Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes
| Autor: | Wendy Choy, Kristine Israelian, J. Joshua Smith, Simon Schenk, Siva Lavu, David P. Carney, Olivier Boss, Philip D. Lambert, Lei Jin, David J. Gagne, David A. Sinclair, Michael R. Jirousek, Andre Iffland, Amy V. Lynch, Jean Bemis, Roger Xie, Robert B. Perni, Pui Yee Ng, Hongying Yang, Jill C. Milne, Jeremy S. Disch, Chi B. Vu, Peter J. Elliott, Jerrold M. Olefsky, Christoph H. Westphal, Heidi Galonek, Oliver Medvedik, Joseph J. Nunes |
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| Rok vydání: | 2007 |
| Předmět: |
Blood Glucose
Male medicine.medical_specialty medicine.medical_treatment Calorie restriction Adipose tissue Resveratrol Heterocyclic Compounds 4 or More Rings Article Cell Line Rats Sprague-Dawley Mice chemistry.chemical_compound SRT1720 Insulin resistance Sirtuin 1 Catalytic Domain Internal medicine Stilbenes medicine Animals Humans Insulin Sirtuins Glucose homeostasis Caloric Restriction Multidisciplinary biology Acetylation medicine.disease Dietary Fats Mitochondria Rats Rats Zucker Disease Models Animal Drosophila melanogaster Endocrinology Diabetes Mellitus Type 2 chemistry biology.protein Allosteric Site hormones hormone substitutes and hormone antagonists |
| Zdroj: | Nature. 450:712-716 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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 sensitivity3–9. 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 survival10–14. 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. |
| Databáze: | OpenAIRE |
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