We observed that imatinib reduced the FPG and HbA1c concentration in subjects with T2DM. However, due to the design of our study, we cannot establish a real therapeutic effect of imatinib in subjects with T2DM. As described previously, only three of the eleven subjects with T2DM reduced their hypoglycemic therapy, but four remained with the same anti-diabetic treatment. HbA1c reduction indicates that FG was reduced, especially in subjects with high-starting HbA1c values; as in most diabetes clinical trials the magnitude of improvement in HbA1c is related to baseline A1c, the higher the A1c the greater the drop, so when A1c is normal you cannot expect a lot of improvement.
Imatinib inhibits the phosphorylation of proteins which may result in better signaling, better function of effectors, or both, with improvement in insulin sensitivity; thus, decreasing HbA1c levels in patients with high-starting values. Therefore, we can assume there is a therapeutic benefit in patients with T2DM. We cannot attribute this effect entirely to the imatinib treatment, but data in our study suggests there is a relationship between its administration and the lowering of FPG concentration.
Due to our study population, formed by Hispanic subjects with cancer, many confounding factors can alter the results. Nausea, vomiting, weight loss, hydroxyurea, and redistribution of adipose tissue [9] could influence glucose metabolism and insulin resistance. Even though there are animal trials that confirm the effect of imatinib on insulin resistance and glucose metabolism, these confounding variables need to be evaluated in prospective studies. We could not assess the effect after discontinuing therapy as Agostino et al. [2].
Ethnicity could affect imatinib’s treatment response. Several studies compared the difference of imatinib therapy response between different ethnic groups, but few studies have enough Hispanic subjects to compare against other ethnic groups. Lee et al. performed a study with more Hispanic subjects with CML compared to non-Hispanics [60.9% vs 39.1%, respectively], and concluded that Hispanic subjects achieved better treatment responses to imatinib when compared to non-Hispanic subjects [10].
We reviewed the pathophysiology of T2DM and several animal and human studies that aimed to establish the mechanism by which imatinib lowers FPG concentration. T2DM derives from the abnormal metabolism of carbohydrates, fats, and proteins which leads to hyperglycemia and hyperlipidemia. Within time, high levels of glucose and lipids induce changes in the metabolic pathways of insulin causing impaired insulin secretion from the β-cells of pancreatic islets, insulin resistance and decreased glucose use in peripheral tissues, and abnormal hepatic glucose production. Imatinib has shown to interfere in these pathways [11].
Mice models with type 1 diabetes mellitus (T1DM) and T2DM treated with TKIs have shown beneficial effects, improving several aspects of the disease. A study by Louvet et al. reported non-obese diabetic mice with new-onset T1DM experienced the regression of the disease when treated with imatinib [7]. Additionally, Chang Qing et al. established that there is an increase in the production of insulin in residual β-cells, with or without glucose stimulation, through an indirect control of the genetic expression of insulin in response to glucose, and through the promotion of the expression of glucose transporter-2 (GLUT-2) in β-cells [12]. Furthermore, it has been proven that TKIs prevent β-cell apoptosis via activation of antiapoptotic nuclear factor kappa-light-chain-enhancer of activated B cells (NF-Kb) and/or inhibition of the proapoptotic mitogen-activated protein kinase/c-jun N-terminal kinase (MAPK/JNK) [13, 14]. Moreover, Wijesekara et al. found that adiponectin promotes the phosphorylation of the protein kinase B (Akt/pkB) and the extracellular signal-regulated kinase (ERK) which leads to protection against apoptosis and stimulation of gene expression and secretion in pancreatic beta cells [15]. It has been proven that adiponectin concentration rises three times in plasma after three months of treatment with imatinib [16].
The hypoglycemic effect of this drug might be due to the inhibition of the multiple tyrosine kinases, such as c-Abl [12], PDGFR, Akt/pkB [4], and the extracellular regulatory kinases ERK1 and ERK2 which are crucial to the control and signaling activity of cellular effectors in the insulin pathway [17]. Phosphorylation of ERK by imatinib could result in better signaling, better functioning of the effectors or both [18], and it could also have an antiapoptotic effect [17]. In addition, inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) reduces the degree of islet cell inflammation (insulitis) [19]. Likewise, the tyrosine phosphorylation of insulin receptor and phosphorylation of Akt/pkB after insulin administration was dose-dependent [20]. It is noteworthy that c-kit inhibition is not required for the reversal of hyperglycemia [5]. Markers of endoplasmic reticulum (ER) stress, protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2α (eIF2α), phosphorylated tribbles homolog 3 protein (TRB3), C/EBP homologous protein (CHOP), and phosphorylated JNK, decreased with imatinib [21].
Several case reports and retrospective human studies have been published assessing the effect of imatinib on glucose metabolism. Salalori et al. reported a subject with T1DM with the translocation-ets-leukemia/platelet-derived growth factor receptor β (TEL/PDGFRβ) rearrangement mutation and symptomatic hypoglycemia that had a reduction in the insulin dosage after treatment with imatinib [22]. Breccia et al. performed a study of 7 diabetic subjects with CML treated with imatinib, 6 showed improvements in fasting glucose concentrations, allowing a dose decrease of oral hypoglycemic agents and insulin. Before starting imatinib, they had a mean glucose of 220 mg/dL, after 3 months of treatment the mean FPG concentration was 110 mg/dL and after 12 months 108 mg/dL. The subject who was resistant to imatinib had also a decrease in FPG concentrations [3]. A similar study by Agostino et al. analyzed the effect of multiple TKIs in glucose metabolism, and a subgroup of diabetic subjects (8 of 17, 47%) could discontinue their medications, including insulin in some of them. The mean FPG decreased in all individuals associated with treatment with TKI [2]. Additionally, other case series not only found beneficial effects of imatinib on FPG concentrations, but also in the lipid profile, lowering total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol concentrations [16, 23]. It has been proven that imatinib’s effect on glucose concentrations is stable after the end of treatment in comparison with dasatinib, which also lowered glucose concentrations [23, 24]. It is important to recall that this study has the biggest number of subjects, compared with others with the same topic.
For future studies in this topic, it would be very important to adjust the effect of imatinib on glucose metabolism for important confounders such as weight changes.
