Imatinib and Regression of Type 2 Diabetes
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《新英格兰医药杂志》
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-B 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.
Dino Veneri, M.D.
University of Verona
37126 Verona, Italy
Massimo Franchini, M.D.
City Hospital of Verona
37126 Verona, Italy
Enzo Bonora, M.D., Ph.D.
University of Verona
37126 Verona, Italy
enzo.bonora@univr.it
References
Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037.
Bohmer FD, Karagyozov L, Uecker A, et al. A single amino acid exchange inverts susceptibility of related receptor tyrosine kinases for the ATP site inhibitor STI-571. J Biol Chem 2003;278:5148-5155.
Sanz-Gonzalez SM, Castro C, Perez P, Andres V. Role of E2F and ERK1/2 in STI571-mediated smooth muscle cell growth arrest and cyclin A transcriptional repression. Biochem Biophys Res Commun 2004;317:972-979.
Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 2002;23:599-622.
Lassila M, Allen TJ, Cao Z, et al. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:935-942.
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-B 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.
Dino Veneri, M.D.
University of Verona
37126 Verona, Italy
Massimo Franchini, M.D.
City Hospital of Verona
37126 Verona, Italy
Enzo Bonora, M.D., Ph.D.
University of Verona
37126 Verona, Italy
enzo.bonora@univr.it
References
Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037.
Bohmer FD, Karagyozov L, Uecker A, et al. A single amino acid exchange inverts susceptibility of related receptor tyrosine kinases for the ATP site inhibitor STI-571. J Biol Chem 2003;278:5148-5155.
Sanz-Gonzalez SM, Castro C, Perez P, Andres V. Role of E2F and ERK1/2 in STI571-mediated smooth muscle cell growth arrest and cyclin A transcriptional repression. Biochem Biophys Res Commun 2004;317:972-979.
Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 2002;23:599-622.
Lassila M, Allen TJ, Cao Z, et al. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:935-942.