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Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model
Giovanna Sociali1, Mirko Magnone1, Silvia Ravera2
1Section of Biochemistry, Department of Experimental Medicine, Center of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy.
Abstract:
Sirtuin 6 (SIRT6) is a sirtuin family member involved in a wide range of physiologic and disease processes, including cancer and glucose homeostasis. Based on the roles played by SIRT6 in different organs, including its ability to repress the expression of glucose transporters and glycolytic enzymes, inhibiting SIRT6 has been proposed as an approach for treating type 2 diabetes mellitus (T2DM). However, so far, the lack of small-molecule Sirt6 inhibitors has hampered the conduct of in vivo studies to assess the viability of this strategy. We took advantage of a recently identified SIRT6 inhibitor, compound 1, to study the effect of pharmacological Sirt6 inhibition in a mouse model of T2DM (i.e., in high-fat-diet-fed animals). The administration of the Sirt6 inhibitor for 10 d was well tolerated and improved oral glucose tolerance, it increased the expression of the glucose transporters GLUT1 and -4 in the muscle and enhanced the activity of the glycolytic pathway. Sirt6 inhibition also resulted in reduced insulin, triglycerides, and cholesterol levels in plasma. This study represents the first in vivo study of a SIRT6 inhibitor and provides the proof-of-concept that targeting SIRT6 may be a viable strategy for improving glycemic control in T2DM.-Sociali, G., Magnone, M., Ravera, S., Damonte, P., Vigliarolo, T., Von Holtey, M., Vellone, V. G., Millo, E., Caffa, I., Cea, M., Parenti, M. D., Del Rio, A., Murone, M., Mostoslavsky, R., Grozio, A., Nencioni, A., Bruzzone S. Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model.
Insights
Pharmacological inhibition of Sirtuin 6 (SIRT6) improves glucose tolerance in a mouse model of type 2 diabetes mellitus (T2DM). This study provides the first in vivo evidence that targeting SIRT6 is a viable strategy for T2DM treatment.
Area of Science:
- Biochemistry
- Metabolism
- Endocrinology
Background:
- Sirtuin 6 (SIRT6) plays a role in glucose homeostasis and is implicated in type 2 diabetes mellitus (T2DM).
- SIRT6 represses glucose transporters and glycolytic enzymes, making its inhibition a potential therapeutic strategy for T2DM.
- The lack of small-molecule SIRT6 inhibitors has limited in vivo studies for T2DM treatment.
Purpose of the Study:
- To investigate the in vivo effects of pharmacological SIRT6 inhibition in a mouse model of T2DM.
- To assess the therapeutic potential of targeting SIRT6 for improving glycemic control.
Main Methods:
- Utilized a recently identified SIRT6 inhibitor (compound 1) in high-fat-diet-induced T2DM mice.
- Administered the SIRT6 inhibitor for 10 days and evaluated its tolerability and effects on glucose metabolism.
- Measured oral glucose tolerance, glucose transporter expression (GLUT1, GLUT4), glycolytic pathway activity, and plasma levels of insulin, triglycerides, and cholesterol.
Main Results:
- SIRT6 inhibition was well tolerated in T2DM mice.
- Improved oral glucose tolerance and enhanced GLUT1 and GLUT4 expression in muscle.
- Increased glycolytic pathway activity and reduced plasma insulin, triglyceride, and cholesterol levels.
Conclusions:
- This study provides the first in vivo proof-of-concept for using SIRT6 inhibitors in T2DM.
- Pharmacological SIRT6 inhibition demonstrates a viable strategy for improving glycemic control in type 2 diabetes mellitus.