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.

Dietary and pharmacological modification of the insulin/IGF-1 system: exploiting the full repertoire against cancer

“…43 The relevance of this pathway for tumorigenesis is demonstrated by the fact that humans with the Laron syndrome, a recessively inherited defect in the growth hormone receptor, display extremely low IGF-1 and reduced insulin concentrations and usually do not develop cancer despite high prevalence of obesity and dyslipidemia. 44, 45 …”

A half-century of studies of growth hormone insensitivity/Laron syndrome: A historical perspective

“…The rare conditions of GHI/LS caused by GHRD and postreceptor abnormalities have provided greater understanding of the processes of growth, body composition, and metabolism and will continue to do so [53,54]. Table 3 Adverse events with rhIGF-I administration in 76 patients with growth hormone insensitivity treated a total of 321 patient years [43][44][45][46].…”

Metformin Reduces Prostate Tumor Growth, in a Diet-Dependent Manner, by Modulating Multiple Signaling Pathways

“…On the other hand, metformin treatment in HFD-fed mice was associated with decreased expression of GHR and IGFBP3. Interestingly, GHR appeared to be upregulated in colorectal and breast cancer samples (48), and its downregulation is associated with better metabolic profile and lower cancer incidence (49), whereas IGFBP3 levels are elevated in patients with prostate cancer (50), suggesting that metformin could be partially exerting its beneficial effects under HFD conditions through the regulation of the local expression of different GH/IGF1 axis components. Remarkably, whether these expression changes are accompanied by alterations in protein levels is still to be defined.…”