Figure 1 Simplified representation of the physiological

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Figure 1 Simplified representation of the physiological processes that might link obesity, diabetes, and neoplasia Figure 1 | Simplified representation of the physiological processes that might link obesity, diabetes, and neoplasia. When caloric intake exceeds energy expenditure insulin levels rise and excess energy is stored in adipose tissue. Insulin signals adipocytes to take up glucose and convert it to lipids as a way of storing energy to be used at times of inadequate caloric intake. Chronic excess of caloric intake over energy consumption, however, can lead to insulin resistance in insulin-target tissues, one of the consequences of which is increased hepatic gluconeogenesis — an important cause of hyperglycaemia. If the degree of hyperglycaemia surpasses a defined threshold, type 2 diabetes mellitus (T2DM) will be diagnosed. Importantly, as glucose levels rise, insulin secretion increases, which can reduce glucose levels in some patients, leading to a normoglycaemic, but hyperinsulinaemic, state; however, T2DM characterized by both hyperglycaemia and hyperinsulinaemia develops eventually. Hyperinsulinaemia is hypothesized to stimulate the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway in at least a subset of cancers or cells at risk of malignant transformation, promoting tumour growth or resulting in increased rates of carcinogenesis, respectively. This hypothesis is supported by data from animal models, but remains to be investigated rigorously in the clinic. Other metabolic features of obesity that might influence neoplasia include increased levels of inflammatory cytokines, which stimulate various processes involved in cancer development, and reduced levels of adiponectin, an adipokine that normally inhibits cell proliferation via activation of AMP-activated protein kinase (AMPK). Metformin decreases hyperglycaemia, hyperinsulinaemia, and the consequences of these conditions predominantly by decreasing hepatic gluconeogenesis. This drug might also act directly on cancers or cells at risk of transformation by inducing energy stress, which slows cell proliferation via activation of AMPK and/or other mechanisms. On the other hand, the use of inhibitors of the PI3K pathway to target this signalling cascade in cancer cells could potentially have unintended metabolic consequences, such as hyperglycaemia, owing to off-tumour effects on tissues involved in the regulation of blood glucose, such as adipocytes. mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB. Klil-Drori, A. J. et al. (2016) Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.120