From hyperinsulinemia to cancer progression: how diminishing glucose storage capacity fuels insulin resistance

Type 2 diabetes (T2D) is a complex metabolic disorder characterized by insulin resistance, hyperglycemia and hyperinsulinemia, with a quarter to half of people with T2D unaware of their diagnosis until the disease has reached advanced stages. T2D is associated with increased risk and worse prognosis of cardiovascular disease, cognitive decline, and cancer. Here we propose an updated framework for describing emergence of insulin resistance that precedes development of T2D. We show that diminishing capacity to store excess glucose can qualitatively capture the transition from normal to diabetic phenotype as captured by responses to oral glucose tolerance tests (OGTTs). We then show that an emerging tumor can either progress or regress depending on the metabolic environment of the host, consistent with experimental results of Hopkins et al. (2018), who showed that drug-induced transient diabetic phenotype, and specifically hyperinsulinemia, resulted in loss of therapeutic efficacy, and its reversal restored drug sensitivity and response to therapy. Given the prevalence of hyperinsulinemia in individuals with normoglycemia, addressing this condition emerges as a promising avenue to augment cancer therapy outcomes.