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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

Palmitate induces injury to isolated mouse islets. Following incubation with 0.5 mmol/l palmitate for the indicated periods of time (24, 48 and 72 h), islet (A) viability and (B) apoptosis were analyzed by examining histone-associated DNA fragments and by MTT assay, respectively. Following incubation with 0.5 mmol/l palmitate for 48 h, (C) the insulin mRNA and (D) pancreatic duodenal homeobox 1 (PDX1) mRNA and protein levels were determined by qPCR and immunoblot analysis, respectively. The relative transcript levels were normalized to those of 36B4. n=3 separate islet preparations; *p<0.05; **p<0.01.
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f1-ijmm-36-01-0173: Palmitate induces injury to isolated mouse islets. Following incubation with 0.5 mmol/l palmitate for the indicated periods of time (24, 48 and 72 h), islet (A) viability and (B) apoptosis were analyzed by examining histone-associated DNA fragments and by MTT assay, respectively. Following incubation with 0.5 mmol/l palmitate for 48 h, (C) the insulin mRNA and (D) pancreatic duodenal homeobox 1 (PDX1) mRNA and protein levels were determined by qPCR and immunoblot analysis, respectively. The relative transcript levels were normalized to those of 36B4. n=3 separate islet preparations; *p<0.05; **p<0.01.

Mentions: Following the incubation of the isolated mouse islets for 24, 48 or 72 h, treatment with 0.5 mmol/l palmitate for24, 48 and 72 h led to a significant decrease in islet viability and an increase in cell death in a time-dependent manner (Fig. 1A and B). Since the exposure of the cultured islets for 72 h was severely damaging, we focused on the effects of palmitate on β cell-specific transcription factors after 48 h of treatment. Incubation with palmitate for 48 h did not significantly modify the mRNA expression of insulin (Fig. 1C). Nonetheless, both PDX1 mRNA and protein (Fig. 1D) levels decreased after 48 h of exposure to palmitate. Thus, prolonged exposure to palmitate induces injury to isolated islets.


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)

Palmitate induces injury to isolated mouse islets. Following incubation with 0.5 mmol/l palmitate for the indicated periods of time (24, 48 and 72 h), islet (A) viability and (B) apoptosis were analyzed by examining histone-associated DNA fragments and by MTT assay, respectively. Following incubation with 0.5 mmol/l palmitate for 48 h, (C) the insulin mRNA and (D) pancreatic duodenal homeobox 1 (PDX1) mRNA and protein levels were determined by qPCR and immunoblot analysis, respectively. The relative transcript levels were normalized to those of 36B4. n=3 separate islet preparations; *p<0.05; **p<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-ijmm-36-01-0173: Palmitate induces injury to isolated mouse islets. Following incubation with 0.5 mmol/l palmitate for the indicated periods of time (24, 48 and 72 h), islet (A) viability and (B) apoptosis were analyzed by examining histone-associated DNA fragments and by MTT assay, respectively. Following incubation with 0.5 mmol/l palmitate for 48 h, (C) the insulin mRNA and (D) pancreatic duodenal homeobox 1 (PDX1) mRNA and protein levels were determined by qPCR and immunoblot analysis, respectively. The relative transcript levels were normalized to those of 36B4. n=3 separate islet preparations; *p<0.05; **p<0.01.
Mentions: Following the incubation of the isolated mouse islets for 24, 48 or 72 h, treatment with 0.5 mmol/l palmitate for24, 48 and 72 h led to a significant decrease in islet viability and an increase in cell death in a time-dependent manner (Fig. 1A and B). Since the exposure of the cultured islets for 72 h was severely damaging, we focused on the effects of palmitate on β cell-specific transcription factors after 48 h of treatment. Incubation with palmitate for 48 h did not significantly modify the mRNA expression of insulin (Fig. 1C). Nonetheless, both PDX1 mRNA and protein (Fig. 1D) levels decreased after 48 h of exposure to palmitate. Thus, prolonged exposure to palmitate induces injury to isolated islets.

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