This study is the first to systematically reveal significant U-shaped associations between GPR and short-term and long-term mortality risk in a large cohort of sepsis patients, and confirms the clinical value of GPR as an independent prognostic marker. Based on multiple analyses, this study not only verified the generalizability of GPR in the prognostic prediction of sepsis but also deeply interpreted its heterogeneity in different clinical subgroups, thereby providing key evidence to support the clinical application of this novel biomarker.

The present RCS analysis is the first attempt to reveal a nonlinear U-shaped association of GPR with mortality risk in sepsis patients. This finding is of great value for clinical and mechanistic research. Notably, the lowest threshold was 1.49 for GPR associated with 30-day mortality risk, and 1.44 for GPR associated with 90-day to 1-year mortality, suggesting a dynamic evolution of requirements for metabolic regulation at different stages of sepsis. The biological basis of this U-shaped association may involve dual pathological mechanisms. Specifically, high GPR may result from a synergistic effect of stress hyperglycemia and hypokalemia, whereas low GPR reflects metabolic imbalance: hypoglycemia with hyperkalemia. High GPR in sepsis is attributed to a significant increase in blood glucose, which is due to increased secretion of catecholamines, cortisol, and glucagon that promote glycogenolysis and hepatic gluconeogenesis while suppressing insulin secretion^15,16. It was shown that high blood glucose levels in sepsis patients were positively associated with the levels of inflammatory cytokines such as IL-6, TNF-α, and IL-1β, and negatively associated with the levels of CD4⁺/CD8⁺, suggesting that hyperglycemia may exacerbate the inflammatory response and inhibit the immune function, thereby increasing the risk of infections and multiple organ dysfunction¹⁷. In addition, the release of large amounts of inflammatory mediators in sepsis exacerbated insulin resistance by interfering with the insulin signaling pathway, resulting in decreased insulin sensitivity of peripheral tissues and decreased glucose utilization¹⁸. Hypokalemia was associated with intracellular transfer of potassium ions driven by increased secretion of stress hormones in sepsis^19,20. In the presence of a low GPR, hypoglycemia results from impaired gluconeogenesis¹⁸ and increased glucose consumption in peripheral tissues²¹. In the course of sepsis, the occurrence of hyperkalemia involves two pathological processes: on the one hand, over-activated inflammatory response can cause cellular destruction and tissue injury, which contributes to the intracellular efflux of potassium ions, and on the other hand, sepsis-associated acute renal injury (AKI) can lead to impaired renal potassium excretion, further exacerbating the risk of hyperkalemia^22,23, and hyperkalemia can induce fatal cardiac arrhythmias²⁴. Restricted cubic spline (RCS) analysis confirmed that glucose/potassium ratio (GPR), as a composite indicator of metabolic disruption in sepsis, was significantly associated with patient prognosis, suggesting that clinicians need to closely monitor the levels of glucose and potassium in blood. The optimal GPR range (1.44–1.49) determined based on statistical association can be converted into a clinical stratification strategy. First, as an initial risk screening tool: calculate baseline GPR for ICU sepsis patients upon admission; if it exceeds the threshold ( 1.49), clinicians should prioritize metabolic disorder assessment. Second, as a dynamic monitoring tool: establish a 4–6 h blood glucose/potassium monitoring process for patients with baseline GPR outside the threshold, and combine the SOFA score to track disease evolution. Third, as an individualized intervention target: when GPR remains  1.49, strengthen blood glucose control and screen for severe hypokalemia. It should be emphasized that this threshold is not an independent diagnostic criterion but an auxiliary decision-making tool in the sepsis management process. Clinical application requires individualized analysis based on pre-existing diseases, organ function, and response to treatment.

Sepsis patients often have comorbid metabolic disorders or receive treatments that affect glucose-potassium homeostasis. These factors may influence the assessment of the association between GPR and mortality risk. Based on this, we performed subgroup analysis to reveal the heterogeneity of GPR in different clinical situations. The strength of the association of GPR with mortality risk was reduced in the diabetic subgroup compared with non-diabetic patients. This may be related to the pattern of metabolic disruption specific to type 2 diabetes (T2D), with a core pathological mechanism of islet β-cell dysfunction and insulin resistance²⁵, which manifests as metabolic imbalance due to abnormalities of insulin synthesis and release as well as defects in the response of peripheral tissues²⁶. In patients with sepsis complicated by diabetes, an increased GPR mostly reflects homeostasis imbalance in diabetes rather than an alteration that characterizes the acute stress response during sepsis, which provides an important insight into the clinical interpretation of this indicator.

