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Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Abstract

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes1,2. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity3,4,5,6,7,8,9. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival10,11,12,13,14. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

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Figure 1: Identification of potent SIRT1 activators unrelated to resveratrol.
Figure 2: In vitro characterization of activators of human SIRT1.
Figure 3: SIRT1 activators in mouse models of type 2 diabetes.
Figure 4: SIRT1 activator SRT1720 in the Zucker fa/fa rat model.

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Acknowledgements

We thank C. Ozbal and W. LaMarr from BioTrove, Inc. for running the mass spectrometry samples; S. Schaertl, D. Winkler, N. Fay and T. Hesterkamp for work on the SIRT1 fluorescence polarization assay development; M. Saberi, P. P. Li , M. Lu, and A. Hevener for assistance and advice with the Zucker fa/fa studies; P. Romero, K. Normington, and M. Dipp for experimental advice and comments on the manuscript; M. Inghilterra for help in data analysis and data mining. D.A.S. is supported by an Ellison Medical Foundation Senior Scholarship, and grants from NIH/NIA and the Paul F. Glenn Medical Foundation. J.M.O. is supported by a University of California Discovery Biostar grant and NIH. S.S. is supported by a Mentor-Based Postdoctoral Fellowship from the American Diabetes Association awarded to J.M.O.

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Correspondence to Christoph H. Westphal.

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All authors declare competing financial interests except for S.S. All authors except for S.S., J.M.O. and D.S. are employees of Sirtris Pharmaceuticals. D.S. is a co-founder, Board member and consultant to Sirtris Pharmaceuticals. J.M.O. is a consultant to Sirtris Pharmaceuticals. Sirtris is a company whose goal is to develop drugs to treat age-related diseases.

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Milne, J., Lambert, P., Schenk, S. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007). https://doi.org/10.1038/nature06261

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