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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.

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Abbreviations

GH:

Growth hormone

GHR:

Growth hormone receptor

IGFBP:

IGF-1-binding protein

MAPK:

Mitogen-activated phosphokinase

PI3K:

Phosphatidylinositol 3-kinase

PKA:

Protein kinase A

TOR:

Target of rapamycin

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The authors declare that there is no duality of interest associated with this manuscript.

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JG-A provided the initial draft, which was edited and finalised by both authors.

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Correspondence to Jaime Guevara-Aguirre.

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Guevara-Aguirre, J., Rosenbloom, A.L. Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency. Diabetologia 58, 37–42 (2015). https://doi.org/10.1007/s00125-014-3397-3

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  • DOI: https://doi.org/10.1007/s00125-014-3397-3

Keywords

  • Apoptosis
  • Cancer
  • Diabetes
  • Growth hormone receptor
  • IGF-1
  • Insulin
  • Obesity
  • Review