Causality Between Insulin Therapy, Hyperinsulinemia, and Cancer Development in Diabetes

Diabetes mellitus, particularly type 2 diabetes, is associated with an increased risk of several malignancies, raising important questions at the interface of endocrinology, metabolism, and cancer biology. Among the proposed contributors to this association, insulin-related hormonal exposures - including chronic endogenous hyperinsulinemia and exogenous insulin therapy - have been widely investigated. Experimental and clinical evidence indicates that sustained insulin signaling may influence tumor development through endocrine and metabolic mechanisms such as enhanced cellular proliferation, altered apoptosis, and activation of insulin and insulin-like growth factor (IGF) receptor pathways. However, the causal relevance of these mechanisms in human populations remains incompletely understood. Despite extensive investigation, whether insulin exposure plays a causal role in cancer development, rather than acting as a marker of underlying metabolic dysregulation, remains a key unresolved question.A major challenge in this field lies in disentangling the effects of insulin itself from those of insulin resistance, obesity, diabetes duration, and related metabolic comorbidities. These factors frequently coexist and interact, complicating interpretation of observational findings and limiting their translational relevance. Importantly, exogenous insulin therapy and endogenous hyperinsulinemia represent biologically and clinically distinct exposures, yet are often conflated in observational research. As a result, uncertainty persists regarding whether cancer risk in people with diabetes is driven primarily by insulin exposure, underlying hormonal dysregulation, or broader metabolic disturbances.This Research Topic aims to advance endocrinology-focused research that clarifies whether, how, and under which conditions insulin therapy and/or hyperinsulinemia contribute to cancer development in individuals with diabetes. We particularly welcome studies that integrate hormonal, metabolic, and mechanistic perspectives with clinically relevant epidemiological designs. The emphasis of this collection is on endocrine and hormonal mechanisms, treatment decisions, and metabolic regulation, rather than on cancer biology alone.Key objectives include distinguishing the effects of exogenous insulin from endogenous hyperinsulinemia, elucidating the role of insulin resistance and IGF-axis signaling as mediators of cancer risk, and assessing potential differences across insulin formulations, treatment strategies, and cancer types. Contributions that enhance clinical decision-making, inform prevention or screening approaches, or identify endocrine-related biomarkers and therapeutic targets are especially encouraged.To foster multidisciplinary discussion within the scope of endocrinology, this Research Topic welcomes original research articles, reviews, and meta-analyses addressing, but not limited to, the following themes:- Endocrine and metabolic mechanisms linking insulin and IGF signaling to tumor initiation and progression- Clinical and population-based studies of cancer risk in diabetes, considering hyperinsulinemia, insulin resistance, disease duration, and metabolic comorbidities- Comparative evaluations of insulin therapies, analogs, dosing strategies, and delivery patterns in relation to cancer outcomes- Cancer site–specific analyses with clear relevance to hormonal and metabolic regulation (e.g., liver, pancreas, breast, colorectal, endometrial, thyroid)- Preclinical and translational models examining insulin-driven metabolic–oncogenic interactions- Systematic reviews and meta-analyses adhering to PRISMA guidelines, with conclusions directly relevant to endocrinology and hormonal regulationSubmissions should maintain clear relevance to endocrinology and hormonal regulation. Manuscripts focusing on non-endocrine diseases, purely bibliometric analyses, or computational studies of public datasets without appropriate validation fall outside the scope of this Research Topic. Topic editors: Massimo Vicentini, Durgesh Wankhede Source: https://www.frontiersin.org/research-topics/77872/causality-between-insulin-therapy-hyperinsulinemia-and-cancer-development-in-diabetes