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

Tejas Desai,Lemieux Luu,Evangelia L Tsiani,Michael B Wheeler,Aleksandar Ivovic,Khajag Koulajian,Danna M Breen,Adria Giacca

doi:10.1038/s41387-019-0075-z

Tejas Desai, Lemieux Luu + Show 6 more

Open Access

https://doi.org/10.1038/s41387-019-0075-z

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Journal: Nutrition & diabetes	Publication Date: Mar 19, 2019
Citations: 10	License type: open-access

Affiliation: University of Toronto, Brock University

Abstract

BackgroundThere 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.MethodsOur 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.ResultsLipid 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).ConclusionThese results suggest that SIRT1 is a therapeutic target in decreased β-cell function specifically induced by fat.

Highlights

Over the last decade it has become quite evident that sirtuins and sirtuin 1 (SIRT1) are key factors in the regulation of nutrient metabolism
A few key studies have examined the importance of SIRT1 within the β-cell and demonstrated that SIRT1 overexpression or knock-out mouse models display increased or decreased insulin secretion respectively[1,2]. These studies attributed the changes in insulin secretion to changes in UCP2, which is a transcriptional target that has been shown to be repressed by SIRT1
There were no significant differences in plasma glucose levels between groups during the clamp (Fig. 1b)

Summary

Introduction

Over the last decade it has become quite evident that sirtuins and SIRT1 are key factors in the regulation of nutrient metabolism. A few key studies have examined the importance of SIRT1 within the β-cell and demonstrated that SIRT1 overexpression or knock-out mouse models display increased or decreased insulin secretion respectively[1,2]. These studies attributed the changes in insulin secretion to changes in UCP2, which is a transcriptional target that has been shown to be repressed by SIRT1. Subsequent studies further demonstrated that a lack of NAD availability, which is essential to sirtuin function, results in decreased SIRT1 activity and decreased β-cell function[3]. There is evidence that sirtuin 1 (SIRT1), a key regulator of nutrient metabolism, increases β-cell secretory function. We attempted to attenuate the lipid-induced decrease in β-cell function in vivo using pharmacological and genetic models of SIRT1 activation

Methods

Results

Conclusion