title: Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency.
abstract: Obesity with insulin-resistant diabetes and increased cancer risk is a global problem. We consider the alterations of metabolism attendant on the underlying pathogenic overnutrition and the role of the growth hormone (GH)-IGF-1 axis in this interaction. Obesity-induced insulin resistance is a determinant of diabetes. Excess glucose, and an elevated concentration of insulin acting through its own receptors along with complex interactions with the IGF-1 system, will add extra fuel and fuel signalling for malignant growth and induce anti-apoptotic activities, permitting proliferation of forbidden clones. In Ecuador there are ~100 living adults with lifelong IGF-1 deficiency caused by a GH receptor (GHR) mutation who, despite a high percentage of body fat, have markedly increased insulin sensitivity compared with age- and BMI-matched control relatives, and no instances of diabetes, which is present in 6% of unaffected relatives. Only 1 of 20 deceased individuals with GHR deficiency died of cancer vs 20% of ~1,500 relatives. Fewer DNA breaks and increased apoptosis occurred in cell cultures exposed to oxidant agents following addition of serum from GHR-deficient individuals vs serum from control relatives. These changes were reversible by adding IGF-1 to the serum from the GHR-deficient individuals. The reduction in central regulators of pro-ageing signalling thus appears to be the result of an absence of GHR function. The complex inter-relationship of obesity, diabetes and cancer risk is related to excess insulin and fuel supply, in the presence of heightened anti-apoptosis and uninhibited DNA damage when GHR function is normal.
authors.affiliation: Universidad San Francisco de Quito, Diego de Robles & Via Interoceanica, Quito, Ecuador, jguevara@usfq.edu.ec.
authors.forename: Jaime
authors.initials: J
authors.lastname: Guevara-Aguirre
authors.forename: Arlan L
authors.initials: AL
authors.lastname: Rosenbloom
mesh_terms: D000328:Adult; D001823:Body Composition; D016022:Case-Control Studies; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000453:epidemiology* / Q000235:genetics; D004484:Ecuador / Q000453:epidemiology; D006801:Humans; D007328:Insulin / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D046150:Laron Syndrome / Q000150:complications / Q000453:epidemiology* / Q000235:genetics; D009369:Neoplasms / Q000150:complications / Q000453:epidemiology* / Q000235:genetics; D009765:Obesity / Q000150:complications / Q000453:epidemiology* / Q000235:genetics
chemical_list: D007328:Insulin; D007334:Insulin-Like Growth Factor I