Diabetes-Induced Modulation of Cancer Cell Dynamics

Diabetes mellitus, particularly when characterised by chronic hyperglycaemia, exerts profound effects on cancer cell behaviour through metabolic and signalling reprogramming. Elevated glucose levels fuel anabolic processes, enhance glycolytic flux and generate reactive metabolites that collectively promote proliferation, migration and resistance to apoptosis. Concurrent dysregulation of insulin and insulin-like growth factor signalling can activate intracellular kinases and transcription factors, reinforcing oncogenic programmes and epithelial–mesenchymal transition. In addition, hyperglycaemia alters the tumour microenvironment by modulating immune cell function, promoting paracrine loops that upregulate immune checkpoints and extracellular matrix remodelling. Such interactions accelerate metastatic dissemination and may impair responses to chemotherapy or immunotherapy. Understanding these mechanisms reveals potential interventions, including glucose-lowering strategies, pathway-specific inhibitors and metabolic modulators, to mitigate the compounding effects of diabetes on cancer progression.

Research from Nature Portfolio

Recent studies have revealed that tobacco-related compounds can induce hyperglycaemia and metabolic syndrome traits, driving lung cancer progression via macrophage reprogramming. Increased expression of glucose transporters in tumour-associated macrophages elevates insulin-like growth factor 2 secretion, which activates insulin receptors in cancer cells and, through nucleophosmin cooperativity, enhances PD-L1 expression. This paracrine circuit links metabolic dysregulation to immune evasion and tumour growth. In another investigation, high-glucose conditions in cholangiocarcinoma cells were shown to activate STAT3 signalling, leading to increased proliferation, adhesion, migration and invasion. Elevated nuclear phosphorylated STAT3 and its downstream targets, including cyclin D1, vimentin and MMP2, were observed in patient samples with diabetes. Lowering glucose levels or pharmacological inhibition of STAT3 attenuated these aggressive phenotypes, underlining the importance of glycaemic control and targeted blockade of key transcriptional regulators.

Diabetes-Induced Modulation of Cancer Cell Dynamics publication trend

The graph below shows the total number of articles in diabetes-induced modulation of cancer cell dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Hyperglycaemia: A persistent elevation of blood glucose that drives metabolic imbalances in both normal and malignant cells.

Epithelial–Mesenchymal Transition (EMT): A process by which epithelial cells acquire motility and invasive properties characteristic of mesenchymal cells.

Insulin-like Growth Factor 2 (IGF2): A peptide growth factor that binds insulin receptors to activate proliferative and survival pathways in cancer cells.

Signal Transducer and Activator of Transcription 3 (STAT3): A transcription factor activated by phosphorylation, promoting gene expression linked to cell growth, invasion and immune modulation.

Polyol Pathway: A metabolic route converting glucose to sorbitol and subsequently to fructose, often upregulated in hyperglycaemic conditions.

Ketohexokinase-A (KHK-A): A nuclear isoform of fructose-phosphorylating enzyme that can modulate gene expression and drive metastatic programmes.

Autophagy–Lysosomal Pathway: A cellular degradation system that removes damaged components and can be suppressed by aberrant metabolic signalling.

References

1. Tobacco-induced hyperglycemia promotes lung cancer progression via cancer cell-macrophage interaction through paracrine IGF2/IR/NPM1-driven PD-L1 expression. Nature Communications (2024).
2. High glucose enhances progression of cholangiocarcinoma cells via STAT3 activation. Scientific Reports (2016).
3. The polyol pathway and nuclear ketohexokinase A signaling drive hyperglycemia-induced metastasis of gastric cancer. Experimental & Molecular Medicine (2024).
4. High glucose levels promote glycolysis and cholesterol synthesis via ERRα and suppress the autophagy–lysosomal pathway in endometrial cancer. Cell Death & Disease (2025).