Having just seen a news article on NBC concerning a potential new treatment for diabetes using imatinib mesylate, sold as Gleevec ™ and made by Novartis. I’ve looked it up and initial findings are very interesting. While testing it for other conditions several years ago, researchers noted a major improvement in fasting blood glucose (FG) among their diabetic subjects. After this effect was studied, this paper was published in 2004:
Journal of Clinical Oncology, Vol 22, No 22 (November 15), 2004: pp. 4653-4655
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.04.217
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Imatinib Mesylate May Improve Fasting Blood Glucose in Diabetic Ph+ Chronic Myelogenous Leukemia Patients Responsive to Treatment
M. Breccia, M. Muscaritoli, Z. Aversa, F. Mandelli, G. Alimena
University “La Sapienza,” Rome, Italy
To the Editor:
Imatinib mesylate therapy has shown significant activity against Philadelphia-chromosome positive chronic myelogenous leukemia (Ph + CML). This drug is a selective competitive inhibitor of the Bcr-Abl tyrosine kinase, but at therapeutic concentrations, it also inhibits the activity of other tyrosine kinases such as platelet-derived growth factor receptor beta (PDGF-ß) and c-kit.1 Imatinib can be safely administered in CML patients with type 2 diabetes.
Here we report on our experience on the treatment of seven diabetic CML patients with imatinib. In six of these patients, we observed an improvement of fasting blood glucose levels (FG), which allowed a consequent reduction of oral antidiabetic drugs or insulin dosage. Of the seven patients, three were men, and four were women; median age was 66 years (range, 57 to 70 years). Four patients were in chronic phase, and all were given imatinib at 400 mg/d; of these four patients, three were resistant to prior interferon alfa (IFN-
) given for a median of 25 months, while in one patient, imatinib was the first-line therapy. Three patients were in accelerated phase and were given imatinib at 600 mg/d; all of them had been pretreated with IFN- and hydroxyurea for a median time of 20 months.
All patients had been diagnosed as diabetic at least 10 years before CML onset. Three patients were using insulin, and four patients were taking oral antidiabetic drugs for glycemic control. Before starting with imatinib the median glucose level was 220 mg/dL (range, 162 to 305 mg/dL). After 3 months of therapy, six of seven patients had obtained a complete cytogenetic response. At the same time, concomitant improvement of FG with consequent reduction of antidiabetic drugs dosage was observed, although patients had apparently maintained the same lifestyle and alimentary habits. In particular, median FG was 110 mg/dL (range, 96 to 127 mg/dL), as compared with an FG of 160 mg/dL (range, 96 to 220 mg/dL; P = .0004) as evaluated after 3 months of precedent IFN- therapy. At the time of this writing, all patients have completed 12 months of therapy, six have maintained cytogenetic response and concomitant good glycemic control (median glucose level, 108 mg/dL; range, 89 to 124 mg/dL; as compared with 208 mg/dL; range, 171 to 245 mg/dL after 12 months of precedent therapy; P = .004) still on reduced antidiabetic drugs dosage. Only the accelerated-phase patient (patient 1), who was resistant to imatinib after 1 year of therapy, did not obtain a good control of blood glucose level despite increasing insulin dosages. Differences between fasting glucose concentrations before and after imatinib therapy are shown in Figure 1.
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The mechanism(s) through which imatinib could improve FG in CML patients is presently not known. Boren et al2 reported the in vitro evidence for decreased proliferation of Bcr-Abl-positive K562 human myeloid blast cells under treatment with imatinib at increasing doses with the concomitant reduction of glucose carbon incorporation into RNA, and of palmitate synthesis. This finding was ascribed to a direct effect of imatinib on key enzymes of glucose metabolism, such as hexokinase, glucose-6-phosphate dehydrogenase, and transketolase, which are primary targets of the drug. Further confirmatory evidence that the imatinib mechanism of action might include interference with glucose metabolism comes from the finding that the activation of Bcr-Abl tyrosine kinase is associated with the stimulation of glucose transport, and, therefore, a pivotal role by glucose metabolism may be played in the survival of stem cells in CML.3 Moreover, it has been shown4 that imatinib induces early functional changes in tumor glucose metabolism, which also correlate with tumor response in other cell types, such as gastrointestinal stromal tumors cells, characterized by surface expression of CD117 (c-kit).
