Association of hyperglycemia and molecular subclass on survival in IDH-wildtype glioblastoma

Abstract

Background Hyperglycemia has been associated with worse survival in glioblastoma. Attempts to lower glucose yielded mixed responses which could be due to molecularly distinct GBM subclasses. Methods Clinical, laboratory, and molecular data on 89 IDH-wt GBMs profiled by clinical next-generation sequencing and treated with Stupp protocol were reviewed. IDH-wt GBMs were subclassified into RTK I (Proneural), RTK II (Classical) and Mesenchymal subtypes using whole genome DNA methylation. Average glucose was calculated by time-weighting glucose measurements between diagnosis and last follow-up. Results Patients were stratified into three groups using average glucose: tertile one (<100mg/dL), tertile two (100-115 mg/dL), and tertile three (>115 mg/dL). Comparison across glucose tertiles revealed no differences in performance status (KPS), dexamethasone dose, MGMT methylation, or methylation subclass. Overall survival (OS) was not affected by methylation subclass (p=0.9) but decreased with higher glucose (p=0.015). Higher glucose tertiles were associated with poorer OS among RTK I (p=0.08) and mesenchymal tumors (p=0.05), but not RTK II (p=0.99). After controlling for age, KPS, dexamethasone, and MGMT status, glucose remained significantly associated with OS (aHR=5.2, p=0.02). Methylation clustering did not identify unique signatures associated with high or low glucose levels. Metabolomic analysis of 23 tumors showed minimal variation across metabolites without differences between molecular subclasses. Conclusion Higher average glucose values were associated with poorer OS in RTKI and Mesenchymal IDH-wt GBM, but not RTKII. There were no discernible epigenetic or metabolomic differences between tumors in different glucose environments, suggesting a potential survival benefit to lowering systemic glucose in selected molecular subtypes.

Diabetes Mellitus Management in the Context of Cranial Tumors

“…Nevertheless, Barami et al noted a similar pattern in the negative association between HbA1C and overall survival in GBS patients [69]. Lastly, this trend was further corroborated by Lui and colleagues in 2022, who were able to stratify the isocitrate dehydrogenase (IDH)-wildtype GBS based on molecular subclass-namely, RTK I, RTK II, and mesenchymal [70]. While tumor methylation status was not associated with variations in overall survival (p = 0.9), greater glucose levels were associated with shorter overall survival in RTK I (p = 0.08) and mesenchymal tumors (p = 0.05).…”

“…Because GBS expresses the same insulin receptors found in the periphery, hyperinsulinemias caused by hyperglycemia may promote tumor proliferation independently [86][87][88][89]. Liu et al discovered increased insulin signalling in conjunction with PI3K-AKT and MAPK upregulation [70,90].…”