Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model

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 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 ( 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 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.

A Review of the Recent Advances Made with SIRT6 and Its Implications on Aging Related Processes, Major Human Diseases and Possible Therapeutic Targets

“…This compound was administered for 10 days and results indicated an improvement in glucose regulation via oral glucose tolerance test (OGTT) leading the researchers to conclude that small molecule inhibitors of SIRT6 may be a functional strategy in the improvement of glycemic control for type 2 diabetics. In addition to these positive findings, there was also a notable increase in glucose transporters as well as reduced levels of insulin, triglycerides and cholesterol observed in the same study possibly paving way for small molecule inhibition of SIRT6 for other diseases as well [89].…”

Inhibition of Sirtuin 6 Induces Neuroblastoma Differentiation

“…No specific small molecule inhibitors of SIRT6 had been identified at the time of this study. However, one SIRT6 inhibitor was recently identified by Sociali et al; this SIRT6 inhibitor improves glucose tolerance in a mouse model of type 2 diabetes (27). Another report showed that the SIRT3-specific inhibitor, LC-0296, inhibits cell survival and proliferation, and promotes apoptosis of head and neck cancer cells.…”

The Effect of Daily Intake of Vitamin D-Fortified Yogurt Drink, With and Without Added Calcium, on Serum Adiponectin and Sirtuins 1 and 6 in Adult Subjects with Type 2 Diabetes

“…Nevertheless, various studies have documented that both inhibition and enhancing SIRT6 may improve glucose tolerance in T2D. In murine model of T2D, inhibition of SIRT6 for ten days resulted in overexpression of muscular GLUT-1 and GLUT-4, enhanced glycolysis, decreased serum insulin as well as blood lipid concentrations and improved oral glucose tolerance [43]. On the other hand, experimental studies provided strong evidence for SIRT6 in pancreatic β-cells function [44,45].…”