Study Protocol: insulin and its role in cancer

The association of diabetes mellitus and cancer has been reported more than 100 years ago [1]. Population studies have shown increased evidence of this association. Diabetes has been recognized as a risk factor for development of breast, endometrial, colorectal and pancreatic carcinomas [2]. Breast, endometrial, colorectal and pancreatic carcinomas are best studied with regard to their association with diabetes/insulin resistance. Population studies have shown that the effects of diabetes mellitus on colorectal cancer may be mediated through mechanisms ranging from increased colonic transit time to hyperinsulinaemia. In relation to the latter, at least in the early phase of development, type 2 diabetes mellitus is associated with increased circulating insulin concentrations [3, 4]. A large cohort study concluded that diabetes is associated with a modestly increased risk for endometrial cancer among women [5]. Future research, particularly prospective studies with biological samples, could be very helpful in answering questions aimed at clarifying these mechanisms [5]. Data suggest that type 2 diabetes might be associated with up to 10–20% excess risk for breast cancer and that it could also have detrimental effects on the natural history, diagnosis, and treatment of breast cancer [1, 6].

In the past few years both laboratory investigations and population studies have provided some circumstantial evidence that insulin growth factor (IGF) physiology influences cancer risk [7]. Insulin resistance is the underlying pathology of type 2 diabetes mellitus and is a component of metabolic syndrome [8, 9]. Over the years, prospective studies have shown that metabolic syndrome and its consequent biochemical derangements may contribute to carcinogenesis. Several studies implicate hyperinsulinism, a condition that prevails prior to the onset of diabetes (part of metabolic syndrome) as candidate mediator in carcinogenesis [10]. Studies have revealed that high levels of circulating insulin decreases levels of insulin like growth factor binding protein 1 and 3 (IGFBP 1,3). Thus free IGF-1 levels increase in circulation [11, 12]. Another aspect of IGF physiology is the IGF signaling. In this signaling process, IGF-1 receptor is a predominant factor and is crucial for tumor transformation and survival of malignant cell. It has comparatively less role in normal cell growth [13]. Thus role of IGF-1 in promoting carcinogenesis and its prognosis is well established. Over the recent years, IGF-1 physiology has been widely studied. The IGF system, comprises of insulin-like IGF-I, IGF-II, and IGFBPs. IGF-1 as a growth factor plays a dominant role over IGF-2 and hence is widely studied. Until recently, growth hormone was the only known stimulant of IGF-1 production. Different lines of evidence suggest that the IGF/IGFBP system may be regulated by factors other than growth hormones. States of nutritional deprivation, such as starvation and protein caloric under-nutrition and type 1 diabetes mellitus, in animal models have long been known to influence the production of IGFs [14–16]. Various studies have shown that resistance to insulin action, as found in diabetic patients, has been associated with an increase IGFBP-3 protease activity, there by reducing IGFBP-3 levels [17]. Also, Insulin increases IGF-I bioavailability through IGFBP-1 suppression [14, 18, 19]. Thus there is ample evidence to suggest that insulin resistant states increase free IGF-1 levels.

Medical literature suggests that well controlled biochemical and genetic studies are required to establish the link between insulin, IGF-1, diabetes and cancer. We propose to investigate the role of hyperinsulinemia in carcinogenesis.

The primary objective of the study is to investigate the role of insulin resistance or sensitivity in carcinogenesis. This is done by studying the relation between insulin resistance/sensitivity and IGF-1 levels in cancer patients. The secondary objective is to study the above mentioned association with organ specific cancers if possible.

Carcinogenesis is multi-factorial. The metabolic and genetic derangements that take place during carcinogenesis may be induced by carcinogens and inherited genetic factors. The role of either could be variable in a given case. We hypothesize that people with insulin resistance are at risk of developing cancer due to high levels of circulating IGF-1. Such a risk would increase if other such factors are prevalent/acquired. A person with high levels of IGF-1 may be predisposed to cancer and his/her risk of developing cancer would increase with the presence of other such factors. Cancer being a non-communicable disease, with multiple risk factors, modifiable risk factors are very few. Controlling hyperinsulinaemia would modify one major risk factor. IGF-1 levels in body change with age. In addition, risk factors for cancer and carcinogen exposure increase with age [20]. Thus age and known carcinogens could be major confounders.

In a pilot study conducted at our centre (unpublished data) to test the above hypothesis we found a strong trend towards significance in patients under the age of 50. Genetic factors play a major role in carcinogenesis in young patients (below 50 yrs). Hence IGF-1 and insulin may play a larger role in patients below 50 years. Thus we limit our study to cancer patients below the age of 50.

IGF-1 has high bioactivity on epithelial cells. Thus their role in carcinomas is of significance rather than other types of malignancies. Hence we limit our study to carcinomas of breast, GIT, liver, prostate, uterus, cervix and ovaries.

Since carcinogenesis is multifactorial, various external carcinogens, genetic factors and metabolic derangements contribute to carcinogenesis. Diabetes mellitus type 2 and its associated metabolic derangements have been studied for their role in development of cancer. Hyperinsulinaemia ensues in early phase of insulin resistance which is responsible for variety of metabolic derangements. Hyperinsulinaemia has also been implicated as a candidate mediator in carcinogenesis [10].

High levels of insulin decrease binding proteins of IGF-1 [14, 18, 19]. IGF-1 signaling has been highly implicated in development of cancers, especially epithelial cell cancers (carcinomas). The IGF-1 signaling system plays a crucial role in tumor transformation, malignant cell turn over and survival of cancer cells. Such roles in normal cell growth are comparatively less [13, 24, 25]. The insulin IGF-1 system relationship and role of IGF-1 in carcinogenesis have been independent lines of investigations. However, well controlled studies in humans are essential to study the link between insulin resistance, hyperinsulinaemia, IGF-1 and carcinogenesis.

We hypothesize that hyperinsulinaemia which marks the early phase of insulin resistance could decrease IGFBP production. This results in increase in free IGF-1 in blood. Thus, bioavailability of free IGF-1 increases, which could mediate carcinogenesis in presence of other mediating factors. Should this hypothesis test positive, then it would be show insights to the role of insulin and insulin resistance in carcinogenesis.

A pilot study on 63 subjects was conducted to test this hypothesis (unpublished data). A trend towards significance of association between insulin resistance/sensitivity and IGF-1 levels was seen. The trend was stronger in patients below the age of 50. Insulin resistance and associated derangements are largely attributed to genetic factors [26, 27]. Thus, advanced age could be a confounder for this line of investigation. The study shall be conducted on cancer patients, below the age of 50 years, with solid tumors (carcinomas). The study also includes a control group consisting of subjects from normal population. Various associations between IGF-1 and insulin resistance/sensitivity shall be determined by suitable statistical methods. However, the precise role of IGF-1 and the extent of influence of IGF-1 system on carcinogenesis cannot be determined in this study

This study could add to the knowledge and insights into insulin's relationship with IGF-1 system and insulin's role in carcinogenesis. The role of insulin and insulin resistance would be an interesting subject in cancer prevention and treatment.