Obesity is associated with an increased incidence of more than one dozen tumor types, and a poorer prognosis of most of these. Intriguingly, interventions which improve the metabolic phenotype of obese individuals – including exercise, weight loss, and treatment with metformin, the most commonly prescribed anti-diabetes drug in the world – slow tumor growth in animals and may have a tumor-slowing effect in humans. The mechanisms for this association have been the subject of numerous studies and are still an area of active debate. Here I will present data arguing that obesity-associated hyperinsulinemia resulting from insulin resistance drives tumor growth in murine models of colon and breast cancer by promoting tumor glucose uptake and oxidation, measured using novel stable isotope methods. In vitro studies reveal that these findings regarding the ability of hyperinsulinemia to drive glucose oxidation are generalizable across multiple human and mouse cell lines from obesity-associated tumors (prostate, breast, ovarian, colon, and pancreatic cancer) but not obesity-independent tumors (small cell lung cancer, melanoma, lymphoma, osteosarcoma). Of particular importance, three insulin-sensitizing and -lowering agents with divergent mechanisms of action slowed breast and colon tumor growth in an insulin-dependent manner: 1) dapagliflozin, a sodium-glucose contransporter-2 (SGLT2) inhibitor, which promotes glycosuria, 2) metformin, which inhibits gluconeogenesis, and 3) a functionally liver-targeted controlled-release mitochondrial protonophore (CRMP), which reverses non-alcoholic fatty liver disease by increasing hepatic mitochondrial oxidation, and thereby improves both hepatic and peripheral insulin sensitivity (the latter due to reduced very low-density lipoprotein export). Restoring hyperinsulinemia via continuous insulin infusion using subcutaneous pellets abrogated the effect of each agent to slow tumor growth. I will further show data indicating that both glucose uptake and oxidation in these obesity-associated tumors is insulin-responsive: diet-induced obesity, causing hyperinsulinemia, increased both glucose uptake and oxidation, whereas insulin-lowering interventions reversed these effects, and restoring hyperinsulinemia by subcutaneous insulin infusion increased tumor glucose uptake and oxidation in mice treated with insulin-lowering agents. These data are contrary to the commonly held view that tumor glucose uptake is constitutively high, and argue that rates of glucose oxidation in tumors may vary dynamically with the hormonal milieu. In summary, I will argue that hyperinsulinemia per semediates the majority of the effect of obesity to drive tumor growth in murine models of colon and breast cancer by increasing tumor glucose uptake and oxidation. These data highlight an important role for insulin-lowering therapies, some of which are already in the clinic (diet and exercise, in particular a ketogenic diet; metformin; SGLT2 inhibitors), and others of which are in preclinical development (liver-targeted mitochondrial uncouplers) to prevent or slow obesity-associated cancer progression.

Citation Format: Rachel J. Perry. Hyperinsulinemia mediates the effect of obesity to promote tumor growth in murine breast and colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY28-02.