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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) signaling exerts inhibitory effects on the generation of reactive oxygen species (ROS). (A and B) Following pre-incubation 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, ROS levels were detected byDCFH-DA, and (C) the mRNA expression of NAD(P)H oxidase components [including NADPH oxidase 4 (NOX4), p22phox and gp91phox], and (D) antioxidant genes [superoxide dismutase 2 (SOD2) and glutathione peroxidase-1 (GPx-1)] was detected by qPCR. n=3 separate isolated islet preparations; *p<0.05; **p<0.01; ***p<0.001.
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f8-ijmm-36-01-0173: Glucagon-like peptide-1 receptor (GLP-1R) signaling exerts inhibitory effects on the generation of reactive oxygen species (ROS). (A and B) Following pre-incubation 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, ROS levels were detected byDCFH-DA, and (C) the mRNA expression of NAD(P)H oxidase components [including NADPH oxidase 4 (NOX4), p22phox and gp91phox], and (D) antioxidant genes [superoxide dismutase 2 (SOD2) and glutathione peroxidase-1 (GPx-1)] was detected by qPCR. n=3 separate isolated islet preparations; *p<0.05; **p<0.01; ***p<0.001.

Mentions: Given the intermediary role of oxidative stress in palmitate-induced injury, we hypothesized that GLP-1R signaling may re-shape the oxidative balance by suppressing the generation of ROS and enhancing antioxidant defenses. The inhibition of GLP-1R signaling by exendin-(9-39) (in combination with palmitate) also slightly increased the production of ROS (p=0.045; Fig. 8A). Furthermore, the activation of GLP-1R by liraglutide decreased the ROS levels in the isolated islets (p=0.038; Fig. 8B). Notably, these changes were directly confirmed by qPCR, which revealed a clear and widespread reshaping of the oxidative balance. Treatment with liraglutide attenuated the palmitate-induced activation of NAD(P)H oxidase components, including NADPH oxidase 4 (NOX4), p22phox and gp91phox (Fig. 8C). Simultaneously, treatment with liraglutide upregulated the expression of mitochondrial-specific superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx-1) (Fig. 8D).


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) signaling exerts inhibitory effects on the generation of reactive oxygen species (ROS). (A and B) Following pre-incubation 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, ROS levels were detected byDCFH-DA, and (C) the mRNA expression of NAD(P)H oxidase components [including NADPH oxidase 4 (NOX4), p22phox and gp91phox], and (D) antioxidant genes [superoxide dismutase 2 (SOD2) and glutathione peroxidase-1 (GPx-1)] was detected by qPCR. n=3 separate isolated 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

f8-ijmm-36-01-0173: Glucagon-like peptide-1 receptor (GLP-1R) signaling exerts inhibitory effects on the generation of reactive oxygen species (ROS). (A and B) Following pre-incubation 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, ROS levels were detected byDCFH-DA, and (C) the mRNA expression of NAD(P)H oxidase components [including NADPH oxidase 4 (NOX4), p22phox and gp91phox], and (D) antioxidant genes [superoxide dismutase 2 (SOD2) and glutathione peroxidase-1 (GPx-1)] was detected by qPCR. n=3 separate isolated islet preparations; *p<0.05; **p<0.01; ***p<0.001.
Mentions: Given the intermediary role of oxidative stress in palmitate-induced injury, we hypothesized that GLP-1R signaling may re-shape the oxidative balance by suppressing the generation of ROS and enhancing antioxidant defenses. The inhibition of GLP-1R signaling by exendin-(9-39) (in combination with palmitate) also slightly increased the production of ROS (p=0.045; Fig. 8A). Furthermore, the activation of GLP-1R by liraglutide decreased the ROS levels in the isolated islets (p=0.038; Fig. 8B). Notably, these changes were directly confirmed by qPCR, which revealed a clear and widespread reshaping of the oxidative balance. Treatment with liraglutide attenuated the palmitate-induced activation of NAD(P)H oxidase components, including NADPH oxidase 4 (NOX4), p22phox and gp91phox (Fig. 8C). Simultaneously, treatment with liraglutide upregulated the expression of mitochondrial-specific superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx-1) (Fig. 8D).

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