Pharmacological intersections between type 2 diabetes and cancer: Metabolic crosstalk, antidiabetic therapies and clinical implications
Abstract
Type 2 diabetes (T2D) and cancer frequently coexist and are connected by hyperinsulinemia, hyperglycemia, obesity, chronic inflammation, and multiorgan metabolic dysfunction. These alterations activate insulin/insulin-like growth factor 1, PI3K/AKT/mTOR, MAPK, JAK/STAT, and NF-κB signaling while reshaping the tumor microenvironment through endocrine, immune, and metabolic pathways. This review synthesizes epidemiological and mechanistic evidence linking T2D with cancer and evaluates the oncological implications of major antidiabetic therapies. We discuss how dysfunction of skeletal muscle, adipose tissue, liver, pancreas, and hormonal axes may converge on tumor growth, immune evasion, and treatment resistance. We then critically examine metformin, insulin analogs, sulfonylureas, sodium-glucose cotransporter 2 inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and dual GIP/GLP-1 receptor agonists. Metformin has demonstrated extensive preclinical antitumor activity, whereas randomized clinical studies have generally yielded neutral cancer-specific outcomes. Human findings for other agents vary according to cancer type, metabolic phenotype, treatment duration, and study design, with observational estimates particularly sensitive to diabetes severity, obesity, treatment selection, and reverse causality. In clinical practice, glucose-lowering therapy is therefore best guided by glycemic efficacy, cardiovascular and renal…
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