Obesity, Diabetes, the Cardiorenal Syndrome, and Risk for Cancer

Abstract

Numerous epidemiological studies confirm that the prevalence of obesity and the cardiorenal metabolic syndrome (CRS) is extraordinarily high and that the rates have increased dramatically in the last three decades. In addition, epidemiological data demonstrate that obesity, the CRS, and diabetes are inextricably linked and are all associated with an increased incidence of a number of solid tissue cancers. The mechanisms for this association have been examined, including, but not limited to, higher levels of insulin and free levels of insulin-like growth factor and insulin resistance in obesity and the CRS. Mortality, morbidity, and the associated health care costs which are the link between obesity, the CRS, and diabetes are just beginning to be examined. In addition, we review the advantages of implementing lifestyle and surgical changes to modify obesity, lessening the development of the CRS, diabetes, and associated cancers. Epidemiological data regarding the general mechanisms of the pathogenesis of cancers associated with obesity, the CRS, and diabetes (specifically colon, pancreas, esophageal, liver, breast, prostate, thyroid, and renal carcinomas) are reviewed. The mechanisms by which obesity and other components of the CRS contribute to the pathogenesis of these cancers, such as hormone alterations and insulin- and insulin-like growth factor-dependent pathways of tumor pathogenesis, include the attending roles of inflammation and oxidative stress. Emphasis has been placed on obesity as a modifiable risk factor which, when addressed, provides a reduction in the rate of cancer deaths. In a second part to be published in the next issue of this journal, the relationship between diabetes and cancer will be reviewed in detail.

Fig. 1

Overnutrition and insulin resistance in the pathogenesis of cancer. In obesity, an increased release of FFA from adipose tissue and TNF-α as well as a reduced release of adiponectin lead to the development of insulin resistance and compensatory hyperinsulinemia. Increased insulin levels upregulate the hepatic synthesis of IGF-1. These IGF-1 effects are mediated through several downstream signaling pathways, including the PI3K-Akt system. Insulin and IGF-1 signal through the insulin and IGF-1 receptors, respectively, promote cellular proliferation, and inhibit apoptosis in many tissue types. These effects might contribute to tumorigenesis.

Fig. 2

Obesity-promoting insulin- and IGF-1-dependent pathways of tumorigenesis. There is increased aromatase activity in adipose tissues. Therefore, in obese individuals, there is typically an increased conversion of the androgens androstenedione and testosterone into the estrogens estrone and estradiol by aromatase enzyme. In parallel, obesity leads to hyperinsulinemia, which in turn causes a reduction in the hepatic synthesis and circulating levels of SHBG. The combined effect of the increased formation of estrone and estradiol along with the reduced levels of SHBG leads to an increase in the bioavailable fractions of estradiol that can diffuse to target cells, and, in some tissues, for example breast epithelium and endometrium, they promote cellular proliferation and inhibit apoptosis.