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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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Related in: MedlinePlus

Expression of Glucokinase, G6Pase and PEPCK level in young and aging mice treated with PBS or exendin-4.n = 7 in each group of 3 months old mice, n = 5 in each group of aging mice. A, mRNA expression. B, protein level, the western blot was semiquantified. Values were shown as Mean±SEM, ***P<0.01 vs control group as determined by student's t test.
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pone-0020443-g005: Expression of Glucokinase, G6Pase and PEPCK level in young and aging mice treated with PBS or exendin-4.n = 7 in each group of 3 months old mice, n = 5 in each group of aging mice. A, mRNA expression. B, protein level, the western blot was semiquantified. Values were shown as Mean±SEM, ***P<0.01 vs control group as determined by student's t test.

Mentions: Glucose homeostasis is mainly regulated through balanced glucose output and uptake in the hepatocyte. As the improved blood glucose response in both young and aging mice were not accompanied by increased insulin secretion or beta cell mass, we further checked the glucose metabolism in the liver by examining the expression level of a series of genes participating in hepatic gluconeogenesis and glucolysis in the exendin-4 treated mice. In both 3 and 20 to 22-months old mice, glucokinase expression was not changed by exendin-4. However, exendin-4 therapy inhibited both G6Pase and PEPCK in 3-months old mice but in aging mice, this effect was attenuated (Figure 5). The western blot results were consistent with the real-time PCR data. These results suggested that inhibited liver gluconeogenesis was at least partially involved in the glucose lowering effect of exendin-4 in 3-months old but was attenuated in aging mice.


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)

Expression of Glucokinase, G6Pase and PEPCK level in young and aging mice treated with PBS or exendin-4.n = 7 in each group of 3 months old mice, n = 5 in each group of aging mice. A, mRNA expression. B, protein level, the western blot was semiquantified. Values were shown as Mean±SEM, ***P<0.01 vs control group as determined by student's t test.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020443-g005: Expression of Glucokinase, G6Pase and PEPCK level in young and aging mice treated with PBS or exendin-4.n = 7 in each group of 3 months old mice, n = 5 in each group of aging mice. A, mRNA expression. B, protein level, the western blot was semiquantified. Values were shown as Mean±SEM, ***P<0.01 vs control group as determined by student's t test.
Mentions: Glucose homeostasis is mainly regulated through balanced glucose output and uptake in the hepatocyte. As the improved blood glucose response in both young and aging mice were not accompanied by increased insulin secretion or beta cell mass, we further checked the glucose metabolism in the liver by examining the expression level of a series of genes participating in hepatic gluconeogenesis and glucolysis in the exendin-4 treated mice. In both 3 and 20 to 22-months old mice, glucokinase expression was not changed by exendin-4. However, exendin-4 therapy inhibited both G6Pase and PEPCK in 3-months old mice but in aging mice, this effect was attenuated (Figure 5). The western blot results were consistent with the real-time PCR data. These results suggested that inhibited liver gluconeogenesis was at least partially involved in the glucose lowering effect of exendin-4 in 3-months old but was attenuated in aging mice.

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