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 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. 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 survival. 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.

• Authors: Jill C Milne, Philip D Lambert, Simon Schenk, David P Carney, Jesse J Smith, David J Gagne, Lei Jin, Olivier Boss, Robert B Perni, Chi B Vu, Jean E Bemis, Roger Xie, Jeremy S Disch, Pui Yee Ng, Joseph J Nunes, Amy V Lynch, Hongying Yang, Heidi Galonek, Kristine Israelian, Wendy Choy, Andre Iffland, Siva Lavu, Oliver Medvedik, David A Sinclair, Jerrold M Olefsky, Michael R Jirousek, Peter J Elliott, Christoph H Westphal
• Journal: Nature (Nature) Vol. 450 Issue 7170 Pg. 712-6 (Nov 29 2007) ISSN: 1476-4687 [Electronic] England
• PMID: 18046409 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Dietary Fats
• Heterocyclic Compounds, 4 or More Rings
• Insulin
• SRT1460
• SRT1720
• SRT2183
• Stilbenes
• SIRT1 protein, human
• Sirtuin 1
• Sirtuins
• Resveratrol

Topics

• Acetylation
• Allosteric Site
• Animals
• Blood Glucose (metabolism)
• Caloric Restriction
• Catalytic Domain
• Cell Line
• Diabetes Mellitus, Type 2 (drug therapy)
• Dietary Fats (administration & dosage, pharmacology)
• Disease Models, Animal
• Drosophila melanogaster
• Heterocyclic Compounds, 4 or More Rings (pharmacology, therapeutic use)
• Humans
• Insulin (metabolism, pharmacology)
• Male
• Mice
• Mitochondria (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Rats, Zucker
• Resveratrol
• Sirtuin 1
• Sirtuins (agonists, metabolism)
• Stilbenes (chemistry, pharmacology)