Effects of O-GlcNAc Transferase and Autophagy on Beta-Cell Mass and Function

Abstract

Type II diabetes is one of the most researched metabolic diseases due to its increasing prevalence in society. It is characterized by insulin resistance and β-cell failure. Studies suggest levels of proteins such as O-GlcNAc Transferase (OGT) and proteins related to autophagy

impact insulin resistance. OGT is a post-translational protein modification enzyme that adds O- GlcNAc to proteins to regulate cellular mechanisms and ensure homeostasis. Mice with a

decrease in β-cell OGT expression demonstrated impaired insulin secretion and a loss of β-cell mass. Autophagy is a cellular process that breaks down dysfunctional cellular matter. It has been implicated in playing a protective role to prevent insulin resistance by reducing oxidative stress however it has also been proposed that an excess in autophagy leads to cell death. This study aimed to provide a deeper understanding into the relationship between OGT and autophagy within β-cells by using both an in vivo model and an in vitro model. βOGT-/+ mice were compared to βOGT-/+; ULK-/+ mice with regards to glucose tolerance, plasma insulin levels, and β-cell mass. Min6 and Ins1 cell lines were treated with STO and PUGNAc to observe the effects of inhibiting OGT and OGA respectively. The results from these experiments suggested that a reduction in autophagy in addition to decreased β-cell OGT expression encouraged a trend towards better glucose control and increased insulin secretion but these changes were not the result of a change in β-cell mass. Also, an increase in O-GlcNAcylation correlated with an increase in expression of Beclin-1, an autophagy promoting protein, however, these findings are not conclusive due to the lack of experimental replicates.