Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.
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.
Milne
Jill C
JC
Sirtris Pharmaceuticals Inc., 790 Memorial Drive, Cambridge, Massachusetts 02139, USA.
Lambert
Philip D
PD
Schenk
Simon
S
Carney
David P
DP
Smith
Jesse J
JJ
Gagne
David J
DJ
Jin
Lei
L
Boss
Olivier
O
Perni
Robert B
RB
Vu
Chi B
CB
Bemis
Jean E
JE
Xie
Roger
R
Disch
Jeremy S
JS
Ng
Pui Yee
PY
Nunes
Joseph J
JJ
Lynch
Amy V
AV
Yang
Hongying
H
Galonek
Heidi
H
Israelian
Kristine
K
Choy
Wendy
W
Iffland
Andre
A
Lavu
Siva
S
Medvedik
Oliver
O
Sinclair
David A
DA
Olefsky
Jerrold M
JM
Jirousek
Michael R
MR
Elliott
Peter J
PJ
Westphal
Christoph H
CH
D000107:Acetylation; D000495:Allosteric Site; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D031204:Caloric Restriction; D020134:Catalytic Domain; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000819:agonists* / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology
D001786:Blood Glucose; D004041:Dietary Fats; D006576:Heterocyclic Compounds, 4 or More Rings; D007328:Insulin; C525424:SRT1460; C525422:SRT1720; C525423:SRT2183; D013267:Stilbenes; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol