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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

The glucagon-like peptide-1 receptor (GLP-1R) signaling agonist, liraglutide, attenuates lipotoxicity-induced islet dysfunction. Isolated non-diabetic islets were pre-treated with 100 nmol/l liraglutide and/or 0.5 µmol/l exendin-(9-39) 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 (C) pancreatic duodenal homeobox 1 (PDX1) mRNA levels (detected by qPCR). n=3 separate islet preparations. (D) After 8 weeks on their respective diets, the mRNA expression of PDX1, glucose transporter 2 (GLUT2) and Nkx6.1 was detected in the pancreata of the mice. (E) The plasma insulin levels were detected by insulin enzyme-linked immunosorbent assay (ELISA). n=6–7 mice/group; *p<0.05; **p<0.01; ***p<0.001.
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f5-ijmm-36-01-0173: The glucagon-like peptide-1 receptor (GLP-1R) signaling agonist, liraglutide, attenuates lipotoxicity-induced islet dysfunction. Isolated non-diabetic islets were pre-treated with 100 nmol/l liraglutide and/or 0.5 µmol/l exendin-(9-39) 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 (C) pancreatic duodenal homeobox 1 (PDX1) mRNA levels (detected by qPCR). n=3 separate islet preparations. (D) After 8 weeks on their respective diets, the mRNA expression of PDX1, glucose transporter 2 (GLUT2) and Nkx6.1 was detected in the pancreata of the mice. (E) The plasma insulin levels were detected by insulin enzyme-linked immunosorbent assay (ELISA). n=6–7 mice/group; *p<0.05; **p<0.01; ***p<0.001.

Mentions: Considering the short biological half-life of exendin-(9-39) [Kieffer et al (28)], we used the stable, long-lived GLP-1 analog, liraglutide, which is an agonist of GLP-1R. Intriguingly, compared to treatment with palmitate alone, treatment with liraglutide significantly increased islet viability (Fig. 5A) and decreased islet cell apoptosis (Fig. 5B) to levels close to those of the controls. Liraglutide also markedly upregulated PDX1 mRNA expression by 7.70-fold, and this increase was attenuated by treatment with palmitate (Fig. 5C). Moreover, the protective effects of liraglutide were completely abrogated by exendin-(9-39) (Fig. 5A–C). We also investigated the effects of liraglutide on islet function in mice fed a HFD. In the HFD group, liraglutide also increased the mRNA expression of the β cell markers, PDX1, Nkx6.1 and glucose transporter 2 (GLUT2) (Fig. 5D). Compared to the mice fed a HFD alone, treatment with liraglutide reduced the plasma insulin concentration (Fig. 5E).


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)

The glucagon-like peptide-1 receptor (GLP-1R) signaling agonist, liraglutide, attenuates lipotoxicity-induced islet dysfunction. Isolated non-diabetic islets were pre-treated with 100 nmol/l liraglutide and/or 0.5 µmol/l exendin-(9-39) 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 (C) pancreatic duodenal homeobox 1 (PDX1) mRNA levels (detected by qPCR). n=3 separate islet preparations. (D) After 8 weeks on their respective diets, the mRNA expression of PDX1, glucose transporter 2 (GLUT2) and Nkx6.1 was detected in the pancreata of the mice. (E) The plasma insulin levels were detected by insulin enzyme-linked immunosorbent assay (ELISA). n=6–7 mice/group; *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

f5-ijmm-36-01-0173: The glucagon-like peptide-1 receptor (GLP-1R) signaling agonist, liraglutide, attenuates lipotoxicity-induced islet dysfunction. Isolated non-diabetic islets were pre-treated with 100 nmol/l liraglutide and/or 0.5 µmol/l exendin-(9-39) 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 (C) pancreatic duodenal homeobox 1 (PDX1) mRNA levels (detected by qPCR). n=3 separate islet preparations. (D) After 8 weeks on their respective diets, the mRNA expression of PDX1, glucose transporter 2 (GLUT2) and Nkx6.1 was detected in the pancreata of the mice. (E) The plasma insulin levels were detected by insulin enzyme-linked immunosorbent assay (ELISA). n=6–7 mice/group; *p<0.05; **p<0.01; ***p<0.001.
Mentions: Considering the short biological half-life of exendin-(9-39) [Kieffer et al (28)], we used the stable, long-lived GLP-1 analog, liraglutide, which is an agonist of GLP-1R. Intriguingly, compared to treatment with palmitate alone, treatment with liraglutide significantly increased islet viability (Fig. 5A) and decreased islet cell apoptosis (Fig. 5B) to levels close to those of the controls. Liraglutide also markedly upregulated PDX1 mRNA expression by 7.70-fold, and this increase was attenuated by treatment with palmitate (Fig. 5C). Moreover, the protective effects of liraglutide were completely abrogated by exendin-(9-39) (Fig. 5A–C). We also investigated the effects of liraglutide on islet function in mice fed a HFD. In the HFD group, liraglutide also increased the mRNA expression of the β cell markers, PDX1, Nkx6.1 and glucose transporter 2 (GLUT2) (Fig. 5D). Compared to the mice fed a HFD alone, treatment with liraglutide reduced the plasma insulin concentration (Fig. 5E).

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