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Glycemic dysregulation in a patient with type 2 diabetes treated with 5-azacitidine: a case report
© The Author(s). 2018
- Received: 29 October 2017
- Accepted: 13 April 2018
- Published: 3 July 2018
Diabetes and myelodysplastic syndrome are two conditions that may coexist in a single patient, since both diseases are prevalent in the elderly. The pathophysiology of myelodysplastic syndrome involves recurrent genetic mutations, especially in genes controlling epigenetic regulation. Although the pathophysiology of diabetes is not well understood, several studies suggest a role of epigenetics in type 2 diabetes.
We report here for the first time the case of a 75-year-old Caucasian man who was treated for both diabetes and acute myeloid leukemia secondary to myelodysplastic syndrome, with a temporal association between glycemic dysregulation and the intake of 5-azacitidine. In fact, 2–3 days after starting each 7-day cycle of 5-azacitidine, he reported higher blood glucose levels, requiring an increased dose of self-administered insulin.
This observation could help to understand the pathophysiology of these two conditions and could encourage physicians to monitor blood glucose levels in patients under hypomethylating agent with a history of diabetes.
- Myelodysplastic syndrome
- Hypomethylating agent
- Acute myeloid leukemia
The incidence of type 2 diabetes (T2D) is 5.8% in the population aged 45–64 years and reaches 13.4% in individuals over 75. The pathophysiology of T2D involves impaired insulin secretion by β-cells and insulin resistance in peripheral cells. The pathophysiology of T2D has not been fully elucidated but recent studies suggest a combination of non-genetic risk factors, such as sedentary behaviors, ageing, and obesity, and genetic risk factors . There is emerging evidence for the involvement of epigenetic regulation in the pathophysiology of diabetes [1, 2]. Epigenetic regulation is the control of gene expression without changes in desoxynucleic acid (DNA) sequence, through the modification of DNA methylation and histone acetylation. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), occurs on the cytosines of CpG dinucleotides, resulting in the generation of 5-methylcytosine. CpG hypermethylation of promoter regions results in low chromatin access to transcription factors and gene expression inhibition. Cancer cells exhibit distinct regions of DNA hypermethylation in promoters of tumor-suppressor genes.
Myelodysplastic syndromes (MDS) are clonal myeloid malignancies characterized by ineffective hematopoiesis resulting in blood cytopenia. MDS are more common in the elderly, with a median age at diagnosis ranging between 65 and 70 years and an incidence of 1.75/100,000 and 37.8/100,000 in individuals aged 50–54 and 75–79 years, respectively. In MDS, myeloid progenitor cells carry one or more recurrent point mutations in genes involved in epigenetic regulation, leading to transcription silencing of genes . DNMT3A, isocitrate deshydrogenase-1 and 2 or TET-2 methylcytosine dioxygenase genes are often mutated in patients with high-risk MDS, and are involved in skewing DNA methylation patterns.
5-azacitidine is a structural analogue of cytosine that incorporates into DNA and covalently inhibits DNMT. 5-azacitidine has been approved for the treatment of patients with higher-risk MDS and acute myeloid leukemia (AML) based on the results of a phase 3 study showing a survival advantage compared to conventional treatment . We describe a case of glycemic dysregulation in a patient with diabetes treated with 5-azacitidine for AML.
To the best of our knowledge, this is the first case of this potential side effect of 5-azacitidine reported so far. Such a metabolic effect has been reported with decitabine , another hypomethylating agent. Several cases of hyperglycemia have been reported in a clinical trial assessing 5-azacitidine . However, the systematic temporal association seen in our case has not been reported to date. Thus, we assumed that 5-azacitidine could reversibly impair glucose regulation mechanisms. The mechanism of such dysregulation has not been fully identified. In our opinion, 5-azacitidine could impair β-cell function in pancreatic islets through an epigenetic mechanism. Dayeh et al. have analyzed the genome-wide DNA methylation pattern in pancreatic islets isolated from patients with T2D as well as non-diabetic patients . The methylome analysis identified 1649 CpG sites with significantly different DNA methylation levels. Decreased methylation was observed in 1596 of these CpG sites and was associated with increased gene expression in T2D patient islets. Overexpression of some hypomethylated genes was associated with a significant decrease in glucose-induced insulin secretion by β-cells . We hypothesized that 5-azacitidine injections induced hypomethylation in pancreatic islets and led to overexpression of such genes.
In the case described here, the temporal association between higher blood glucose levels and the initiation of 5-azacitidine, with an improvement after each cycle is consistent with a causative role of this drug. We assumed that the epigenetic pathway could be the link between 5-azacitidine and the glycemic dysregulation. This observation could encourage physicians to carefully monitor blood glucose levels in patients under hypomethylating agents with a history of diabetes.
AP and EG wrote the manuscript. NF, MD, KA, ME, and SR contributed to patient care and recovered information. AJB helped on pharmacology. AP, OH, PC, and EG revised the manuscript. All authors read and approved the manuscript.
Consent for publication
The written informed consent we have in the patient’s file has already been approved by a central review Board. Written informed consent was obtained from the patient’s next-of-kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Emmanuel Gyan has received research funding and travel grants from Celgene, Corp. All other authors declare that they have no competing interests.
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