Pharmacologic or genetic activation of SIRT1 attenuates the fat-induced decrease in beta-cell function in vivo

摘要

Background There is evidence that sirtuin 1 (SIRT1), a key regulator of nutrient metabolism, increases β-cell secretory function. Excess circulating fat, as seen in obesity, has been shown to decrease β-cell function, an effect that may involve decreased SIRT1 activity. Consequently, SIRT1 activation may increase β-cell function in conditions of elevated plasma-free fatty acid levels. Here we attempted to attenuate the lipid-induced decrease in β-cell function in vivo using pharmacological and genetic models of SIRT1 activation. Methods Our pharmacologic model involved 48?h intravenous infusion of Wistar rats with either saline or oleate with or without the SIRT1 activator resveratrol. Additionally, we used β-cell-specific SIRT1 overexpressing (BESTO) mice and wild-type littermates infused for 48?h intravenously with either saline or oleate. In both models, the infusion period was followed by assessment of β-cell function using the hyperglycemic clamp method. Results Lipid infusion resulted in a significant decrease in β-cell function as expected in both rats ( p ?&?0.05) and mice ( p ?&?0.001). Both models of SIRT1 activation, which did not alter β-cell function in the absence of fat, resulted in partial protection from the fat-induced decrease in β-cell function (NS vs. control). Conclusion These results suggest that SIRT1 is a therapeutic target in decreased β-cell function specifically induced by fat.