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

FIGURES

Figure 1. The role of SIRT1 in the regulation of glucose homeostasis. The tissue-specific metabolic functions of SIRT1 in pancreatic beta cells, liver, skeletal muscle, and white adipose tissue are schematically depicted. In pancreatic beta cells, SIRT1 promotes glucose-stimulated insulin secretion and might contribute to beta cell adaptation in response to insulin resistance. In the liver, SIRT1 regulates glucose production through the activation of PGC-1alpha and appears to regulate insulin sensitivity negatively. SIRT1 also regulates LXRalpha function, but the importance of this interaction for insulin sensitivity is unclear. In skeletal muscle, SIRT1 might play an important role in improving insulin sensitivity by increasing fatty acid oxidation through the activation of PGC-1alpha and repressing the expression of PTP1B. In white adipose tissue, SIRT1 promotes fatty acid mobilization by repressing PPARgamma function. SIRT1 also regulates the production of adipokines, such as adiponectin, and FGF21 through FOXO1 and/or PPARgamma. The total effect of SIRT1 in white adipose tissue on insulin sensitivity is still unclear.

Figure 2. The activation of SIRT1 is a potential therapeutic approach for the treatment and prevention of type 2 diabetes. SIRT1 activation by transgenic manipulation or small chemical activators induces the improvement of glucose tolerance and possibly insulin sensitivity, the enhancement of mitochondrial function, and the protection from hepatic steatosis. Details are described in text.

Figure 3. NAD biosynthetic pathways in yeast, invertebrates, and mammals. (A) The NAD biosynthetic pathways in the budding yeast Saccharomyces cerevisiae and invertebrates, such as C. elegans and Drosophila. PNC1, NPT1, NMA1 and NMA2, QNS1, and QPT1 are nicotinamidase, nicotinic acid phosphoribosyltransferase, nicotinic acid mononucleotide adenylyltransferase 1 and 2, NAD synthetase, and quinolinic acid phosphoribosyltransfease, respectively. Only SIR2 is shown as a representative NAD-dependent protein deacetylase. NIC, nicotinamide; NA, nicotinic acid; NaMN, nicotinic acid mononucleotide. B) The NAD biosynthetic pathways in mammals. The de novo pathway and the NAD biosynthetic pathway from nicotinic acid are evolutionarily conserved, while the NAD biosynthetic pathway from nicotinamide (red arrows) is vertebrate-specific and mediated by nicotinamide phosphoribosyltransferase (NAMPT). Nicotinamide is the main precursor for NAD biosynthesis in mammals. While multiple enzymes break NAD into nicotinamide and ADP-ribose, only SIRT1 is shown here. NMN, nicotinamide mononucleotide. C) The reaction catalyzed by NAMPT. PPi, inorganic pyrophosphate.