Abstract
AimsType 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.MethodsWe 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.ResultsExendin-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.ConclusionBased 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.
Highlights
Incretin based therapy has been clinically applied for the treatment of diabetes
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
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
Summary
Incretin based therapy has been clinically applied for the treatment of diabetes. the glucose regulating mechanism and potential danger are still less known and under hot discussion. We used young and aging rodent models to evaluate the potential effect of aging on Glucagon like peptide-1 (GLP-1) mimetic exendin-4 therapy. Exendin-4 is a DPPIV resistant GLP-1 receptor agonist [1]. Exendin-4 exerts insulinotropic effects and has multiple glucose regulatory functions through activation of GLP-1 receptor in the mammalian cells [2]. Exendin-4 treatment increases proliferation, neogenesis and survival of beta cells through activation of PKA and AKT with associated gene expression [3,4,5,6,7,8]. Exendin-4 treatment improves glucose and lipid metabolism[16], independent of insulin disposal the exact mechanism remains to be clarified [17]. It was reported that exendin-4 inhibited hepatocyte and cholangiocyte apoptosis [18,19]
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