Metabolic reprogramming in diabetes and cancer: the role of PI3K/AKT/mTOR and beyond.

Abstract

Diabetes mellitus and cancer are among the most prevalent chronic diseases worldwide, and accumulating evidence suggests a significant association between these conditions. The metabolic disturbances characteristic of diabetes, including hyperglycemia, hyperinsulinemia, insulin resistance, and chronic inflammation, create a favorable environment for tumor initiation and progression. These alterations contribute to cellular metabolic reprogramming, enhanced proliferative signaling, and resistance to apoptosis. Key molecular pathways such as PI3K/AKT/mTOR, along with dysregulated glucose, lipid, and amino acid metabolism, play central roles in linking diabetic and oncogenic processes. In addition to metabolic alterations, genetic and epigenetic modifications, including mutations in oncogenes and tumor suppressor genes, as well as the involvement of non-coding RNAs, further strengthen this association. Emerging evidence also highlights the gut microbiome's role in modulating inflammation, metabolic homeostasis, and cancer susceptibility in diabetic conditions. Therapeutically, antidiabetic agents such as metformin, GLP-1 receptor agonists, and SGLT2 inhibitors have shown potential in modulating cancer-related pathways, although clinical evidence remains variable and requires further validation. This review provides a comprehensive overview of the shared metabolic and molecular mechanisms underlying the diabetes-cancer link, emphasizing the interplay between metabolic dysregulation, genetic alterations, and microbiome dynamics. A better understanding of these interconnected pathways may support the development of targeted therapeutic strategies and improve clinical outcomes. However, further well-designed studies are necessary to establish causal relationships and translate these findings into effective clinical interventions.