Correspondence
Imatinib and Regression of Type 2 Diabetes
N Engl J Med 2005; 352:1049-1050March 10, 2005
- Article
To the Editor:
We report the case of a nulliparous, 70-year-old woman with long-standing type 2 diabetes mellitus who had regression of the disease during treatment of chronic myeloid leukemia with imatinib, an antineoplastic agent. Type 2 diabetes mellitus was diagnosed when the patient was 62 years of age and weighed 60 kg (body-mass index [the weight in kilograms divided by the square of the height in meters], 24.2) She was treated with diet for one year, oral agents for four years, and insulin thereafter. After the detection of leukocytosis and immature myeloid cells in the blood, chronic myeloid leukemia was diagnosed (in March 2004) and treatment with imatinib (400 mg per day) was initiated. Hematologic remission was documented two months later. During treatment with imatinib, the patient's blood glucose level progressively declined, and insulin doses were titrated down. Insulin treatment was discontinued in June 2004. In July 2004, a standard oral glucose-tolerance test revealed the following plasma glucose values: 6.7 mmol per liter (121 mg per deciliter) while the patient was fasting, 10.7 mmol per liter (193 mg per deciliter) at one hour, and 8.2 mmol per liter (148 mg per deciliter) at two hours. The corresponding serum insulin values were 105, 336, and 315 pmol per liter. Therefore, the diagnosis of type 2 diabetes mellitus was no longer tenable. During the succeeding months, regression of type 2 diabetes mellitus was confirmed. During the past year, the patient's diet, physical activity, and weight (67 kg; body-mass index, 26.8) have not changed, and she has not taken any medication known to affect glucose metabolism.
Imatinib mesylate (Gleevec, Novartis) is a potent inhibitor of the BCR-ABL tyrosine kinase associated with chronic myeloid leukemia1 and several protein kinases, including platelet-derived growth factor receptor, Akt (protein kinase B), and extracellular regulated kinase 1 and 2 (ERK1 and ERK2).2,3 The phosphorylation of these proteins is crucial in insulin signaling and in controlling the activity of cellular insulin effectors, such as enzymes. Inhibition of phosphorylation by imatinib may result in better signaling, better functioning of effectors, or both, with improvement in insulin sensitivity. Imatinib may also inhibit phosphorylation processes involved in impaired insulin secretion. It is important to emphasize that inflammation and oxidant stress, which seem to play a crucial role in the pathogenesis of type 2 diabetes mellitus,4 share several mechanisms with aberrations in cell differentiation, growth, and proliferation. These mechanisms, which involve nuclear factor-κB and other transcription factors, might be affected by imatinib. Therefore, long-term treatment with imatinib might favorably act at steps controlling not only cell growth and replication but also physiological functions responsible for maintaining glucose homeostasis. Interestingly, a recent article suggested that imatinib can prevent atherosclerosis,5 which has common roots with type 2 diabetes mellitus. In conclusion, this case report suggests that the search for a cure for type 2 diabetes mellitus should include investigation of drugs affecting mechanisms that are targeted by antineoplastic agents such as imatinib.
5 ReferencesDino Veneri, M.D.
University of Verona, 37126 Verona, ItalyMassimo Franchini, M.D.
City Hospital of Verona, 37126 Verona, ItalyEnzo Bonora, M.D., Ph.D.
University of Verona, 37126 Verona, Italy
enzo.bonora@univr. it 1
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- Citing Articles (16)
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J. J. Oh, S. K. Hong, Y. M. Joo, B. K. Lee, S. H. Min, S. Lee, S.-S. Byun, S. E. Lee. (2012) Impact of Sunitinib Treatment on Blood Glucose Levels in Patients with Metastatic Renal Cell Carcinoma. Japanese Journal of Clinical Oncology
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Michael W. Deininger, Paul Manley. (2011) What do kinase inhibition profiles tell us about tyrosine kinase inhibitors used for the treatment of CML?. Leukemia Research
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Eirini Thanopoulou, Ian Judson. (2011) The safety profile of imatinib in CML and GIST: long-term considerations. Archives of Toxicology
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Heikki Joensuu, Jonathan C. Trent, Peter Reichardt. (2011) Practical management of tyrosine kinase inhibitor-associated side effects in GIST. Cancer Treatment Reviews 37:1, 75-88
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Susannah O’Sullivan, Dorit Naot, Karen E. Callon, Maureen Watson, Greg D. Gamble, Marianne Ladefoged, Morten A. Karsdal, Peter Browett, Jillian Cornish, Andrew Grey. (2011) Imatinib Mesylate Does Not Increase Bone Volume In Vivo. Calcified Tissue International 88:1, 16-22
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Serap Gur, Philip J. Kadowitz, Wayne J.G. Hellstrom. (2010) A Protein Tyrosine Kinase Inhibitor, Imatinib Mesylate (Gleevec), Improves Erectile and Vascular Function Secondary to a Reduction of Hyperglycemia in Diabetic Rats. The Journal of Sexual Medicine 7:10, 3341-3350
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Pascal Wolter, Patrick Schöffski. (2010) Targeted therapies in the treatment of GIST: Adverse events and maximising the benefits of sunitinib through proactive therapy management. Acta Oncologica 49:1, 13-23
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Dariush Mokhtari, Nils Welsh. (2009) Potential utility of small tyrosine kinase inhibitors in the treatment of diabetes. Clinical Science 118:4, 241-247
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Radu Gologan, Gabriela Constantinescu, Daniela Georgescu, Daniela Ostroveanu, Didona Vasilache, Camelia Dobrea, Daniela Iancu, Viola Popov. (2009) Hypolipemiant besides antileukemic effect of imatinib mesylate. Leukemia Research 33:9, 1285-1287
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Susannah O'Sullivan, Dorit Naot, Karen Callon, Fran Porteous, Anne Horne, Diana Wattie, Maureen Watson, Jill Cornish, Peter Browett, Andrew Grey. (2007) Imatinib Promotes Osteoblast Differentiation by Inhibiting PDGFR Signaling and Inhibits Osteoclastogenesis by Both Direct and Stromal Cell-Dependent Mechanisms. Journal of Bone and Mineral Research 22:11, 1679-1689
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