Skip to main content
SpringerLink
Log in

Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency

  • Review
  • Published:
Diabetologia Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

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

References

  1. Burke-Gaffney H (1968) The history of medicine in African countries. Med Hist 12:31–412

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Gohdes D, Kaufman S, Valway S (1993) Diabetes in American Indians. An overview. Diabetes Care 6:239–243

    Article  Google Scholar 

  3. Steyn K, Fourie J, Bradshaw D (1992) The impact of chronic diseases of lifestyle and their major risk factors on mortality in South Africa. S Afr Med J 82:227–231

    CAS  PubMed  Google Scholar 

  4. Reaven G (1988) Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607

    Article  CAS  PubMed  Google Scholar 

  5. Phillips C, Keese-Guoyot E, McManus R et al (2012) High dietary saturated fat intake accentuates obesity risk associated with the fat mass and obesity-associated gene in adults. J Nutr 142:824–831

    Article  CAS  PubMed  Google Scholar 

  6. Belpomme D, Irigaray P, Hardell R et al (2007) The multitude and diversity of environmental carcinogens. Environ Res 105:414–429

    Article  CAS  PubMed  Google Scholar 

  7. Wolin KY, Carson K, Colditz GA (2010) Obesity and cancer. Oncologist 15:556–565

    Article  PubMed Central  PubMed  Google Scholar 

  8. Knudeson A (2001) Two genetic hits to cancer. Nat Rev Cancer 2:157–162

    Article  Google Scholar 

  9. Pollak M, Schernhammer E, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518

    Article  CAS  PubMed  Google Scholar 

  10. Hsu I, Kim S, Kabir M, Bergman R (2007) Metabolic syndrome, hyperinsulinaemia, and cancer. Am J Clin Nutr 86:867–871

    Google Scholar 

  11. Otake S, Takeda H, Suzuki Y et al (2005) Association of visceral fat accumulation and plasma adiponectin with colorectal adenoma: evidence for participation of insulin resistance. Clin Cancer Res 11:3642–3646

    Article  CAS  PubMed  Google Scholar 

  12. Thissen J, Ketelslegers H, Underwood L (1994) Nutritional regulation of the insulin like growth factors. Endocrinol Rev 15:80–101

    CAS  Google Scholar 

  13. Dupont J, Kahan J, Bao-He Q, Metzler P, Helman L, LeRoith D (2001) Insulin and IGF-I induce different patterns of expression in mouse fibroblast NIH-3T3 cells: identification by cDNA microarray analysis. Endocrinology 142:4969–4975

    Article  CAS  PubMed  Google Scholar 

  14. Guevara-Aguirre J, Al R, Guevara-Aguirre M, Saavedra J, Procel P (2013) Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects. J Clin Endocrinol Metab 98:839–845

    Article  CAS  PubMed  Google Scholar 

  15. Longo V, Fontana L (2010) Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci 31:89–98

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Milazzo G, Giorgino F, Damante G et al (1992) Insulin receptor expression and function in human breast cancer cell lines. Cancer Res 52:3924–3930

    CAS  PubMed  Google Scholar 

  17. Birsoy K, Possemato R, Lorbeer FK et al (2014) Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508:108–112

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Baserga R, Peruzzi F, Krystof R (2003) The IGF-I receptor in cancer biology. Int J Cancer 107:873–877

    Article  CAS  PubMed  Google Scholar 

  19. Ferguson R, Novossyadlyy R, Fierz Y et al (2012) Hyperinsulinaemia enhances c-Myc-mediated mammary tumour development and advances metastatic progression to the lung in a mouse model of type 2 diabetes. Breast Cancer Res 14:R8

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Klement R, Kämmerer U (2011) Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutr Metab (Lond) 8:75

    Article  CAS  Google Scholar 

  21. Drake I, Sonestedt D, Gulberg B et al (2012) Dietary intakes of carbohydrates in relation to prostate cancer risk: a prospective study in the Malmö diet and cancer cohort. Am J Nutr 96:1409–1418

    Article  CAS  Google Scholar 

  22. Samani A, Yakar S, LeRoith D, Brodt P (2007) The role of the IGF-I system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28:20–47

    Article  CAS  PubMed  Google Scholar 

  23. Rosenbloom A, Goldstein S, Yip CC (1976) Insulin binding to cultured human fibroblasts increases with normal and precocious aging. Science 193:412–415

