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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

High-fat diet (HFD) induces intra-islet glucagon-like peptide-1 (GLP-1) system activation. (A) Representative images of immunofluorescence staining for insulin (green) and prohormone convertase 1/3 (PC1/3) (red) in the pancreatic islets of mice that were fed a low-fat diet (LFD) (n=6) or a HFD (n=7) for 8 weeks. The arrows indicate the insulin-negative and PC1/3-positive cells. (B) PC1/3 mRNA expression in the pancreata of mice from each group was detected by qPCR. (C) Plasma GLP-1 levels in the mice were detected by insulin enzyme-linked immunosorbent assay (ELISA). LFD compared with HFD; **p<0.01; ***p<0.001.
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f3-ijmm-36-01-0173: High-fat diet (HFD) induces intra-islet glucagon-like peptide-1 (GLP-1) system activation. (A) Representative images of immunofluorescence staining for insulin (green) and prohormone convertase 1/3 (PC1/3) (red) in the pancreatic islets of mice that were fed a low-fat diet (LFD) (n=6) or a HFD (n=7) for 8 weeks. The arrows indicate the insulin-negative and PC1/3-positive cells. (B) PC1/3 mRNA expression in the pancreata of mice from each group was detected by qPCR. (C) Plasma GLP-1 levels in the mice were detected by insulin enzyme-linked immunosorbent assay (ELISA). LFD compared with HFD; **p<0.01; ***p<0.001.

Mentions: After 8 weeks of being fed a HFD, PC1/3 protein expression in the HFD group markedly increased (Fig. 3A). Normally, insulin co-localizes with PC1/3 (Fig. 3A), which is known to cleave pro-insulin at the B-chain/C-peptide (26). However, we identified a few PC1/3-positive cells in the extracellular β cell compartments (Fig. 3A). When the PC1/3-positive and insulin-negative α cells were quantified, an increased number of these cells (163 cells) was found in the HFD group (n=7) compared with the LFD group (n=6; 48 cells) in every 20 slices (data not shown). In addition to intestinal L cells, PC1/3, the key enzyme governing GLP-1 formation, is expressed in islet β cells and pro-α cells (27), suggesting that the elevated number of PC1/3-positive and insulin-negative cells may be pro-α cells. Notably, in the HFD group, pancreatic PC1/3 mRNA expression was upregulated (Fig. 3B), and the plasma GLP-1 concentrations were increased compared with the LFD group (Fig. 3C), which was in accordance with the increase in PC1/3 protein expression (Fig. 3A) and may be the result of the activation of the intra-islet GLP-1 system. These results demonstrated that a HFD also induced the formation of pro-α cells and the release of GLP-1 through the upregulation of the expression of PC1/3.


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)

High-fat diet (HFD) induces intra-islet glucagon-like peptide-1 (GLP-1) system activation. (A) Representative images of immunofluorescence staining for insulin (green) and prohormone convertase 1/3 (PC1/3) (red) in the pancreatic islets of mice that were fed a low-fat diet (LFD) (n=6) or a HFD (n=7) for 8 weeks. The arrows indicate the insulin-negative and PC1/3-positive cells. (B) PC1/3 mRNA expression in the pancreata of mice from each group was detected by qPCR. (C) Plasma GLP-1 levels in the mice were detected by insulin enzyme-linked immunosorbent assay (ELISA). LFD compared with HFD; **p<0.01; ***p<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-ijmm-36-01-0173: High-fat diet (HFD) induces intra-islet glucagon-like peptide-1 (GLP-1) system activation. (A) Representative images of immunofluorescence staining for insulin (green) and prohormone convertase 1/3 (PC1/3) (red) in the pancreatic islets of mice that were fed a low-fat diet (LFD) (n=6) or a HFD (n=7) for 8 weeks. The arrows indicate the insulin-negative and PC1/3-positive cells. (B) PC1/3 mRNA expression in the pancreata of mice from each group was detected by qPCR. (C) Plasma GLP-1 levels in the mice were detected by insulin enzyme-linked immunosorbent assay (ELISA). LFD compared with HFD; **p<0.01; ***p<0.001.
Mentions: After 8 weeks of being fed a HFD, PC1/3 protein expression in the HFD group markedly increased (Fig. 3A). Normally, insulin co-localizes with PC1/3 (Fig. 3A), which is known to cleave pro-insulin at the B-chain/C-peptide (26). However, we identified a few PC1/3-positive cells in the extracellular β cell compartments (Fig. 3A). When the PC1/3-positive and insulin-negative α cells were quantified, an increased number of these cells (163 cells) was found in the HFD group (n=7) compared with the LFD group (n=6; 48 cells) in every 20 slices (data not shown). In addition to intestinal L cells, PC1/3, the key enzyme governing GLP-1 formation, is expressed in islet β cells and pro-α cells (27), suggesting that the elevated number of PC1/3-positive and insulin-negative cells may be pro-α cells. Notably, in the HFD group, pancreatic PC1/3 mRNA expression was upregulated (Fig. 3B), and the plasma GLP-1 concentrations were increased compared with the LFD group (Fig. 3C), which was in accordance with the increase in PC1/3 protein expression (Fig. 3A) and may be the result of the activation of the intra-islet GLP-1 system. These results demonstrated that a HFD also induced the formation of pro-α cells and the release of GLP-1 through the upregulation of the expression of PC1/3.

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