[Frontiers in Bioscience 14, 2983-2995, January 1, 2009]

Therapeutic potential of SIRT1 and NAMPT-mediated NAD biosynthesis in type 2 diabetes

Shin-ichiro Imai1, Wieland Kiess2

1Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA, 2University Hospital for Children and Adolescents, University of Leipzig, Leipzig 04103, Germany

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. SIRT1, a key regulator that connects NAD, metabolism, and aging 3.1. The function of SIRT1 in pancreatic beta cells: A possible therapeutic target to restore beta cell adaptation in response to insulin resistance
3.2. The role of SIRT1 in the regulation of insulin sensitivity: A promising target to treat insulin resistance?
3.3. SIRT1 as a therapeutic target for type 2 diabetes
4. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated systemic NAD biosynthesis
4.1. NAMPT, a key NAD biosynthetic enzyme in mammals and its peculiar features
4.2. The role of NAMPT as a systemic NAD biosynthetic enzyme in the regulation of glucose-stimulated insulin secretion in pancreatic beta cells
4.3. A connection between SIRT1, NAMPT-mediated systemic NAD biosynthesis, and age-associated decline in beta cell function
5. Conclusions and perspectives
6. Acknowledgments
7. References

1. ABSTRACT

Both genetic and environmental factors contribute to the pathogenesis of type 2 diabetes, and it is critical to understand the interplay between these factors in the regulation of insulin secretion and insulin sensitivity to develop effective therapeutic interventions for type 2 diabetes. For the past several years, studies on the mammalian NAD-dependent protein deacetylase SIRT1 and systemic NAD biosynthesis mediated by nicotinamide phosphoribosyltransferase (NAMPT) have demonstrated that these two regulatory components together play a critical role in the regulation of glucose homeostasis, particularly in the regulation of glucose-stimulated insulin secretion in pancreatic beta cells. These components also contribute to the age-associated decline in beta cell function, which has been suggested to be one of the major contributing factors to the pathogenesis of type 2 diabetes. In this review article, the roles of SIRT1 and NAMPT-mediated systemic NAD biosynthesis in glucose homeostasis and the pathophysiology of type 2 diabetes will be summarized, and their potential as effective targets for the treatment and prevention of type 2 diabetes will be discussed.