waist-to-height ratio

Abstract

The recent study published in World Journal of Diabetes by Casillas et al provides compelling evidence that a high waist-to-height ratio (WtHR) cutoff of 0.5 in 39 young adults is associated with insulin resistance and endoplasmic reticulum (ER) stress in platelets. This association is characterized by elevated SERCA expression and increased protein kinase PERK and JNK phosphorylation. The work highlights the value of WtHR as an early marker of metabolic dysfunction. It also establishes platelets as a minimally invasive model for studying systemic ER stress. However, 2 critical aspects warrant further discussion. The first is the dynamic nature of SERCA regulation during disease progression, particularly given the small sample size. The second is the clinical significance of metabolic dysfunction in young adults with elevated WtHR, regardless of their body mass index classification. These findings provide novel perspectives for translational research regarding early metabolic risk stratification.

Key Words: Waist-to-height ratio; Endoplasmic reticulum stress; SERCA; Insulin resistance; Young adults

Core Tip: This commentary extends the findings of Casillas et al. It discusses the biphasic regulation of SERCA as a key determinant of disease progression. It emphasizes the unrecognized metabolic risk in young adults with elevated waist-to-height ratio. It also highlights the cross-disease implications of endoplasmic reticulum stress and JNK activation. These perspectives provide important insights for early risk stratification and mechanism-based interventions.

TO THE EDITOR

We read with great interest the recent article published in World Journal of Diabetes by Casillas et al[1], entitled “Association between high waist-height ratio and endoplasmic reticulum stress of young adults with insulin resistance”. This cross-sectional study demonstrates that a waist-to-height ratio (WtHR) > 0.5 is associated with insulin resistance (IR), atherogenic dyslipidemia, and activation of the endoplasmic reticulum (ER) stress-unfolded protein response (UPR)-JNK pathway in platelets. It makes a significant contribution to our understanding of early metabolic dysfunction in young populations. The use of platelets as a surrogate tissue is particularly noteworthy. It provides a minimally invasive approach to detect molecular alterations that precede overt clinical disease.

SERCA biphasic remodeling may define the transition from adaptive to maladaptive metabolic stress

Among the study findings, the increased SERCA protein expression observed in platelets from young adults with elevated WtHR is especially intriguing. This result contrasts with previous observations in patients with established type 2 diabetes mellitus, in whom SERCA expression and activity are frequently reduced[2,3]. Although the authors interpreted this increase as a compensatory response to early ER stress, we believe this phenomenon may reflect a broader dynamic process of metabolic adaptation and decompensation that deserves further mechanistic consideration.

SERCA is a crucial membrane pump that restores calcium homeostasis by actively transporting Ca²⁺ from the cytosol into the ER/SR lumen. Under early metabolic stress conditions, including central adiposity and lipotoxicity, transient SERCA upregulation may represent an adaptive response aimed at preserving ER calcium storage and limiting excessive UPR activation. However, persistent metabolic overload may eventually exhaust this compensatory mechanism, leading to impaired SERCA activity, ER calcium disequilibrium, sustained PERK/JNK activation, and progressive worsening of IR[4].

PERK activation involves phosphorylation and subsequent signaling that reduces the protein-folding burden in the ER. JNK is triggered by dual phosphorylation and acts as a negative regulator of insulin signaling. The transition from compensatory SERCA upregulation to dysfunction may represent a “metabolic tipping point” from reversible adaptation to irreversible injury (Figure 1).

Figure 1 The biphasic role of SERCA and the endoplasmic reticulum stress signaling pathway in the progression of metabolic dysfunction. The schematic illustrates the transition from an early adaptive phase to a progressive maladaptive stage in platelets. Early adaptive stage: In response to initial metabolic stress, platelets undergo compensatory upregulation of SERCA expression, facilitating efficient Ca²⁺ sequestration into the endoplasmic reticulum (ER) to maintain homeostasis and promote cell survival. Progressive dysfunction stage: Persistent metabolic overload leads to SERCA dysfunction and Ca²⁺ depletion in the ER lumen, causing cytosolic Ca²⁺ overload. This triggers maladaptive unfolded protein response activation, characterized by sustained PERK phosphorylation and JNK. ER: Endoplasmic reticulum; UPR: Unfolded protein response.

Notably, similar biphasic remodeling patterns occur in other metabolic contexts. Discrepancies in SERCA levels across different studies may be influenced by sample types, participant comorbidities, and varying etiologies[5,6]. To our knowledge, this study is the first to link WtHR with platelet ER stress and IR in young adults.