    Article  CAS  PubMed  Google Scholar 

  24. Wijsman C, Rozing M, Streefland T, Leiden Longevity Study group et al (2011) Familial longevity is marked by enhanced insulin sensitivity. Aging Cell 10:114–121

    Article  CAS  PubMed  Google Scholar 

  25. Benetou B, Trichopoulou A, Orfanos P et al (2008) Conformity to traditional Mediterranean diet and cancer incidence: the Greek EPIC cohort. Brit J Cancer 99:191–195

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Colman R, Anderson R, Johnson S et al (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Fruman DA, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13:140–156

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Ikeno Y, Hubbard GB, Lee S et al (2009) Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci 64:522–529

    Article  PubMed  Google Scholar 

  29. Dossus L, Kaaks R (2004) Nutrition, metabolic factors and cancer risk. Nat Cancer Rev 4:579–591

    Article  Google Scholar 

  30. Sancar A, Lindsey-Boltz L, Unsal-Kacmaz K, Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Ann Rev Biochem 73:39–85

    Article  CAS  PubMed  Google Scholar 

  31. van Heijst J, Niessen H, Hoekman K, Schalkwijk CG (2005) Advanced glycation end products in human cancer tissues: detection of Nε-(carboxymethyl)lysine and argpyrimidine. Ann NY Acad Sci 1043:725–733

    Article  PubMed  Google Scholar 

  32. Dingli D, Chalub F, Santos F, van Segbroeck S, Pacheco J (2009) Cancer phenotype as the outcome of an evolutionary game between normal and malignant cells. Br J Cancer 101:1130–1138

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Halberg H, Henriksen M, Soderhamn N et al (2005) Effect of intermittent fasting and re-feeding on insulin action in healthy men. J Appl Physiol 99:2128–2136

    Article  CAS  PubMed  Google Scholar 

  34. Lee P, Durham S, Martínez V, Vásconez O, Powell D, Guevara-Aguirre J (1997) Kinetics of insulin-like growth factor (IGF) and IGF-binding protein responses to a single dose of growth hormone. J Clin Endocrinol Metab 82:2266–2274

    CAS  PubMed  Google Scholar 

  35. Wolpin B, Michaud D, Giovannucci E et al (2007) Circulating insulin-like growth factor binding protein-I and the risk of pancreatic cancer. Cancer Res 67:7923–7928

    Article  CAS  PubMed  Google Scholar 

  36. Wu Y, Yakar S, Hennighausen L, LeRoith D (2002) Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res 62:1030–1035

    CAS  PubMed  Google Scholar 

  37. Kolb E, Gorlick R, Maris J et al (2012) Combination testing (Stage 2) of the anti-IGF-I receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer 58:729–735

    Article  PubMed Central  PubMed  Google Scholar 

  38. MacEwen E, Pastor J, Kutzke J et al (2004) IGF-I receptor contributes to the malignant phenotype in human and canine osteosarcoma. J Cell Biochem 92:77–91

    Article  CAS  PubMed  Google Scholar 

  39. Chhabra Y, Waters J, Brokks A (2011) Role of the growth hormone/IGF-I axis in cancer. Expert Rev Endocrinol Metab 6:71–84

    Article  CAS  Google Scholar 

  40. Belfioiri A, Frasca F, Pandini G, Sciacca L, Vigneri R (2009) Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 30:586–623

    Article  Google Scholar 

  41. Rinderknecht E, Humbel R (1978) The amino acid sequence of human insulin growth factor-I and its structural homology with pro-insulin. J Biol Chem 253:2769–2776

    CAS  PubMed  Google Scholar 

  42. Brzozowski A, Dodson E, Dodson G et al (2002) Structural origins of the functional divergence of human insulin growth factor-I and insulin. Biochemistry 41:9389–9397

    Article  CAS  PubMed  Google Scholar 

  43. Kim J, Accili D (2002) Signaling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res 12:84–90

    Article  CAS  PubMed  Google Scholar 

  44. Huo J, Xu S, Lin B, Chng WJ, Lam KP (2013) Fas apoptosis inhibitory molecule is upregulated by IGF-I signaling and modulates Akt activation and IRF4 expression in multiple myeloma. Leukemia 27:1165–1171

    Article  CAS  PubMed  Google Scholar 

  45. Hanahan D, Weinberg R (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  46. Renehan A, Zwahalen M, Minder C, O’Dwyer S, Shalet M, Egger M (2004) Insulin-like growth factor (IGF)-I, IGF-binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363:1346–1353

