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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

Liraglutide normalizes the islet architecture of mice fed a high-fat diet (HFD). (A) Representative images of staining for insulin (green) and glucagon (red). After immunofluorescence, areas labeled for insulin (β-cell) and glucagon (red) were measured, and the results are expressed as the mean (B) islet size, (C) α/β ratio, (D) β cell mass and (E) α cell mass. Analyses were performed on histological sections obtained from mice fed a low-fat diet (LFD) + the placebo (phosphate-buffered saline) (LFD; n=6), a HFD + placebo (phosphate-buffered saline) (HFD; n=7) or a HFD + liraglutide (n=6). *p<0.05; ***p<0.001.
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f6-ijmm-36-01-0173: Liraglutide normalizes the islet architecture of mice fed a high-fat diet (HFD). (A) Representative images of staining for insulin (green) and glucagon (red). After immunofluorescence, areas labeled for insulin (β-cell) and glucagon (red) were measured, and the results are expressed as the mean (B) islet size, (C) α/β ratio, (D) β cell mass and (E) α cell mass. Analyses were performed on histological sections obtained from mice fed a low-fat diet (LFD) + the placebo (phosphate-buffered saline) (LFD; n=6), a HFD + placebo (phosphate-buffered saline) (HFD; n=7) or a HFD + liraglutide (n=6). *p<0.05; ***p<0.001.

Mentions: Unlike the defined α cell mantle and β cell core characteristics of the islets from the mice fed a LFD, the islets from the mice fed a HFD maintained a more scattered organization and a higher percentage of α cells. Furthermore, in the HFD group, there was a greater difference in the expression of insulin (Fig. 6A). As expected, treatment with liraglutide reverted the cell structure to a more normal islet structure (Fig. 6A). Despite the differences in the mean islet areas of the 3 groups (Fig. 6B), the elevated proportions of medium islets (5,000–10,000 µm2) and large islets (>5,000 µm2), as well as the mean area of small islets (<5,000 µm2) that were induced by a HFD were altered by treatment with liraglutide (Table II). In accordance with an elevated α/β cell ratio, the HFD group exhibited a significant increase in α cell mass (Fig. 6C and E). Treatment with liraglutide decreased the β cell mass (Fig. 6D). However, these results do not completely agree with previously published findings (29), possibly due to the different experimental conditions used, the increased β cell proportion and the inhibitory effects of a HFD on insulin expression.


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)

Liraglutide normalizes the islet architecture of mice fed a high-fat diet (HFD). (A) Representative images of staining for insulin (green) and glucagon (red). After immunofluorescence, areas labeled for insulin (β-cell) and glucagon (red) were measured, and the results are expressed as the mean (B) islet size, (C) α/β ratio, (D) β cell mass and (E) α cell mass. Analyses were performed on histological sections obtained from mice fed a low-fat diet (LFD) + the placebo (phosphate-buffered saline) (LFD; n=6), a HFD + placebo (phosphate-buffered saline) (HFD; n=7) or a HFD + liraglutide (n=6). *p<0.05; ***p<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6-ijmm-36-01-0173: Liraglutide normalizes the islet architecture of mice fed a high-fat diet (HFD). (A) Representative images of staining for insulin (green) and glucagon (red). After immunofluorescence, areas labeled for insulin (β-cell) and glucagon (red) were measured, and the results are expressed as the mean (B) islet size, (C) α/β ratio, (D) β cell mass and (E) α cell mass. Analyses were performed on histological sections obtained from mice fed a low-fat diet (LFD) + the placebo (phosphate-buffered saline) (LFD; n=6), a HFD + placebo (phosphate-buffered saline) (HFD; n=7) or a HFD + liraglutide (n=6). *p<0.05; ***p<0.001.
Mentions: Unlike the defined α cell mantle and β cell core characteristics of the islets from the mice fed a LFD, the islets from the mice fed a HFD maintained a more scattered organization and a higher percentage of α cells. Furthermore, in the HFD group, there was a greater difference in the expression of insulin (Fig. 6A). As expected, treatment with liraglutide reverted the cell structure to a more normal islet structure (Fig. 6A). Despite the differences in the mean islet areas of the 3 groups (Fig. 6B), the elevated proportions of medium islets (5,000–10,000 µm2) and large islets (>5,000 µm2), as well as the mean area of small islets (<5,000 µm2) that were induced by a HFD were altered by treatment with liraglutide (Table II). In accordance with an elevated α/β cell ratio, the HFD group exhibited a significant increase in α cell mass (Fig. 6C and E). Treatment with liraglutide decreased the β cell mass (Fig. 6D). However, these results do not completely agree with previously published findings (29), possibly due to the different experimental conditions used, the increased β cell proportion and the inhibitory effects of a HFD on insulin expression.

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