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Exendin-4 improves blood glucose control in both young and aging normal non-diabetic mice, possible contribution of beta cell independent effects.

Fan R, Kang Z, He L, Chan J, Xu G - PLoS ONE (2011)

Bottom Line: However, the potential influence of aging on the therapeutic effects of this peptide has not been well studied.Real-time PCR and western blot were used to measure protein changes in the liver tissue after exendin-4 treatment.Based on these data, we conclude that the glucose lowering effect of exendin-4 in normal non-diabetic mice was not blunted by aging.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong, China.

ABSTRACT

Aims: Type 2 diabetes is highly prevalent in the elderly population. Glucagon like Peptide-1 mimetic such as exendin-4 augments post-prandial insulin secretion. However, the potential influence of aging on the therapeutic effects of this peptide has not been well studied. In this study, we examined the glucose regulatory effects of exendin-4 in mice with different ages.

Methods: We treated 3-month and 20 to 22-month old C57/DBA mice with 10 nM/kg exendin-4 for 10 days with measurements of blood glucose and body weight. We performed OGTT and ITT to evaluate the glucose response and insulin sensitivity. Islet morphology and beta cell mass were measured by immuno-staining and beta cell proliferation was evaluated by BrdU incorporation and PCNA staining. Real-time PCR and western blot were used to measure protein changes in the liver tissue after exendin-4 treatment.

Results: Exendin-4 treatment improved glycemic control in both 3-month and 20 to 22-month old mice. In both groups of mice, the blood glucose lowering effect was independent of beta cell function as indicated by unchanged beta cell proliferation, insulin secretion or beta cell mass. Moreover, we found that exendin-4 treatment increased hepatic AKT and FOXO1 phosphorylation and inhibited glucose-6-phosphotase (G6P) and Phosphoenolpyruvate carboxykinase (PEPCK) expression in young mice, but this effect was attenuated in aging mice while the insulin sensitivity showed no change in the young group but significantly improved in aging mice.

Conclusion: Based on these data, we conclude that the glucose lowering effect of exendin-4 in normal non-diabetic mice was not blunted by aging. We further showed that although there was slight difference in the glucose modulating mechanism of exendin-4 therapy in young and aged mice, the improved glucose control seemed uncorrelated with increased beta cell mass or insulin secretion.

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Beta cell mass and proliferation evaluation.Beta cell proliferation was evaluated by BrdU staining, the BrdU positive cells (red) to the insulin secreting cell (green) ratio was quantified (Figure 3A). PCNA staining was performed in 3 months old mice and the PCNA positive cells (red) to insulin secreting cell (green) ratio was quantified (Figure 3B). The beta cell mass and islet/pancreas % was also evaluated (Figure 3C) The values were shown as Mean±SEM.
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pone-0020443-g003: Beta cell mass and proliferation evaluation.Beta cell proliferation was evaluated by BrdU staining, the BrdU positive cells (red) to the insulin secreting cell (green) ratio was quantified (Figure 3A). PCNA staining was performed in 3 months old mice and the PCNA positive cells (red) to insulin secreting cell (green) ratio was quantified (Figure 3B). The beta cell mass and islet/pancreas % was also evaluated (Figure 3C) The values were shown as Mean±SEM.

Mentions: Exendin-4 has been reported to improve beta cell regeneration and increase beta cell mass. However, in both 3-months and 20 to 22-months old mice, 10 days' treatment with exendin-4 did not significantly promote beta cell growth. The beta cell morphology was normal and the beta cell mass were not changed in both groups of mice. BrdU is a nuclear acid mimetic which is incorporated into genomic DNA during cell proliferation. We stained the pancreas with BrdU and insulin antibody and quantified the ratio of BrdU positive cells in each islet of the pancreas. In aging mice, the beta cell proliferation rate was very low and showed no difference in both saline and exendin-4 treated groups (Figure 3A). In the 3-month old mice, exendin-4 treatment did not increase beta cell proliferation either. The quantification results suggested a lower trend of proliferation rate in the islets of exendin-4 treated group (Figure 3A),. The PCNA staining results also showed no difference in 3-months old mice, in the aging group, we failed to detect any PCNA positive cells in the pancreatic islets, suggesting that the beta cell proliferation rate was very low in aging mice (Figure 3B). In consistence with this result, beta cell mass and islet area/whole pancreas ratio did not show any increase by exendin-4 treatment in both young and aging mice (Figure 3C).