    Article  CAS  PubMed  Google Scholar 

  47. Huang J, Morehouse C, Streicher K et al (2011) Altered expression of insulin receptor isoforms in breast cancer. PLoS ONE 6:e26177

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Margel D, Urbach D, Lipscombe L et al (2013) Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol 31:3069–3075

    Article  CAS  PubMed  Google Scholar 

  49. Currie C, Poole C, Jenkins-Jones S, Gale E, Johnson J, Morgan C (2012) Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin in survival. Diabetes Care 35:299–304

    Article  PubMed Central  PubMed  Google Scholar 

  50. Madiraju AK, Erion DM, Rahimi Y et al (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510:542–546

    Article  CAS  PubMed  Google Scholar 

  51. Yakar S, LeRoith D, Brodt P (2005) The role of growth hormone /insulin-like growth factor axis in tumour growth and progression: lessons from animal models. Cytokine Growth Factor Rev 16:407–420

    Article  CAS  PubMed  Google Scholar 

  52. Resnicoff M, Copolla D, Sell C et al (1994) Growth inhibition of human melanoma cells in nude mice by anti-sense strategies to the type-I insulin-like growth factor receptor. Cancer Res 54:4848–4850

    CAS  PubMed  Google Scholar 

  53. Suh Y, Atzmon G, Cho M et al (2008) Functionally significant insulin-like growth factor-I receptor mutations in centenarians. Proc Natl Acad Sci 105:3438–3442

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Guevara-Aguirre J, Rosenbloom A, Fielder PJ, Diamond FB Jr, Rosenfeld RG (1993) Growth hormone receptor deficiency in Ecuador: clinical and biochemical phenotype in two populations. J Clin Endocrinol Metab 76:417–423

    CAS  PubMed  Google Scholar 

  55. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Fielder PJ (1990) The little women of Loja: growth hormone receptor deficiency in an inbred population of Southern Ecuador. N Engl J Med 323:1367–1374

    Article  CAS  PubMed  Google Scholar 

  56. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M et al (2011) Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 3:70ra13

    Article  PubMed Central  PubMed  Google Scholar 

  57. Steuerman R, Shivah O, Laron Z (2011) Congenital IGF-I deficiency tends to confer protection against postnatal development of malignancies. Eur J Endocrinol 164:485–489

    Article  CAS  PubMed  Google Scholar 

  58. Gebre-Medhin M, Kindblom LG, Wennbo H, Törnell J, Meis-Kindblom JM (2001) Growth hormone receptor is expressed in human breast cancer. Am J Pathol 158:1217–1222

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Zhou D, Yang J, Huang WD, Wang J, Zhang Q (2013) siRNA-targeted inhibition of growth hormone receptor in human colon cancer SW480 cells. World J Gastroenterol 19:8108–8113

    Article  PubMed Central  PubMed  Google Scholar 

  60. Guevara Aguirre J, Rosenbloom AL, Balasubramaniam P et al (2014) Enhanced insulin sensitivity in subjects with absent growth hormone receptor signaling despite increased body fat content. The Endocrine Society, Chicago, June 21-24, latebreaking abstract LB-OR02-1 (abstract)

  61. Laron Z (2011) Insulin secretion and carbohydrate metabolism in patients with Laron syndrome: from hypoglycaemia to diabetes mellitus. In: Laron Z, Kopchick JJ (eds) Laron syndrome from man to mouse. Springer-Verlag, Berlin/Heidelberg, pp 259–272

    Chapter  Google Scholar 

  62. Vicente TAR, Rocha IES, Salvatori R et al (2013) Lifetime congenital isolated GH deficiency does not protect from the development of diabetes. Endocr Connect 2:112–117

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Duality of interest

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

Contribution statement

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

Author information

Authors and Affiliations

  1. Universidad San Francisco de Quito, Diego de Robles & Via Interoceanica, Quito, Ecuador

    Jaime Guevara-Aguirre

  2. Instituto de Endocrinología IEMYR, Quito, Ecuador

    Jaime Guevara-Aguirre

  3. University of Florida College of Medicine, Gainesville, FL, USA

    Arlan L. Rosenbloom

Authors
  1. Jaime Guevara-Aguirre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arlan L. Rosenbloom
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jaime Guevara-Aguirre.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Keywords

Search

Navigation