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Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets.

Huang C, Yuan L, Cao S - Int. J. Mol. Med. (2015)

Bottom Line: Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels.Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression.Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.

ABSTRACT
The number of pro-α cells is known to increase in response to β cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin‑(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.

No MeSH data available.


Related in: MedlinePlus

Glucagon-like peptide-1 receptor (GLP-1R) inhibition exacerbates the detrimental effects of palmitate. Isolated islets were pre-treated with the GLP-1R antagonist, exendin-(9-39), (0.5 µmol/l) for 2 h, followed by exposure to 0.5 mmol/l palmitate for 48 h. Islet (A) viability (detected by MTT assay) and (B) apoptosis (determined by examining histone-associated DNA fragments), and pancreatic duodenal homeobox 1 (PDX1) (C) mRNA (detected by qPCR) and (D) protein levels (detected by immunoblot analysis). n=3 separate islet preparations; *p<0.05; **p<0.01; ***p<0.001.
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f4-ijmm-36-01-0173: Glucagon-like peptide-1 receptor (GLP-1R) inhibition exacerbates the detrimental effects of palmitate. Isolated islets were pre-treated with the GLP-1R antagonist, exendin-(9-39), (0.5 µmol/l) for 2 h, followed by exposure to 0.5 mmol/l palmitate for 48 h. Islet (A) viability (detected by MTT assay) and (B) apoptosis (determined by examining histone-associated DNA fragments), and pancreatic duodenal homeobox 1 (PDX1) (C) mRNA (detected by qPCR) and (D) protein levels (detected by immunoblot analysis). n=3 separate islet preparations; *p<0.05; **p<0.01; ***p<0.001.

Mentions: Treatment with exendin-(9-39) alone, another GLP-1-derived peptide and a GLP-1R antagonist, did not exert any effects on the isolated islets. When combined with exposure to palmitate for 48 h, treatment with exendin-(9-39) resulted in the progressive loss of islet cells that exhibited decreased viability (Fig. 4A) and higher apoptotic levels (Fig. 4B). Furthermore, treatment with exendin-(9-39) exacerbated the detrimental effects of palmitate on β cell survival by decreasing PDX1 mRNA (Fig. 4C) (p=0.68) and protein expression (Fig. 4D). These results suggest that the activation of the intra-islet GLP-1 system ameliorates the detrimental effects of palmitate.


Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets.

Huang C, Yuan L, Cao S - Int. J. Mol. Med. (2015)

Glucagon-like peptide-1 receptor (GLP-1R) inhibition exacerbates the detrimental effects of palmitate. Isolated islets were pre-treated with the GLP-1R antagonist, exendin-(9-39), (0.5 µmol/l) for 2 h, followed by exposure to 0.5 mmol/l palmitate for 48 h. Islet (A) viability (detected by MTT assay) and (B) apoptosis (determined by examining histone-associated DNA fragments), and pancreatic duodenal homeobox 1 (PDX1) (C) mRNA (detected by qPCR) and (D) protein levels (detected by immunoblot analysis). n=3 separate islet preparations; *p<0.05; **p<0.01; ***p<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494597&req=5

f4-ijmm-36-01-0173: Glucagon-like peptide-1 receptor (GLP-1R) inhibition exacerbates the detrimental effects of palmitate. Isolated islets were pre-treated with the GLP-1R antagonist, exendin-(9-39), (0.5 µmol/l) for 2 h, followed by exposure to 0.5 mmol/l palmitate for 48 h. Islet (A) viability (detected by MTT assay) and (B) apoptosis (determined by examining histone-associated DNA fragments), and pancreatic duodenal homeobox 1 (PDX1) (C) mRNA (detected by qPCR) and (D) protein levels (detected by immunoblot analysis). n=3 separate islet preparations; *p<0.05; **p<0.01; ***p<0.001.
Mentions: Treatment with exendin-(9-39) alone, another GLP-1-derived peptide and a GLP-1R antagonist, did not exert any effects on the isolated islets. When combined with exposure to palmitate for 48 h, treatment with exendin-(9-39) resulted in the progressive loss of islet cells that exhibited decreased viability (Fig. 4A) and higher apoptotic levels (Fig. 4B). Furthermore, treatment with exendin-(9-39) exacerbated the detrimental effects of palmitate on β cell survival by decreasing PDX1 mRNA (Fig. 4C) (p=0.68) and protein expression (Fig. 4D). These results suggest that the activation of the intra-islet GLP-1 system ameliorates the detrimental effects of palmitate.

Bottom Line: Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels.Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression.Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.

ABSTRACT
The number of pro-α cells is known to increase in response to β cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin‑(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.

No MeSH data available.


Related in: MedlinePlus