Insulin resistance and hyperinsulinaemia in the development and progression of cancer

Abstract

Experimental, epidemiological and clinical evidence implicates insulin resistance and its accompanying hyperinsulinaemia in the development of cancer, but the relative importance of these disturbances in cancer remains unclear. There are, however, theoretical mechanisms by which hyperinsulinaemia could amplify such growth-promoting effects as insulin may have, as well as the growth-promoting effects of other, more potent, growth factors. Hyperinsulinaemia may also induce other changes, particularly in the IGF (insulin-like growth factor) system, that could promote cell proliferation and survival. Several factors can independently modify both cancer risk and insulin resistance, including subclinical inflammation and obesity. The possibility that some of the effects of hyperinsulinaemia might then augment pro-carcinogenic changes associated with disturbances in these factors emphasizes how, rather than being a single causative factor, insulin resistance may be most usefully viewed as one strand in a network of interacting disturbances that promote the development and progression of cancer.

Figure 1. Principal signalling pathways activated by the insulin receptor

Positive influences are shown by lines ending in arrows and inhibitory influences by lines ending in bars. MEK, MAPK/extracellular-signal-regulated kinase kinase; PIP3, PtdIns(3,4,5)P₃; PKC, protein kinase C; triglyceride, triacylgycerol.

Figure 2. Hypothetical scheme for enhanced cell growth and survival in insulin resistance

In uncompensated insulin resistance (upper panel), signalling via the PI3K pathway is diminished, glucose uptake by the cell via GLUT-4 transporters is reduced, suppression of gluconeogenesis is reduced and glucose levels rise. In compensated insulin resistance (lower panel), the pancreas responds to the rise in glucose levels with increased insulin secretion, insulin levels rise, signalling through the PI3K pathway is restored and cell glucose uptake and gluconeogenesis are normalized. However, the increased insulin concentrations increase signalling via the kinases of the MAPK pathway {p21Ras, Raf, MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase] and ERK} to increase cell proliferation and survival.

Figure 3. Farnesylation of p21Ras causes it to locate to the plasma membrane where it can undergo GTP loading, which is essential for signalling via the MAPK pathway

Insulin increases activation of farnesyl transferase, which increases farnesylation of p21Ras. As a consequence, the pool of p21Ras-GTP is increased. This has the effect of amplifying growth factor signalling via the MAPK pathway. MEK, MAPK/ERK kinase.

Figure 4. Interaction between insulin resistance and cell proliferation and survival

Theoretically, interactions between the effects of insulin resistance and hyperinsulinaemia could lead to amplification of the cell proliferation and survival signals induced by insulin. This amplification will be even greater against a background of insulin or IGF-1 receptor overexpression or growth signalling protein overexpression. The ability of insulin to increase the pool of p21Ras-GTP by enhancing p21Ras farnesylation has the potential to amplify further these effects.

Figure 5. Coincident promotion of insulin resistance and cell proliferation and survival in inflammation

Activated cells of the immune system release cytokines and ROS, which induce insulin resistance via JNK and cell proliferation and survival via NF-κB. Positive influences are shown by lines ending in arrows and inhibitory influences by lines ending in bars.

Figure 6. Coincident promotion of insulin resistance and cell proliferation and survival in obesity

Positive influences are shown by lines ending in arrows and inhibitory influences by lines ending in bars.

Figure 7. Selected key inter-relationships in an insulin-resistant pro-carcinogenic state associated with increased inflammation, obesity and reduced levels of SIRT1

Potentially beneficial effects, with regard to reducing both insulin resistance and cell proliferation and survival, that are diminished in this state are shown by the broken lines. Positive influences are shown by lines ending in arrows and inhibitory influences by lines ending in bars. Variables independently reduced in insulin-resistant states are shown by the solid arrows.