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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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Exendin-4 induced AKT and FOXO1 phosphorylation in young mice but not aging mice.Phospho-AKT, FOXO1 and AMPK were detected in liver tissues of both young and old mice, the western results were semiquantified (Fig.5). Values were shown as Mean±SD, ***P<0.01.
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pone-0020443-g006: Exendin-4 induced AKT and FOXO1 phosphorylation in young mice but not aging mice.Phospho-AKT, FOXO1 and AMPK were detected in liver tissues of both young and old mice, the western results were semiquantified (Fig.5). Values were shown as Mean±SD, ***P<0.01.

Mentions: Both AMPK and AKT are key kinases which regulate glucose metabolism in the hepatocytes. In our system, liver AMPK phosphorylation was not altered by exendin-4 treatment. In parallel with the G6P and PEPCK changes, AKT phosphorylation level at both Ser473 and Thr308 sites were increased in exendin-4 treated young adult mice but not aging mice (Figure 6A). The increased AKT phosphorylation was paralleled with enhanced FOXO1 phosphorylation, a well established regulator of liver gluconeogenesis (Figure 6A). The enhanced AKT phosphorylation was not accompanied by upregulated insulin level with similar fasting insulin levels in both groups of 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)

Exendin-4 induced AKT and FOXO1 phosphorylation in young mice but not aging mice.Phospho-AKT, FOXO1 and AMPK were detected in liver tissues of both young and old mice, the western results were semiquantified (Fig.5). Values were shown as Mean±SD, ***P<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020443-g006: Exendin-4 induced AKT and FOXO1 phosphorylation in young mice but not aging mice.Phospho-AKT, FOXO1 and AMPK were detected in liver tissues of both young and old mice, the western results were semiquantified (Fig.5). Values were shown as Mean±SD, ***P<0.01.
Mentions: Both AMPK and AKT are key kinases which regulate glucose metabolism in the hepatocytes. In our system, liver AMPK phosphorylation was not altered by exendin-4 treatment. In parallel with the G6P and PEPCK changes, AKT phosphorylation level at both Ser473 and Thr308 sites were increased in exendin-4 treated young adult mice but not aging mice (Figure 6A). The increased AKT phosphorylation was paralleled with enhanced FOXO1 phosphorylation, a well established regulator of liver gluconeogenesis (Figure 6A). The enhanced AKT phosphorylation was not accompanied by upregulated insulin level with similar fasting insulin levels in both groups of 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