Liraglutide protects against glucolipotoxicity-induced RIN-m5F β-cell apoptosis through restoration of PDX1 expression.

Edy Kornelius,Stanley Liu,Yan‐Zin Chang,Chih‐Li Lin,Chien‐Ning Huang,Wei‐Jen Chen,Yi‐Sun Yang,Yi‐Chiao Bai,Chiung‐Huei Peng,Hsin‐Hua Li

doi:10.1111/jcmm.13967

Abstract

Prolonged exposure to high levels of glucose and fatty acid (FFA) can induce tissue damage commonly referred to as glucolipotoxicity and is particularly harmful to pancreatic β‐cells. Glucolipotoxicity‐mediated β‐cell failure is a critical causal factor in the late stages of diabetes, which suggests that mechanisms that prevent or reverse β‐cell death may play a critical role in the treatment of the disease. Transcription factor PDX1 was recently reported to play a key role in maintaining β‐cell function and survival, and glucolipotoxicity can activate mammalian sterile 20‐like kinase 1 (Mst1), which, in turn, stimulates PDX1 degradation and causes dysfunction and apoptosis of β‐cells. Interestingly, previous research has demonstrated that increased glucagon‐like peptide‐1 (GLP‐1) signalling effectively protects β cells from glucolipotoxicity‐induced apoptosis. Unfortunately, few studies have examined the related mechanism in detail, especially the role in Mst1 and PDX1 regulation. In the present study, we investigate the toxic effect of high glucose and FFA levels on rat pancreatic RINm5F β‐cells and demonstrate that the GLP‐1 analogue liraglutide restores the expression of PDX1 by inactivating Mst1, thus ameliorating β‐cell impairments. In addition, liraglutide also upregulates mitophagy, which may help restore mitochondrial function and protect β‐cells from oxidative stress damage. Our study suggests that liraglutide may serve as a potential agent for developing new therapies to reduce glucolipotoxicity.

Highlights

Metabolic syndrome is a collection of symptoms that can cause disruption of the metabolism of carbohydrates, fats and proteins
Given that glucagon‐like peptide‐1 (GLP‐1) is commonly used in the treatment of diabetic hyperglycaemia, we investigated whether liraglutide, a GLP‐1 analogue approved and widely used in the treatment of type 2 diabetes (T2D), protects against high glucose and high free fatty acids (FFA)‐induced glucolipotoxicity in RINm5f β‐cells
ER stress‐induced apoptosis plays a key role in pancreatic duodenal homeobox 1 (PDX1)‐deficient β‐cell during glucolipotoxicity.20,21To determine whether liraglutide protects cells from ER stress‐induced cell death events, we measured two ER stress downstream typical markers, including PKR‐like endoplasmic reticulum kinase (PERK) and eukaryotic translation initiation factor 2α, which activates a signalling network called the unfolded protein response to trigger C/EBP homologous protein‐ mediated apoptosis.[22]

Summary

| INTRODUCTION

Metabolic syndrome is a collection of symptoms that can cause disruption of the metabolism of carbohydrates, fats and proteins. Prolonged exposure of β‐cells to high glucose and FFA levels has been demonstrated to stimulate PDX1 nuclear exclusion and degradation, resulting in decreased insulin gene transcription and cell survival.[13]. Ardestani et al showed that mammalian sterile 20‐like kinase 1 (Mst1) can stimulate ubiquitin‐proteasome degradation of PDX1 and prohibit its function as a transcription factor in the nucleus.[17]. This result indicates that regulation of Mst[1] and PDX1 may be involved in liraglutide‐mediated β‐cell protection. Our results demonstrate that liraglutide restores the expression of PDX1 by inactivating Mst[1], thereby ameliorating the impairments to RINm5F cells due to glucolipotoxicity. Our findings suggest that activation of GLP‐1 signalling by liraglutide may serve as an agent for the development of new therapeutic strategies against metabolic syndrome and T2D

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION