Several studies suggest that genes and environmental interactions through epigenetic modifications influence a person’s susceptibility to diabetes because environmental factors can stimulate intracellular signaling pathways, leading to alterations in gene expression through epigenetic modifications, such as DNA methylation, which integrates genetic susceptibility and environmental factors by adjusting transcriptional regulation with no change in the sequence of underlying DNA [3].
CpG methylation can prevent adjacent gene expression partially or completely. Accordingly, the genes containing the 5′-CpG region transcription rate are frequently inversely proportional to their methylation rates [9].
It has been demonstrated that DNA methylation is affected by age, weight, sex, lifestyle, and genetic background [10]. In the present study, age- and sex-matched T2D and nondiabetic subjects were selected to avoid the effect of age and sex.
This paper introduces an epigenetic study of the IGFBP1 gene that was conducted on an Egyptian cohort. The results indicated an increase in IGFBP1 DNA methylation levels in patients with T2D compared to nondiabetic controls.
A previous study has shown that the region of high CpG density at the 5′-UTR recruits a methyl-CpG binding protein to the promoter region [11].
Some researchers found that fasting IGFBP-1 is a good predictor of abnormal glucose homeostasis, with low values anticipating impaired fasting glucose development, impaired glucose tolerance and T2D in 8–17 years [12].
Type 1 diabetes is associated with a decline in IGFBP-1 DNA methylation levels; this implies the possibility of IGFBP-1 conferring different epigenetic effects in T1D and T2D. Therefore, different IGFBP-1 DNA methylation levels in T1D and T2D may be related to insulin activity [11].
Both types of diabetes are characterized by hyperglycemia; however, the underlying pathogenic mechanism of T1D is different from that of T2D. The development of T1D is due to autoimmune destruction of pancreatic beta cells, leading to insulin deficiency, while T2D hyperglycemia is due to a combination of impaired insulin secretion and insulin resistance. Nevertheless, IGFBP-1 secretion is inhibited by insulin, which means that increased insulin levels in T2D due to insulin resistance are associated with increased methylation of the IGFBP-1 gene [13].
The present work found no significant differences between T2D patients treated with insulin and those treated with OADs, signifying no effect of diabetes treatment on IGFBP1 methylation levels. This might be due to the small numbers of individuals in the subgroups, which goes hand by hand with Gu and his colleagues (2013) [11].
Although nonsignificant, stratification of the subjects according to BMI revealed that type 2 diabetes patients with a BMI >30 kg/m2 had higher DNA methylation levels than those with a BMI <30 kg/m2. The difference in the IGFBP1 DNA methylation levels for the obese group may explain how obesity could contribute to T2D development. The countless metabolic changes taking place during T2D pathogenesis support the presence of a role for epigenetics in chronic disease development. A new data mining methodology was used to search for a possible association between epigenetics and the pathogenesis of T2D [14]. This methodology was based on a search of Medline records where they discovered the presence of methylation and chromatin among the top-five ranked items associated with T2D, based on common shared relationships. The shared relationships were obesity, maternal influence, fatty acids, methylene tetrahydrofolate reductase, cytokines, homocysteine, variable severity, and late-onset of the disease. Based on these findings, a model for T2D pathogenesis was introduced, suggesting that an increase in short-chain fatty acid production as by-products of long-chain fatty acids leads to modifications in DNA methylation that result in dysregulation of pro-inflammatory cytokines [14].
Both genetic and environmental factors have a role in type 2 diabetes development. Another important risk factor for T2D is obesity, which mainly contributes to the rapid increase in T2D patients worldwide [15].
In addition, IGFBP1 DNA methylation levels were discovered to be influenced by family history (FH), which is in agreement with previous work [11] that found that patients with FHD had higher IGFBP1 DNA methylation than those without family history.
The limitations of the present study include the small number of included subjects, and the performance of DNA methylation analyses using whole blood; we did not evaluate the cell-specific pattern for the gene region beforehand.