Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia which is caused by insufficient insulin secretion or insulin resistance. Interaction of genetic, epigenetic and environmental factors plays a significant role in the development of T2DM. Several environmental factors including diet and lifestyle, as well as age have been associated with an increased risk for T2DM. It has been demonstrated that these environmental factors may affect global epigenetic status, and alter the expression of susceptible genes, thereby contributing to the pathogenesis of T2DM. In recent years, a growing body of molecular and genetic studies in diabetes have been focused on the ways to restore the numbers or function of β-cells in order to reverse a range of metabolic consequences of insulin deficiency. The pancreatic duodenal homeobox 1 (PDX-1) is a transcriptional factor that is essential for the development and function of islet cells. A number of studies have shown that there is a significant increase in the level of DNA methylation of PDX-1 resulting in reduced activity in T2DM islets. The decrease in PDX-1 activity may be a critical mediator causing dysregulation of pancreatic β cells in T2DM. This article reviews the epigenetic mechanisms of PDX-1 involved in T2DM, focusing on diabetes and DNA methylation, and discusses some potential strategies for the application of PDX-1 in the treatment of diabetes.

Regulation of Pdx1 by oxidative stress and Nrf2 in pancreatic beta-cells

“…This is associated with reduced PDX1 mRNA levels. The same phenomenon is observed in rat insulinoma beta-like cells (INS 832/13) incubated chronically at high glucose concentrations ( 19 , 79 ). Additionally, treatment of human stem cells with the DNA methylation inhibitor, 5-aza-2′-deoxycytidine, increases PDX1 nuclear levels ( 19 , 96 ).…”

“…The same phenomenon is observed in rat insulinoma beta-like cells (INS 832/13) incubated chronically at high glucose concentrations ( 19 , 79 ). Additionally, treatment of human stem cells with the DNA methylation inhibitor, 5-aza-2′-deoxycytidine, increases PDX1 nuclear levels ( 19 , 96 ). Human and mouse pancreatic islets express hundreds of long non-coding RNAs (lncRNAs), some of which are playing important roles in beta-cell differentiation and function.…”

“…To do so, PDX1 controls the expression of other genes that play important roles in the beta-cell fate. These genes include insulin ( Ins1 , Ins2 ), neurogenin 3 ( Ngn3 ), SRY-box transcription factor 9 ( Sox9 ), hepatocyte nuclear factor 6 and 1b ( Hnf6, Hnf1b ), forkhead box protein a2 ( Foxa2 ), V-Maf musculoaponeurotic fibrosarcoma oncogene homolog A ( MafA ), NK2 homeobox 2 ( Nkx2.2 ), neurogenic differentiation ( NeuroD ), solute carrier family 2 member 2 (Glut2, Slc2a2 ), glucokinase ( Gck ), islet amyloid polypeptide ( Iapp ), NK6 homeobox 1 ( Nkx6.1 ), cyclin D1 ( Ccnd1 ), cyclin D2 ( Ccnd2 ), and the transient receptor potential cation channel family 3 and 6 ( Trpc3,6 ) ( 13 , 16 , 17 , 19 ). In agreement with these findings, homozygous Pdx1 knockout (Pdx1 -/- ) mice exhibit pancreatic agenesis while heterozygous Pdx1 knockout (Pdx1 +/- ) mice present with beta-cell ER stress, beta-cell apoptosis, impaired insulin secretion, decreased beta-cell proliferation and reduced beta-cell mass ( 20 – 25 ).…”

The effect of fermented tempeh aerobic anaerobic (FETAA) on pancreatic duodenal homeobox 1 (Pdx1) gene expression and HOMA-beta index in diabetic mice

“…Pdx1 was an important transcription factor that plays role in the development and function of the β-cell pancreas [16]. In order to know the effect of FETAA on Pdx1 mRNA expression, we carried out a Real-Time PCR analysis.…”

Phytochemicals as Potential Epidrugs in Type 2 Diabetes Mellitus

“…Human T2DM case-control studies and intervention studies in non-diabetic people showed epigenetic alterations of PDX1, CDKN1A (cyclin-dependent kinase inhibitor 1; involved in cell cycle regulation) and GLRA1 (glycine receptor alpha 1; down-regulation of neuronal excitability) genes which seem to contribute to diabetes (6). An increase in the level of DNA methylation of PDX-1 has been related to a reduced activity in pancreatic islets and a dysregulation of pancreatic b-cells in T2DM (8). CDKN1A overexpression decreases insulin secretion and proliferation (9) and GLRA1 silencing in clonal b-cells reduced glucosestimulated insulin secretion (10).…”