Exendin-4 improves blood glucose control in both young and aging normal non-diabetic mice, possible contribution of beta cell independent effects.

Fan R, Kang Z, He L, Chan J, Xu G - PLoS ONE (2011)

Beta cell mass and proliferation evaluation.Beta cell proliferation was evaluated by BrdU staining, the BrdU positive cells (red) to the insulin secreting cell (green) ratio was quantified (Figure 3A). PCNA staining was performed in 3 months old mice and the PCNA positive cells (red) to insulin secreting cell (green) ratio was quantified (Figure 3B). The beta cell mass and islet/pancreas % was also evaluated (Figure 3C) The values were shown as Mean±SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105063&req=5

pone-0020443-g003: Beta cell mass and proliferation evaluation.Beta cell proliferation was evaluated by BrdU staining, the BrdU positive cells (red) to the insulin secreting cell (green) ratio was quantified (Figure 3A). PCNA staining was performed in 3 months old mice and the PCNA positive cells (red) to insulin secreting cell (green) ratio was quantified (Figure 3B). The beta cell mass and islet/pancreas % was also evaluated (Figure 3C) The values were shown as Mean±SEM.
Mentions: Exendin-4 has been reported to improve beta cell regeneration and increase beta cell mass. However, in both 3-months and 20 to 22-months old mice, 10 days' treatment with exendin-4 did not significantly promote beta cell growth. The beta cell morphology was normal and the beta cell mass were not changed in both groups of mice. BrdU is a nuclear acid mimetic which is incorporated into genomic DNA during cell proliferation. We stained the pancreas with BrdU and insulin antibody and quantified the ratio of BrdU positive cells in each islet of the pancreas. In aging mice, the beta cell proliferation rate was very low and showed no difference in both saline and exendin-4 treated groups (Figure 3A). In the 3-month old mice, exendin-4 treatment did not increase beta cell proliferation either. The quantification results suggested a lower trend of proliferation rate in the islets of exendin-4 treated group (Figure 3A),. The PCNA staining results also showed no difference in 3-months old mice, in the aging group, we failed to detect any PCNA positive cells in the pancreatic islets, suggesting that the beta cell proliferation rate was very low in aging mice (Figure 3B). In consistence with this result, beta cell mass and islet area/whole pancreas ratio did not show any increase by exendin-4 treatment in both young and aging mice (Figure 3C).

Bottom Line: However, the potential influence of aging on the therapeutic effects of this peptide has not been well studied.Real-time PCR and western blot were used to measure protein changes in the liver tissue after exendin-4 treatment.Based on these data, we conclude that the glucose lowering effect of exendin-4 in normal non-diabetic mice was not blunted by aging.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong, China.

ABSTRACT

Aims: Type 2 diabetes is highly prevalent in the elderly population. Glucagon like Peptide-1 mimetic such as exendin-4 augments post-prandial insulin secretion. However, the potential influence of aging on the therapeutic effects of this peptide has not been well studied. In this study, we examined the glucose regulatory effects of exendin-4 in mice with different ages.

Methods: We treated 3-month and 20 to 22-month old C57/DBA mice with 10 nM/kg exendin-4 for 10 days with measurements of blood glucose and body weight. We performed OGTT and ITT to evaluate the glucose response and insulin sensitivity. Islet morphology and beta cell mass were measured by immuno-staining and beta cell proliferation was evaluated by BrdU incorporation and PCNA staining. Real-time PCR and western blot were used to measure protein changes in the liver tissue after exendin-4 treatment.

Results: Exendin-4 treatment improved glycemic control in both 3-month and 20 to 22-month old mice. In both groups of mice, the blood glucose lowering effect was independent of beta cell function as indicated by unchanged beta cell proliferation, insulin secretion or beta cell mass. Moreover, we found that exendin-4 treatment increased hepatic AKT and FOXO1 phosphorylation and inhibited glucose-6-phosphotase (G6P) and Phosphoenolpyruvate carboxykinase (PEPCK) expression in young mice, but this effect was attenuated in aging mice while the insulin sensitivity showed no change in the young group but significantly improved in aging mice.

Conclusion: Based on these data, we conclude that the glucose lowering effect of exendin-4 in normal non-diabetic mice was not blunted by aging. We further showed that although there was slight difference in the glucose modulating mechanism of exendin-4 therapy in young and aged mice, the improved glucose control seemed uncorrelated with increased beta cell mass or insulin secretion.

Show MeSH
Related in: MedlinePlus