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: Jaime Guevara-Aguirre, Arlan L Rosenbloom
• Journal: Diabetologia (Diabetologia) Vol. 58 Issue 1 Pg. 37-42 (Jan 2015) ISSN: 1432-0428 [Electronic] Germany
• PMID: 25316432 (Publication Type: Journal Article, Review)

Chemical References

• Insulin
• Insulin-Like Growth Factor I

Topics

• Adult
• Body Composition
• Case-Control Studies
• Cohort Studies
• Diabetes Mellitus, Type 2 (complications, epidemiology, genetics)
• Ecuador (epidemiology)
• Humans
• Insulin (physiology)
• Insulin-Like Growth Factor I (physiology)
• Laron Syndrome (complications, epidemiology, genetics)
• Neoplasms (complications, epidemiology, genetics)
• Obesity (complications, epidemiology, genetics)