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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1628-1629 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.9637
Insulin Resistance and Cancer-Related MortalityMemorial Sloan Kettering Cancer Center, New York, NY
Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ To the Editor: The study by Park et al1 draws attention to fasting hyperglycemia at cancer diagnosis as a risk factor for death over the median study follow-up duration of 3.03 years. The prevalence of the insulin resistant state metabolic syndrome is approximately 25% of adults in the United States, and appears to be increasing.2 The authors mention that the hyperinsulinemia associated with insulin resistance could be selectively mitogenic for neoplastic cells given insulin receptor overexpression in cancer tissue. An area of pathophysiologic common ground between neoplastic diseases and insulin resistance/diabetes mellitus is the inflammatory milieu. We wish to emphasize that the hyperglycemic, hyperinsulinemic, insulin resistant state is proinflammatory and is very different than the euglycemic, hyperinsulinemic state achieved through intensive insulin therapy. Insulin itself possesses anti-inflammatory properties, while hyperglycemia is proinflammatory.3 Intranuclear levels of nuclear factor kappa beta, as well as plasma levels of several inflammatory cytokines (including vascular endothelial cell growth factor) are reduced through intravenous insulin infusion in obese nondiabetics.4,5 Reduction in plasma vascular endothelial cell growth factor levels has also been shown through correction of hyperglycemia and lowering of hemoglobin A1C (HgA1C) with insulin in poorly controlled or newly diagnosed diabetic adults and children.6,7 These data suggest antiangiogenic, as well as anti-inflammatory effects of glycemic control, which could benefit oncologic patients. Other potential mechanisms whereby glycemic control might improve outcomes in cancer patients are through reversal of neutrophil dysfunction8 and hypercoagulability,9 respectively, which are well characterized effects in nononcologic patients. Despite the authors’ scrupulous attempt to distinguish between cancer-related and all cause mortality, diabetic patients may have a subclinical reduction in functional reserve in major organ systems, thereby blurring a precise distinction of cause of death. Subclinical diabetic complications, as opposed to potential adverse cancer specific effects of insulin resistance, may have contributed to the higher mortality rates observed with hyperglycemia before diagnosis of certain cancers. As the authors allude, multifactorial strict diabetic control could improve morbidity and mortality in cancer patients just as it does in noncancer patients.10 Due to a lack of high level evidence and to the numerous clinical issues confronting physicians treating complex cancer patients with variable survival rates, strict glycemic control is not prioritized as highly as in other patient populations. Research exploring the positive or negative effects of aggressively treating the insulin resistant, hyperglycemic state in oncologic patients is needed. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES
1. Park SM, Lim MK, Shin SA, et al: Impact of prediagnosis smoking, alcohol, obesity, and insulin resistance on survival in male cancer patients: National Health Insurance Corporation study. J Clin Oncol 24:5017-5024, 2006 2. Ford ES, Giles WH, Mokdad AH: Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care 27:2444-2449, 2004 3. Dandona P, Mohanty P, Chaudhuri A, et al: Insulin infusion in acute illness. J Clin Invest 115:2069-2072, 2005[CrossRef][Medline] 4. Dandona P, Aljada A, Mohanty P, et al: Insulin suppresses plasma concentration of vascular endothelial growth factor and matrix metalloproteinase-9. Diabetes Care 26:3310-3314, 2003 5. Dandona P, Aljada A, Mohanty P, et al: Insulin inhibits intranuclear nuclear factor 6. Kakizawa H, Itoh M, Itoh Y, et al: The relationship between glycemic control and plasma vascular endothelial growth factor and endothelin-1 concentration in diabetic patients. Metabolism 53:550-555, 2004[CrossRef][Medline] 7. Ashraf A, Mick G, Meleth S, et al: Effect of insulin on plasma vascular endothelial growth factor in children with new-onset diabetes. J Clin Endocrinol Metab 90:4920-4923, 2005 8. Alexiewicz J, Kumar D, Smogorzewski M, et al: Polymorphonuclear leukocytes in non-insulin-dependent diabetes mellitus: Abnormalities in metabolism and function. Ann Intern Med 123:919-924, 1995 9. Aljada A, Ghanim H, Mohanty P, et al: Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. J Clin Endocrinol Metab 87:1419-1422, 2002 10. Gæde P, Vedel P, Larsen N, et al: Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348:383-393, 2003 This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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