Glucose and antidiabetic therapy in temozolomide resistance in glioblastoma

Table 1 Important studies investigating the potential benefits of antidiabetic drugs in glioblastoma therapy

Ref.	Type of study	Number of patients	Follow-up	Drugs	Mechanisms of resistance	Outcome
Yang et al[55]	Experimental in vitro	Temozolomide (TMZ)-resistant glioblastoma cell lines named U87R and U251R	N/A	Metformin and TMZ	N/A	TMZ resistant cell lines were treated with metformin for 2 weeks and then exposed to TMZ, causing survival rate of glioblastoma cells to drop significantly
Seliger et al[41]	Matched case-control analysis	2005 glioma cases and 20 050 matched controls. 55.2% were men. The mean age was 55.5 (+18.7) years	N/A	Sulfonylurea, metformin and insulin	N/A	A study found an inverse relationship between diabetes and the risk of glioma, most pronounced among those with long-term and poorly controlled diabetes. Antidiabetic medications were unrelated to gliomas
Bielecka-Waldman et al[4]	Experimental in vitro and clinical retrospective analysis	Commercial T98G cell line and two primary GBM lines (HROG02, HROG17) treated with TMZ and/or DXM were combined with clinical analysis on 40 patients, 17 women and 23 men	N/A	TMZ, Dexamethasone (DXM)	High glucose concentrations, MGMT methylation, oxygen conditions, gene mutations (IDH 1 and 2, B-Raf)	For higher glucose concentrations, primary GBM cell lines have shown resistance to TMZ. Simultaneous administration of TMZ and DXM enhanced the cytotoxic action of TMZ in cells cultured in the lower glucose medium (0.6 and 1 g/L glucose) but not in the high glucose medium (4.5 g/L). In clinical analysis in patients with glioblastoma, increased glucose level are positively correlated with an increased expression of Ki-67 proliferation index
Zander et al[34]	Experimental in vitro	Cell lines used: Human U87MG and A172, and rat C6 glioma cells	N/A	PPARγ agonists (ciglitazone, LY171833, prostaglandin-J2), PPARα agonist (WY14643), synthetic receptor-antagonists (BADGE)	PPARγ agonist-induced apoptosis is inhibited by BADGE	PPARγ agonists induce apoptosis and redifferentiation in glioma cells; primary murine astrocytes are unaffected
Moezzi et al[57]	Experimental in vitro and in vivo	Not applicable (the study focuses on in-vitro and in-vivo experiments, not on patients)	The study includes long-term stability tests over 100 days	Metformin	The study focuses on overcoming resistance through the use of nanoerythrosomes to deliver metformin effectively to glioma cells by protecting the drug from metabolizing enzymes in the blood-brain barrier and extending its presence in circulation	The nanoerythrosomes successfully encapsulated metformin, maintained its stability, and released the drug in a controlled manner. The study concludes that nanoerythrosomes can be a suitable drug delivery system for therapeutic amounts of metformin to treat glioma
Valtorta et al[58]	Experimental in vitro	Two cell lines, U251 and T98G	N/A	Metformin (MET), TMZ and their combination	Combined-treatment modulated apoptosis by increasing Bax/Bcl-2 ratio and reducing reactive oxygen species (ROS) production	MET enhances TMZ effect on TMZ-sensitive cell line (U251) and overcomes TMZ-resistance in T98G GBM cell line
Feng et al[59]	Experimental in vitro	Glioblastoma cell lines (U87MG, LNZ308, and LN229)	N/A	Temozolomide, Metformin	MGMT expression, epithelial-mesenchymal transition, mitochondrial biogenesis	Metformin decreased cell viability, proliferation, migration, increased apoptosis and ROS in glioblastoma cell lines; combined treatment with TMZ varied (synergistic in U87, antagonistic in LNZ308, and additive in LN229)
Ohno et al[60]	Multicenter single-arm phase I/II study	Phase I included seven patients, between 20 and 74 years of age with newly diagnosed supratentorial GBM to determine MET tolerability, phase II comprised 22 patients	12 months after initial surgery	MET and TMZ combination	Metformin could induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation	Phase I study demonstrated that 2250 mg/day MF combined with TMZ appeared to be well tolerated, phase II is ongoing

GBM: Glioblastoma; MGMT: O6-methylguanine-DNA methyltransferase; MF: Metformin.

Table 2 Summary of current limitations and directions for future research on metformin in glioblastoma

Limitation	Underlying issues	Proposed solutions /future directions
Heterogeneous trial designs	Inconsistent patient selection (MGMT status, IDH mutation)	Stratify future trials by molecular subtypes and metabolic profiles
Variable dosing and exposure	Metformin doses ranged from 1000 to 2250 mg/day; durations varied	Standardize dosing protocols; consider longer duration studies
Inadequate CNS penetration	Metformin is hydrophilic, and the blood-brain barrier limits delivery	Explore alternative delivery systems (nanoerythrosomes, liposomal carriers)[58,60]
Lack of metabolic data	Poor glycemic control and steroid use are often unreported	Integrate glycemic monitoring and steroid adjustment protocols in trial design
Biomarker absence	No validated predictors of response	Identify and validate predictive biomarkers (AMPK activity, gemistocyte index, insulin resistance)

MGMT: O6-methylguanine-DNA methyltransferase; CNS: Central nervous system; IDH: Isocitrate dehydrogenase.