In our experience, only patients responding to imatinib concomitantly obtained an improvement of FG; this suggests that the drug, at therapeutic concentrations, may act not only on Bcr-Abl tyrosine kinase, but also on intracellular pathways involved in peripheral insulin action in the host’s normal cells, through metabolic changes capable of influencing the normal enzyme activities in these cells as well.
In type 2 diabetes, the normal insulin signaling pathways are disrupted, and abnormal signaling in muscle, adipose tissue, liver, and pancreas leads to insulin resistance.5 Insulin resistance is brought about by a reduction of key signaling proteins such as insulin receptor substrate (IRS) -1 and IRS-2, and recently, a role for elevated free fatty acid concentrations and/or accumulation of intracellular lipids has been evoked in reduced-insulin sensitivity. It is possible that, as for K562 cells in vitro, imatinib also exerts its effect on normal cells in vivo by reducing fatty acid concentrations through a low rate of glucose carbon flow. However, it cannot be excluded that imatinib could interfere with any of the potentiallly disrupted molecular mechanisms downstream the IRS in the “diabetic cell,” thus contributing to restore almost normal glucose tolerance.
Another rather simplistic interpretation of our findings could be that glucose tolerance was improved in CML patients as a positive side effect of leukemic response, which could, by itself, imply reduced insulin resistance. However, this hypothesis is weakened by the clinical observation that four of the seven patients studied achieved disease remission with no improvement of FG during prior IFN- therapy.
In conclusion, we suggest that the role of imatinib on glucose metabolism warrants further investigation both in diabetic and nondiabetic CML patients. In fact, gaining insight into the yet partially unknown mechanisms of action of imatinib might, on one hand, contribute to overcoming imatinib resistance in hematologic malignancies and, conversely, help to better understand molecular abnormalities underlying insulin resistance in diabetes and other pathological conditions.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
REFERENCES
1. Kantarjian H, Sawyers C, Hochhaus A, et al: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645–652, 2002[Abstract/Free Full Text]
2. Boren J, Cascante M, Marin S, et al: Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells. J Biol Chem 276:37747–37753, 2001[Abstract/Free Full Text]
3. Bentley J, Walker I, McIntosh E, et al: Glucose transport regulation by p210 Bcr-Abl in a chronic myeloid leukaemia model. Br J Haematol 112:212–215, 2001[CrossRef][Medline]
4. Van den Abbeele AD, Badawi RD: Use of positron emission tomography in oncology and its potential role to assess response to imatinib mesylate therapy in gastrointestinal stromal tumors (GISTs). Eur J Cancer 38:S60–S65, 2002
5. Rhodes CJ, White MF: Molecular insight into insulin action and secretion. Eur J Clin Investig 32:3–13, 2002
Wikipedia has an entry on imatinib, its history and use for cancer, but not diabetes.
http://en.wikipedia.org/wiki/Imatinib
I‘ve been trying to keep up with progress on a cure since the Edmonton Protocol, nearly ten years ago. That involved transplantation of donor beta cells. The problem I had with that strategy was replacing the use of insulin to control diabetes, a process that until biosynthetic insulin analogs, was fairly well understood, with a lifetime of daily immunosuppressive drugs that would greatly increase your chances of aquiring sonething much more severe, cancer, for instance, did not seem like much of a trade-off. Also, the cells came from cadavers, which while not a dealbreaker, wasn’t very appealing. I hoped that research would move into perfecting cloning for stem cells and the recovery of those pluripotent cells from the adult body of the patient, eliminating an immune counter-response. Those cells could then be implanted back into the patient. Subsequent research has indicated not only the liver but also the spleen are suitable base sites for active beta cells, suggesting that location may not be an issue, facilitating easy implantation. This approach and others similiar to it, however, all depend on the perfection of stem-cell recovery and cloning techniques.
Gotta go (left it too late)–back soon
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