A novel SIRT1 activator E6155 improves insulin sensitivity in type 2 diabetic KKAy mice
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China)
Highlights: • E6155, a piperazine 1, 4-diamide compound, was first found to be a SIRT1 activator. • E6155 regulated glucose uptake dependent on SIRT1 in L02 and L6 cells. • E6155 improved glucose tolerance and insulin sensitivity in type 2 diabetic mice. • The antidiabetic effect of E6155 was involved in activation of AMPK and AKT pathways. Sirtuin 1 (SIRT1) is an NAD{sup +}-dependent protein deacetylase that plays a critical role in controlling energy metabolism, stress response and aging. Hence, enhancing SIRT1 activity could be a potential therapeutic strategy to treat metabolic diseases such as diabetes. However, pharmacological activators for SIRT1 are scarce to date. In this study, using the optimized high throughput screening, we identified E6155, a piperazine 1, 4- diamide compound, as a new small molecular activator of SIRT1. We further found that E6155 significantly upregulated glucose uptake in cultured normal liver cells and skeletal muscle cells through increasing SIRT1 deacetylase activity. In type 2 diabetic KKA{sub y} mice, E6155 treatment markedly decreased the level of fasting glucose. Moreover, E6155 improved oral glucose tolerance and insulin tolerance. Euglycemic clamp and the homeostasis model assessment of insulin resistance index showed that E6155 ameliorated the insulin resistance and increased insulin sensitivity in diabetic mice. Mechanistically, we observed that the antidiabetic effects of E6155 were involved in SIRT1 dependent activation of LKB1/AMPK and IRS1/AKT pathways. In conclusion, our findings identified E6155 as a novel SIRT1 activator and suggested that E6155 could be a promising drug candidate for treating insulin resistance and diabetes.
- OSTI ID:
- 23137227
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 498, Issue 3; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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