Background: Some glioblastoma multiforme (GBM) are characterized by the presence of gemistocytes (GCs), a unique phenotype of reactive astrocytes. Certain GCs can be identified as neoplastic cells but these cells were also found to be associated with diabetes in non-neoplastic lesions of the central nervous system. Our aim was to find a correlation between insulin - resistance metabolic features and the presence of GCs in patients with newly diagnosed GBM. Methods: Medical records from histologically confirmed GBM patients were retrospectively extracted for different systemic metabolic variables. A statistic-based comparison was made between GBM, diabetic patients with and without GC. Patients with poorly controlled diabetes (ie, hemoglobin A1C ⩾ 8.0) were also compared between the 2 groups. Results: A total of 220 newly diagnosed GBM patients were included in our study. 58 (26.3%) patients had a history of diabetes mellitus type 2 (DM2) at the time of admission. The rate of poorly-controlled DM2 was nearly as twice in the GC-GBM group than in the non-GC GBM group (18.75% vs 9.5%; P =.130). In the DM2 cohort, the subgroup of GC-GBM was significantly associated with demographic and metabolic features related to insulin resistance such as male gender predominance (89% vs 50%, P =.073) and morbid obesity (weight ⩾85 kg: OR 6.16; P =.0019 and mean BMI: 34.1 ± 11.42 vs 28.7 ± 5.44; P =.034 for group with and without GCs, respectively). In the poorly-controlled DM2 group, none of the GC-GBM patients were using insulin prior to diagnosis, compared to 61.1% in the non-GC GBM patients (OR = 0.04, P =.045). Conclusion: Systemic metabolic factors related to marked insulin resistance (DM2, morbid obesity, male gender) are associated with a unique histologic phenotype of GBM, characterized by the presence of GCs. This feature is prominent in poorly-controlled DM2 GBM patients who are not using synthetic insulin. This novel finding may add to the growing data on the relevance of glucose metabolism in astrocytes and in astrocytes associated with high-grade gliomas. In GBM patients, a correlation between patients’ metabolic status, tumor’s histologic phenotype, tumor’s molecular changes, use of anti-diabetic drugs and the respective impact of these factor on survival warrants further investigation.