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

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

Rongrong Fan et al. PLoS One. 2011.

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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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Effect of exendin-4 treatment on body weight, blood glucose, food and water intake and glucose response in A,3 months and B,20–22 months old mice, n = 7 in each group of 3 months old mice, n = 5 in each group of 20–22 months old mice.

The values were shown as Mean±SEM, **P<0.05 vs control group, ***P<0.01 vs control group.

Figure 2

Figure 2. Glucose stimulated insulin secretion in OGTT time points in A, 3 months and B, 20–22months old mice treated with PBS or exendin-4, n = 7 in each group of 3 months old mice, n = 9 in each group of aging mice.

Values were shown as Mean±SEM, **P<0.05 vs control as determined by student t-test.

Figure 3

Figure 3. 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.

Figure 4

Figure 4. Insulin Tolerance Test(ITT) in 3 months old mice and 20–22 months old mice.

N = 6 in each group of 3 months old mice and n = 4 in each 20–22 months old mice. The Values were presented as Mean±SEM, *P<0.05 as determined by student test.

Figure 5

Figure 5. 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.

Figure 6

Figure 6. 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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