Nevertheless, the current study evaluated only SERCA protein abundance without assessing ATPase activity, intracellular calcium flux, or ER calcium storage capacity. Therefore, it remains unclear whether the observed SERCA increase reflects functional adaptive compensation, dysfunctional protein accumulation, or altered platelet turnover. Moreover, because the study design was cross-sectional, the temporal trajectory of SERCA remodeling could not be determined. Future longitudinal investigations tracking SERCA expression and functional activity across different stages of metabolic dysfunction may help clarify whether SERCA remodeling serves as a biomarker of disease progression and reversibility.

The biphasic role of SERCA and the ER stress signaling pathway in the progression of metabolic dysfunction. The schematic illustrates the transition from an early adaptive phase to a progressive maladaptive stage in platelets. Early adaptive stage: In response to initial metabolic stress, platelets undergo compensatory upregulation of SERCA expression, facilitating efficient Ca²⁺ sequestration into the ER to maintain homeostasis and promote cell survival. Progressive dysfunction stage: Persistent metabolic overload leads to SERCA dysfunction and Ca²⁺ depletion in the ER lumen, causing cytosolic Ca²⁺ overload. This triggers maladaptive UPR activation, characterized by sustained PERK phosphorylation and JNK.

WtHR may identify metabolic risk in young adults overlooked by body mass index-based screening

A key clinical implication of this study is the ability of WtHR to detect metabolic risk in individuals who might be overlooked by body mass index (BMI) based screening. Unlike BMI, WtHR directly reflects central adiposity and visceral fat accumulation[7]. Both factors are strongly associated with IR and ER stress.

The present study excluded participants with BMI < 18.5 kg/m² or > 40 kg/m². Some participants in the high-WtHR group had a BMI that fell within the conventional overweight range. However, these individuals often do not receive early clinical attention. Importantly, WtHR can detect metabolic abnormalities in individuals who may appear healthy according to traditional criteria[8,9]. Future studies could use subgroup analyses based on BMI categories. This approach may clarify the molecular basis of metabolic dysfunction in young adults with high central adiposity[10]. It could also determine if platelet ER stress serves as an early hallmark of hidden metabolic risk.

While lifestyle factors like diet and inactivity are known confounders, others should be considered. Circadian disruption and sleep deprivation are common among young adults[11]. These factors can also contribute to ER stress and impaired insulin sensitivity[12,13]. The current study is limited by its small sample size. Future research should incorporate sleep and circadian assessments to better understand these associations.

Platelet ER stress markers require further functional and systemic validation

The demonstration of increased PERK and JNK phosphorylation in platelets from young adults with elevated WtHR provides novel evidence linking central adiposity with early molecular activation of ER stress pathways. However, whether platelet signaling abnormalities accurately reflect metabolic dysfunction in classical insulin-sensitive tissues, including liver, skeletal muscle, and adipose tissue, remains uncertain[14-16].

Platelets are highly responsive circulating cells that sensitively reflect systemic inflammatory and metabolic conditions, yet their biological properties differ fundamentally from those of canonical metabolic organs. Accordingly, platelet ER stress may represent either a surrogate marker of systemic metabolic vulnerability or a downstream epiphenomenon secondary to inflammation and metabolic dysregulation[17,18]. Additional studies integrating tissue-specific metabolic assessments and circulating inflammatory mediators are therefore needed to validate the systemic representativeness of platelet ER stress markers.

Furthermore, the marked increase in JNK phosphorylation observed in the high-WtHR group may have implications beyond insulin signaling alone. As an important upstream regulator of platelet activation, JNK signaling contributes to platelet aggregation, granule secretion, and prothrombotic phenotype formation[19]. However, pathway activation itself does not necessarily indicate clinically meaningful platelet dysfunction. Functional analyses, including platelet aggregation assays and P-selectin expression measurements, would help determine whether these molecular alterations translate into early prothrombotic changes and increased cardiometabolic risk in young individuals with central adiposity[20,21].

Conclusion

Casillas et al[1] provide compelling preliminary evidence that elevated WtHR in young adults is associated not only with IR but also with early activation of platelet ER stress signaling pathways. Beyond establishing WtHR as a practical screening tool, this study may represent an early molecular portrait of the transition from adaptive metabolic compensation to progressive metabolic dysfunction. In particular, the observed SERCA upregulation raises the important possibility that biphasic SERCA remodeling defines a reversible stage of metabolic stress preceding overt cardiometabolic disease. Further mechanistic and longitudinal investigations are warranted to clarify the temporal dynamics, tissue specificity, and functional significance of platelet ER stress signaling in young populations at metabolic risk. Such efforts may ultimately improve early identification of vulnerable individuals and facilitate the development of more precise preventive strategies targeting the earliest stages of metabolic failure.