Hyperinsulinaemia in cancer

Abstract

Elevated circulating insulin levels are frequently observed in the setting of obesity and early type 2 diabetes, as a result of insensitivity of metabolic tissues to the effects of insulin. Higher levels of circulating insulin have been associated with increased cancer risk and progression in epidemiology studies. Elevated circulating insulin is believed to be a major factor linking obesity, diabetes and cancer. With the development of targeted cancer therapies, insulin signalling has emerged as a mechanism of therapeutic resistance. Although metabolic tissues become insensitive to insulin in the setting of obesity, a number of mechanisms allow cancer cells to maintain their ability to respond to insulin. Significant progress has been made in the past decade in understanding the insulin receptor and its signalling pathways in cancer, and a number of lessons have been learnt from therapeutic failures. These discoveries have led to numerous clinical trials that have aimed to reduce the levels of circulating insulin and to abrogate insulin signalling in cancer cells. With the rising prevalence of obesity and diabetes worldwide, and the realization that hyperinsulinaemia may contribute to therapeutic failures, it is essential to understand how insulin and insulin receptor signalling promote cancer progression.

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Fig. 1: Mechanisms of insulin resistance and hyperinsulinaemia development.
Fig. 2: Insulin receptor and insulin-like growth factor 1 receptor dimers, ligands and signalling pathways.
Fig. 3: Preclinical in vivo models linking hyperinsulinaemia, insulin receptor signalling and cancer progression.
Fig. 4: Mechanisms through which insulin-like growth factor 1 receptor targeting of monoclonal antibodies results in hyperinsulinaemia.
Fig. 5: Mechanisms of hyperinsulinaemia in response to PI3K inhibition in cancer therapy.

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The authors contributed equally to all aspects of the article.

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Correspondence to Emily J. Gallagher.

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E.J.G. served on an advisory board for Novartis in 2019. D.L.R. served on the advisory boards for Mannkind and AstraZeneca in 2018–2019.

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Glossary

Body mass index

(BMI). Calculated as weight (kg)/(height (m))2. Normal weight is defined as BMI of 18.5–24.9; overweight, as BMI of 25–29.9; and obese, as BMI ≥30.

Endogenous hyperinsulinaemia

The hyperinsulinaemia that results from insulin resistance. It is associated with metabolic syndrome and is to be distinguished from exogenous insulin therapies.

Metabolic syndrome

A syndrome that includes visceral adiposity, insulin resistance and the concomitant dysglycaemia, hypertension and dyslipidaemia.

Visceral adipose tissue

(VAT). Intra-abdominal fat bound by parietal peritoneum, or transversalis fascia, excluding the vertebral column and paraspinal muscles.

Subcutaneous adipose tissue

(SAT). Fat under the skin superficial to the muscles.

Heterogeneous nuclear ribonucleoproteins

(hnRNPs). RNA-binding proteins involved in splicing.

Nesidioblastosis

Hyperinsulinaemic hypoglycaemia caused by β-cell hyperplasia.

Streptozotocin

(STZ). An alkylating agent that damages DNA and destroys pancreatic β-cells, thus mimicking insulin-deficient diabetes. It can also damage other tissues, depending on the dose administered.

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Gallagher, E.J., LeRoith, D. Hyperinsulinaemia in cancer. Nat Rev Cancer 20, 629–644 (2020). https://doi.org/10.1038/s41568-020-0295-5

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