The kidneys are a central regulator of potassium homeostasis in the body. Patients with acute kidney failure (AKF) often present with hyperkalemia, a characteristic electrolyte disturbance²⁷, which leads to a change specific to GPR, thereby significantly affecting the predictive power of GPR in the subgroup with AKF. Despite the interference from AKI, GPR still had statistically significant predictive value for prognosis in this subgroup, highlighting its robustness in assessing metabolic disturbances. However, in the subgroup with CLD, the predictive power of GPR showed significant heterogeneity (p > 0.05), which may be partly due to limited statistical power caused by the insufficient sample size in this subgroup. Furthermore, there may be underlying reasons involved: hypoglycemia caused by decreased hepatic glycogen reserve²⁸ and hypokalemia²⁹ due to disturbance of aldosterone metabolism³⁰. These pathological changes make it difficult for GPR to accurately reflect the metabolic profile of sepsis patients. Similarly, when patients are treated with hydrocortisone, the drug can cause glucose metabolism disturbance by directly impairing pancreatic endocrine function and Suppressing insulin sensitivity of peripheral tissues, leading to steroid-induced diabetes in about 2% of patients³¹. This metabolic disturbance stems from interference by glucocorticoids and is different from the pattern of metabolic disruption specific to type 2 diabetes. Notably, this drug-specific metabolic alteration may mask sepsis-induced stress hyperglycemia, which in turn affects the effectiveness of clinical interpretation of GPR. The above findings suggest that clinicians should develop treatment options based on GPR in conjunction with patients’ pre-existing diseases rather than GPR alone. Our findings also call for the future development of improved predictive models for specific patient populations to improve the accuracy of prognostic assessment by integrating more metabolic parameters and to provide new ideas for precise individualized treatment and stratified treatment. Meanwhile, to verify the robustness of the association of GPR with 30DM in sepsis patients, we performed sensitivity analysis and found that an increased GPR was positively associated with 30DM, 90DM, 180DM, and 1YM, regardless of whether or not sepsis patients had comorbid diabetes. Similarly, the results remained stable after the exclusion of patients with acute renal failure or CLD, indicating that GPR can be used as an independent risk factor to directly reflect the pathophysiological status of sepsis patients, and that its predictive ability is not affected by comorbidities and can remain stable over different time windows. Therefore, GPR can not only serve as a risk warning signal in the acute phase but also guide the management of long-term follow-up.

Significance and limitations

This study is the first to systematically verify the predictive power of GPR for prognosis in sepsis patients, thus revealing its unique value for clinical application. Compared with complex scoring systems such as the SOFA score, GPR has the significant advantage of eliminating the need for complex calculations by integrating changes in both blood glucose and potassium, thereby enabling clinicians rapidly and dynamically to assess the ICU patient’s condition at the bedside. However, there are still some limitations in this study. First, as it is an observational study, we cannot determine a causal relationship between GPR and all-cause mortality, and it is difficult to control confounders. Although multivariate adjustment and subgroup analysis were used in this study to address potential confounders, the lack of key information such as the site of infection, causative pathogens, treatment regimen, and cause of death in sepsis patients in the database may have led to residual confounding. However, E-value analysis indicates that unmeasured confounding would need to be extremely strong to fully explain away the association between GPR and mortality (point estimate E = 1.39, lower bound E = 1.33), providing additional robust Support for the conclusion. Nonetheless, residual confounding remains a methodological limitation inherent to observational studies. Future multicenter collaborative studies should be conducted to supplement existing evidence. Second, a single measurement of GPR may not identify metabolic fluctuation after therapeutic intervention. It is therefore required to explore the prognostic value of the rate of 24-hour dynamic change in GPR in the future. Third, this study relies on the proportional hazards assumption in the Cox proportional hazards model. Although the robustness of the results was cross-validated through RCS analysis, KM curve separation trends, and sensitivity analysis, no formal schoenfeld residual test was performed. Future studies may further explore time-varying risk patterns. Finally, the generalizability of the MIMIC-IV database may be limited by the following factors: First, differences in demographic characteristics: The 31,717 patients included in this study were primarily from the ICU, a tertiary academic medical center in the United States (Caucasians: 65.5%, Asians: 1.7%; males: 57.7%; a median age of 67 years [IQR: 56–78]), and their distribution by race and age differs significantly from that of ICU populations in Asian/African regions. Second, a difference in the causes of sepsis: Pulmonary sepsis is predominant in the United States, while abdominal sepsis is more common in Asia. This regional difference in etiology may affect the generalizability of GPR for prognostic assessment. Third, differences in clinical practice: The MIMIC-IV database reflects a standardized clinical process in the ICU in the United States, but regions with limited resources often face issues such as restricted antibiotic choices and insufficient life support equipment, which may limit the clinical application of GPR as a marker for intervention guidance. Given these limitations, although this study provides important evidence for the clinical application of GPR, its generalizability still needs to be further verified through large-scale, multicenter studies. The results should be interpreted with caution in clinical practice. Future research will focus on the following: prospective validation of the role of the GPR threshold in improving clinical outcomes; concomitant exploration of the effectiveness of dynamic monitoring data combined with multidimensional indicators in guiding treatment, so as to ultimately optimize risk stratification and precision intervention strategies for sepsis patients.