Epigenetic modification and therapeutic targets of diabetes mellitus

Abstract

The prevalence of diabetes and its related complications are increasing significantly globally. Collected evidence suggested that several genetic and environmental factors contribute to diabetes mellitus. Associated complications such as retinopathy, neuropathy, nephropathy and other cardiovascular complications are a direct result of diabetes. Epigenetic factors include deoxyribonucleic acid (DNA) methylation and histone post-translational modifications. These factors are directly related with pathological factors such as oxidative stress, generation of inflammatory mediators and hyperglycemia. These result in altered gene expression and targets cells in the pathology of diabetes mellitus without specific changes in a DNA sequence. Environmental factors and malnutrition are equally responsible for epigenetic states. Accumulated evidence suggested that environmental stimuli alter the gene expression that result in epigenetic changes in chromatin. Recent studies proposed that epigenetics may include the occurrence of 'metabolic memory' found in animal studies. Further study into epigenetic mechanism might give us new vision into the pathogenesis of diabetes mellitus and related complication thus leading to the discovery of new therapeutic targets. In this review, we discuss the possible epigenetic changes and mechanism that happen in diabetes mellitus type 1 and type 2 separately. We highlight the important epigenetic and non-epigenetic therapeutic targets involved in the management of diabetes and associated complications.

Keywords: Molecular Targets; diabetes mellitus; epigenetics.

Figure 1. The histone methylation protein attached to N-terminal of H3; in unmethylated form it leads to start the transcription

In the presence of DNMT that methylated the H3 of the histone resulted in the de novo methylation of DNA. The link of H3K9 with methylation of histone is carried out in the formation of complex of DNMT and UHRF, which resulted in repression of transcription. Abbreviation: UHRF, ubiquitin-like, containing PHD and RING finger domains, 1.

Figure 2. Factors involved in Type 1 diabetes pathophysiology

Figure 3. Epigenetic modification in IUGR islet

In pancreases, Pdx1 region remains in the unmethylated form, the nucleosome is in the acetylated form at H3K4, which leads to recruitment of USF-1 transcription factor, resulted in Pdx1 expression and generation of β cell. In IUGR fetal and IUGR 2-week islets, the association of mSin3a-HDAC-DNAMT1 to the histone leads to dimethylation of H3K9, which leads to Pdx1 repression and this complex also leads to inactivation of chromatin with dimethylated of H3K9 which resulted in pdx1 transcription silencing and decease in β-cell generation. In IUGR adult muscle, histone acetylation was lost, due to the recruitment of HDAC1 and HDAC4, but methylation occurs on CpG island. But CpG island directly related with complex of repressor DNAMT3A, DNAMT3B and MeCP2. This makes the recruitment of suv39H1 which leads to methylation of H3K9 and its enhanced the recruitment of HP1α, that inactive the GLUT4 expression. Abbreviations: DNAMT3A/B, DNA methyltransferase 3 α/β; GLUT4, glucose transporter type 4; suv39H1, suppressor of variegation 3-9 homolog 1.

Figure 4. Insulin binds with the insulin receptor, leads to phosphorylation of the receptor, which activates the PI3K/AKT pathways

Same time, the acetylation of histone protein, leads to attachment of myoD and Mef2a which emphasizes the release of the GLUT4. GLUT4 transfers the glucose from the outside cell to inside of the cell. Under the influence of HDACs (HDAC2 and 4) and DNAMT3A/3B, the histone deacetylation and hypermethylation of histone protein occurred. Which resulted in decrease or inhibition the expression of GLUT4. HDAC and DNAMT3A/3B inhibitor blocked these enzymes and helped in reversal the mechanism into normal conditions. Abbreviation: DNAMT3A/3B, DNA methyltransferase 3 α/β.

Figure 5. In adipocytes/macrophages, SIRT1 deacetylation leads to a decrease in the expression of several inflammatory mediators such as MCP-1 and TNF-α

SIRT1 inactivation leads to NF-kB phosphorylation related to activation of mammalian target of rapamycin (mTOR) and decrease in expression of AMP-activated kinase (AMPK). In adipocytes, SIRT1 deacetylates the nuclear factor NF-kB p65, leads to a decrease in the expression of TNF-α and MCP-1. In skeletal muscle, SIRT1 induces the expression of peroxisome proliferator-activated receptor (PPAR-) co-activator 1α. Under diabetes condition mitochondrial oxidative capacity reduced which leads to the generation of free radical oxygen species, free fatty acids and TNFα reduced the insulin signaling via insulin receptor substrate phosphorylation. SIRT1 also activate phosphoinositide 3-kinase (PI3K). SIRT1 activates the PGC-1α induces the mitochondrial biogenesis which reduced the generation of ROS, increase the generation of GLUT4. SIRT1 deacetylates the forkhead box protein O1 (FOXO1) and increased the recruitment with CAAT/enhancer-binding protein (C/EBPα) which increase the generation of adiponectin1 in adipocytes. Adiponectin also activates the calcium/calmodulin-dependent protein kinase kinase (CaMKK) and calcium/calmodulin-dependent protein kinase kinase (CaMK). Adiponectin activates the SIRT1 via AMPK pathway activation. Its leads to deacetylation of PGC-1α resulted in mitochondrial biogenesis.

Figure 6. DPP4 degrades the GLP1 and incretion, which leads to suppression of the insulin secretion

DPP-4 inhibitor inhibits the DDP4 enzyme, which resulted in increase the level of GLP1 level and increases the insulin secretion.

Figure 7. Insulin sensitivity mechanism of PPARγ ligands, PPARγ mainly expressed in adipose tissue

Ligands binding to the receptor led to a specific change in the expression of a gene. Inhibition in the expression of an adipose-related gene such as, fatty acid transporter that inhibited the production of free fatty acids which resulted in an increase in the insulin sensitivity. The change in expression of genes such as CAP or 11βhSD1 helped to increase the insulin action in adipose tissue and decrease adipose visceral fat. Other factors TNF-α, resistin, and Acrp30 were also involved indirectly in insulin sensitivity in adipose tissue. Abbreviations: 11β-hydroxysteroid dehydrogenase type 1; Acrp30, adipocyte compliment protein 30; CAP, catabolite activator protein.

Figure 8. Glucose re-absorption by glucose transporter in a normal individual and diabetic person

SGLT2 is major co-transporter for the glucose re-absorption present at apically in epithelial cells of PCT. It reabsorbs ∼90% of glucose from outside to the blood and ∼10% glucose is reabsorbed by SGLT1. For re-absorption of glucose, these two co-transporters need ATP for active transportation of sodium-potassium. This exchange resulted in re-absorption of glucose via GLUT. The inhibition of these co-transporter leads to inhibit the re-absorption of glucose into blood which resulted in excretion of glucose by urine.