Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation

Chang, Tien-Jyun; Tseng, Hsing-Chi; Liu, Meng-Wei; Chang, Yi‐Cheng; Hsieh, Meng-Lun; Chuang, Lee‐Ming

doi:10.1038/srep23403

Cited by 26 publications

(29 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous studies have suggested that activation of GLP‐1 signalling can protect and improve pancreatic β‐cell function against glucotoxicity and lipotoxicity . Given that 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 T2D, protects against high glucose and high FFA‐induced glucolipotoxicity in RINm5f β‐cells.…”

Section: Resultsmentioning

confidence: 99%

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

Kornelius

Peng

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

Kornelius

Peng

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…MGO can induce the activation of AMPK [33], a known inducer of autophagy [34]. Therefore, we measured AMPK phosphorylation as a possible mechanism underlying the observed effects of MGO on Trx1 and Glo2.…”

Section: Resultsmentioning

confidence: 99%

Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells

Dafre

Schmitz

Maher

2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

Methylglyoxal (MGO) is a major glycating agent that reacts with basic residues of proteins and promotes the formation of advanced glycation end products which are believed to play key roles in a number of pathologies, such as diabetes, Alzheimer’s disease, and inflammation. We previously showed that MGO treatment targets the thioredoxin and the glyoxalase systems, leading to a decrease in Trx1 and Glo2 proteins in immortalized mouse hippocampal HT22 nerve cells. Here, we propose that autophagy is the underlying mechanism leading to Glo2 and Trx1 loss induced by MGO. The autophagic markers p62, and the lipidated and active form of LC3, were increased by MGO (0.5 mM). Autophagy inhibition with bafilomycin or chloroquine prevented the decrease in Trx1 and Glo2 at 6 and 18 h after MGO treatment. Proteasome inhibition by MG132 exacerbated the effect of MGO on Trx1 and Glo2 degradation (18 h), further suggesting a role for autophagy. ATG5 small interfering RNA protected Trx1 and Glo2 from MGO-induced degradation, confirming Trx1 and Glo2 loss is mediated by autophagy. In the search for the signals that control autophagy, we found that AMPK activation, a known autophagy inducer, was markedly increased by MGO treatment. AMPK activation was confirmed by increased acetyl coenzyme A carboxylase phosphorylation, a direct AMPK substrate and by decreased mTOR phosphorylation, an indirect marker of AMPK activation. To confirm that MGO-mediated Trx1 and Glo2 degradation was AMPK-dependent, AMPK-deficient mouse embryonic fibroblasts (MEFs) were treated with MGO. Wildtype MEFs presented the expected decrease in Trx1 and Glo2, while MGO was ineffective in decreasing these proteins in AMPK-deficient cells. Overall, the data indicate that MGO activates autophagy in an AMPK-dependent manner, and that autophagy was responsible for Trx1 and Glo2 degradation, confirming that Trx1 and Glo2 are molecular targets of MGO.

show abstract

“…To increase protein glycation, cells were treated with 0.5 mM of MGO, a working concentration widely used in various studies303132. We found that this treatment increased protein glycation without increasing overall cytotoxicity (submitted manuscript).…”

Section: Resultsmentioning

confidence: 91%

Glycation potentiates neurodegeneration in models of Huntington’s disease

Miranda

Gomes

Branco-Santos

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. By modifying amino-groups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington’s disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models. We found that glycation impairs HTT clearance thereby promoting its intracellular accumulation and aggregation. Interestingly, under these conditions autophagy increased and the levels of mutant HTT released to the culture medium decreased. Furthermore, increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity, and suggests it may constitute a novel target for therapeutic intervention in HD.

show abstract

Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation

Cited by 26 publications

References 50 publications

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

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

Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells

Glycation potentiates neurodegeneration in models of Huntington’s disease

Contact Info

Product

Resources

About