Energy balance and cancer: the role of insulin and insulin-like growth factor-I

Abstract

Recent theories propose that a Western lifestyle may increase cancer risk through alterations in the metabolism of insulin and insulin-like growth factors (IGF; McKeown-Eyssen, 1994; Giovannucci, 1995; Kaaks, 1996; Werner & LeRoith, 1996). Insulin regulates energy metabolism, and increases the bioactivity of IGF-I, by enhancing its synthesis, and by decreasing several of its binding proteins (IGFBP; IGFBP-1 and -2). Insulin and IGF-I both stimulate anabolic processes as a function of available energy and elementary substrates (e.g. amino acids). The anabolic signals by insulin or IGF-I can promote tumour development by inhibiting apoptosis, and by stimulating cell proliferation. Furthermore, both insulin and IGF-I stimulate the synthesis of sex steroids, and inhibit the synthesis of sex hormone-binding globulin (SHBG), a binding protein that regulates the bioavailability of circulating sex steroids to tissues. The present paper reviews epidemiological findings relating the risk of cancers of the colo-rectum, pancreas, breast, endometrium and prostate to body size (obesity, height) and physical activity, and discusses the relationships between obesity and physical activity and plasma levels of insulin, IGF-I and IGFBP. Subsequent sections review epidemiological findings relating cancer risk to indices of chronic hyperinsulinaemia, and to plasma levels of IGF-I and IGFBP. Conclusions are that chronic hyperinsulinaemia may be a cause of cancers of the colon, pancreas and endometrium, and also possibly of the breast. On the other hand, elevated plasma IGF-I, as total concentrations or relative to levels of IGFBP-3, appears to be related to an increased risk of prostate cancer, breast cancer in young women, and possibly colo-rectal cancer. For cancers of the endometrium, breast and prostate, these findings are discussed in the context of relationships between insulin and IGF-I and levels of bioavailable sex steroids.

Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts

“…Studies have implicated obesity, lack of exercise, dietary glycemic load (an estimation of post-prandial glucose response), and diabetes mellitus as risk factors for pancreatic cancer (Gapstur et al, 2000;Michaud et al, 2001Michaud et al, , 2002Eberle et al, 2005;Huxley et al, 2005;Larsson et al, 2005). The mechanisms by which these factors increase cancer risk have been hypothesized to involve insulin and the insulin-like growth factor axis, which are intimately involved in glucose and energy homeostasis (Kaaks and Lukanova, 2001;Jerome et al, 2003).…”

Body mass index, waist circumference and waist–hip ratio and serum levels of IGF-I and IGFBP-3 in European women

“…36 It has been hypothesized that the nonlinear relationship between increasing adiposity and circulating IGF-I levels is due to weight-related disruptions in insulin and GH secretion. 13,45,46 Prolonged fasting, as observed in patients with anorexia nervosa, and short-term fasting of normal-weight subjects, results in decreased IGF-I levels, 47,48 and there is a stepwise increment of IGF-I values related to weight gain in anorexic patients. 49 Short-term overfeeding of normalweight women also results in increased IGF-I levels.…”

Dietary Determinants of Circulating Insulin-like Growth Factor (IGF)-I and IGF Binding Proteins 1, -2 and -3 in Women in the Netherlands

“…Energy balance, dietary energy intake, and to a lesser extent protein intake, may be linked to cancer risk [47,48] and have been implicated in the modulation of the IGF-system. Experimental studies in animals and humans have shown that severe dietary energy and protein restriction (e.g.…”