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

Abstract

SIRT1, an NAD+-dependent deacetylase that acts on proteins involved in cellular regulation, has been implicated in longevity and as a mediator of the beneficial effects of calorie restriction. A new screening programme has identified a series of small-molecule SIRT1 activators that are structurally unlike, and 1,000-fold more potent than, resveratrol, the well-known SIRT1 activator found in red wine. These new compounds improve metabolic function in animal models of diabetes and obesity, suggesting that they may have therapeutic potential in type 2 diabetes and insulin resistance. This work describes the identification and characterization of novel small molecule activators of SIRT1, an NAD+-dependent deacetylase that mediates the beneficial effects of caloric restriction. These small molecules are structurally unrelated to, and much more potent than, resveratrol, and improve metabolic function in animal models of diabetes and obesity. 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.