Diabetes and its link with cancer: providing the fuel and spark to launch an aggressive growth regime

Abstract

Diabetes is a disease involving metabolic derangements in multiple organs. While the spectrum of diabetic complications has been known for years, recent evidence suggests that diabetes could also contribute to the initiation and propagation of certain cancers. The mechanism(s) underlying this relationship are not completely resolved but likely involve changes in hormone and nutrient levels, as well as activation of inflammatory and stress-related pathways. Interestingly, some of the drugs used clinically to treat diabetes also appear to have antitumour effects, further highlighting the interaction between these two conditions. In this contribution we review recent literature on this emerging relationship and explore the potential mechanisms that may promote cancer in diabetic patients.

Figure 1

Under normal conditions, insulin is secreted from pancreatic β-cells in response to an increase in plasma glucose levels. It promotes glucose uptake into skeletal muscle and adipose tissue while suppressing hepatic glucose output, resulting in maintenance of blood glucose concentration to ~5 mM (a). In insulin resistant individuals, an increased amount of insulin is required to compensate for diminished effects on insulin-target organs, giving rise to hyperinsulinaemia. As insulin resistance worsens, blood glucose level gradually increases despite increased insulin secretion and a prediabetic state is established (b). In susceptible individuals, relative insulin deficiency progressively develops due to failure of β-cells to secrete adequate levels of insulin, resulting in loss of glucose homeostasis if exogenous insulin is not provided (c).

Figure 2

Glycolysis and glutaminolysis are two of the most important pathways for cancer cells. Increased glucose uptake, together with reduced glycolytic flux, accumulates glycolytic intermediates for synthesis of biomolecules such as nucleotides, amino acids, and lipids. Similarly, glutamine uptake is also increased. Glutamine is converted to glutamate by mitochondrial glutaminase. Glutamate is then converted to α-ketoglutarate which can be oxidised in the TCA cycle to generate ATP or reductively carboxylated to citrate. Citrate is exported to the cytoplasm where it is converted to acetyl-Co-A or oxaloacetate, which are used for synthesis of fatty acids or amino acids, respectively. Metabolic changes in cancer cells are driven by changes in the regulation of critical enzymes. Examples of these enzymes are shown in bold. Regulation of metabolic pathways by oncogenes (Myc and K-Ras) and tumour suppressor genes (p53) is also shown. Glycolysis is shown in red. Glutaminolysis is shown in orange. Biosynthetic pathways are shown in green. Other pathways are shown in grey.