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Diabetes Care 29:1989-1990, 2006
DOI: 10.2337/dc06-0874
© 2006 by the American Diabetes Association
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Letters: Comments and Responses

Increased Cancer-Related Mortality for Patients With Type 2 Diabetes Who Use Sulfonylureas or Insulin

Response to Bowker et al.

Azeez Farooki, MD and Stephen H. Schneider, MD

From the Memorial Sloan Kettering Cancer Center, New York, New York; and the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Address correspondence to Azeez Farooki, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave., Box 296, New York, NY 10021. E-mail: farookia{at}mskcc.org

We read with interest the article by Bowker et al. (1), which suggests that sulfonylurea or insulin therapy may increase cancer-related mortality. The premise that insulin is mitogenic for neoplastic cells is not proven. An expanding body of epidemiologic literature has linked insulin resistance and IGF-I, rather than absolute levels of insulin, with cancer incidence and prognosis.

There are several inherent limitations to this retrospective analysis. A total of 82.4% of the metformin group was also treated with sulfonylureas over the observation period. Also, patients requiring insulin likely had relatively poor glycemic control, longer duration of disease, and more subclinical or overt diabetes complications, perhaps not accounted for by the chronic disease score. These factors might increase mortality.

An area of pathophysiologic common ground between insulin resistance/diabetes and neoplastic diseases is the inflammatory milieu, which likely contributes to both of these disease states. The hyperglycemic, hyperinsulinemic, insulin-resistant state is proinflammatory and is very different than the euglycemic, hyperinsulinemic state achieved with intensive insulin therapy. Insulin itself possesses anti-inflammatory properties (2). Intranuclear levels of nuclear factor {kappa}ß, important in cancer progression, as well as plasma levels of several inflammatory cytokines (including vascular endothelial cell growth factor, i.e., vascular endothelial growth factor) are reduced through intravenous insulin infusion in obese nondiabetic subjects (3,4). Reduction in plasma vascular endothelial growth factor levels has also been shown during insulinization of poorly controlled or newly diagnosed diabetic adults and children (5,6). These data suggest that insulin possesses antiangiogenic as well as anti-inflammatory properties, which could benefit oncologic patients. As the authors point out, establishing a cause-and-effect relationship by a retrospective study in such a complex population is not possible. The positive or negative effects of aggressive insulinization in cancer patients remains an opened question that urgently requires randomized controlled clinical trials.

References

  1. Bowker SL, Majumdar SR, Veugelers P, Johnson JA: Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29:254–258, 2006[Abstract/Free Full Text]
  2. Dandona P, Mohanty P, Chaudhuri A, Garg R, Aljada A: Insulin infusion in acute illness. J Clin Invest 115:2069–2072, 2005[Medline]
  3. Dandona P, Aljada A, Mohanty P, Ghanim H, Bandyopadhyay A, Chaudhuri A: Insulin suppresses plasma concentration of vascular endothelial growth factor and matrix metalloproteinase-9. Diabetes Care 26:3310–3314, 2003[Abstract/Free Full Text]
  4. Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S: Insulin inhibits intranuclear nuclear factor B and stimulates IB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 86:3257–3265, 2001[Abstract/Free Full Text]
  5. Kakizawa H, Itoh M, Itoh Y, Imamura S, Ishiwata Y, Matsumoto T, Yamamoto K, Kato T, Ono Y, Nagata M, Hayakawa N, Suzuki A, Goto Y, Oda N: The relationship between glycemic control and plasma vascular endothelial growth factor and endothelin-1 concentration in diabetic patients. Metabolism 53:550–555, 2004[Medline]
  6. Ashraf A, Mick G, Meleth S, Abdullatif H, Wang X, McCormick K: Effect of insulin on plasma vascular endothelial growth factor in children with new-onset diabetes. J Clin Endocrinol Metab 90:4920–4923, 2005[Abstract/Free Full Text]

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This Article
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Google Scholar
Right arrow Articles by Farooki, A.
Right arrow Articles by Schneider, S. H.
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Right arrow Articles by Schneider, S. H.
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