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• W2013806370 abstract "Genes formerly thought to be involved solely in the regulation of life span have increasingly become implicated in the regulation of metabolic processes. Moynihan et al., 2005Moynihan K.A. Grimm A.A. Plueger M.M. Bernal-Mizrachi E. Ford E. Cras-Meneur C. Permutt M.A. Imai S. Cell Metab. 2005; 2 (this issue): 105-117Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar [this issue of Cell Metabolism]) now demonstrate that increasing levels of Sirt1 in the pancreatic β cells of mice result in a more efficient glucose handling due to enhanced glucose-stimulated insulin secretion. Genes formerly thought to be involved solely in the regulation of life span have increasingly become implicated in the regulation of metabolic processes. Moynihan et al., 2005Moynihan K.A. Grimm A.A. Plueger M.M. Bernal-Mizrachi E. Ford E. Cras-Meneur C. Permutt M.A. Imai S. Cell Metab. 2005; 2 (this issue): 105-117Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar [this issue of Cell Metabolism]) now demonstrate that increasing levels of Sirt1 in the pancreatic β cells of mice result in a more efficient glucose handling due to enhanced glucose-stimulated insulin secretion. The idea that life span and calorie intake/handling might be interrelated is not new. Classic literature and recent data show that restricted calorie intake extends life span of a number of organisms including yeast, worms, flies, and even mammals (Guarente and Picard, 2005Guarente L. Picard F. Cell. 2005; 120: 473-482Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar). A study in this issue of Cell Metabolism now shows how nutrient sensing in the endocrine pancreas may be affected by one of the key genes involved in modulating life span. Sir2 (silent information regulator 2) was first identified in yeast for its role in chromatin remodeling associated with gene silencing and prolonged life span. SIRT1, the mammalian ortholog of yeast Sir2, is one of seven mammalian sirtuins (Sirt1–7). Sirt1 is a protein deacetylase, located in the cell nucleus. It requires oxidized NAD as a cofactor and is negatively regulated by either NADH or the deacetylation product nicotinamide. A decrease in the NAD/NADH ratio inhibits Sirt1 activity, and this dependency on NAD may link Sirt1 activity to cellular metabolic changes. In higher eukaryotes, the role of Sirt1 has been mainly studied in the context of calorie restriction, a condition that results in Sirt1 activation. In differentiated fat cells, upregulation of Sirt1 triggers lipolysis and mobilization of free fatty acids into the blood (Picard et al., 2004Picard F. Kurtev M. Chung N. Topark-Ngarm A. Senawong T. Machado de Oliveira R. Leid M. McBurney M.W. Guarente L. Nature. 2004; 429: 771-776Crossref PubMed Scopus (1552) Google Scholar). In liver cells, activation of Sirt1 leads to the inactivation of glycolysis, and the activation of gluconeogenesis, which results in an increased hepatic glucose output (Rodgers et al., 2005Rodgers J.T. Lerin C. Haas W. Gygi S.P. Spiegelman B.M. Puigserver P. Nature. 2005; 434: 113-118Crossref PubMed Scopus (2346) Google Scholar). The phenotype of a mouse that overexpresses Sirt1 in the pancreatic β cell, i.e., BESTO mice, is now described by Moynihan and coworkers. Most interestingly, BESTO mice exhibit an improved glucose tolerance due to enhanced glucose-stimulated insulin secretion (GSIS). The pancreatic β cell is a very efficient fuel sensor that immediately converts the blood glucose concentration into signals that allow both the release and the production of insulin in adequate amounts in order to maintain glucose homeostasis. In doing so, the β cell depends on an efficient metabolism of glucose by glycolysis and oxidative phosphorylation. The complex processes that finally result in insulin exocytosis, often referred to as the glucose-stimulus-insulin-secretion coupling, start with the uptake of glucose by high-Km/low-affinity glucose transporters and proceed with the conversion of glucose into glucose-6-phosphate by the β cell isoform of glucokinase. Metabolism of glucose by glycolysis and the Krebs cycle results in the generation of ATP. The resting membrane potential of the pancreatic β cell is set by the ATP-sensitive potassium (KATP) channel. Elevation in the ATP/ADP ratio leads to closure of KATP channels, which in turn results in depolarization of the plasma membrane. The subsequent opening of voltage-gated L type Ca2+ channels leads to an increase in the cytoplasmic free Ca2+ concentration, which promotes insulin secretion. Sirt1 has previously been shown to affect glucose metabolism in liver cells by activating the transcriptional coactivator PGC-1α, with subsequent expression of gluconeogenic genes and repression of glycolytic genes (Rodgers et al., 2005Rodgers J.T. Lerin C. Haas W. Gygi S.P. Spiegelman B.M. Puigserver P. Nature. 2005; 434: 113-118Crossref PubMed Scopus (2346) Google Scholar). In agreement with these results, overexpression of PGC-1α in pancreatic β cells leads to the activation of the gluconeogenic gene glucose-6-phosphatase and repression of genes involved in β cell glucose uptake and glycolysis with a marked inhibition of GSIS (Yoon et al., 2003Yoon J.C. Xu G. Deeney J.T. Yang S.N. Rhee J. Puigserver P. Levens A.R. Yang R. Zhang C.Y. Lowell B.B. et al.Dev. Cell. 2003; 5: 73-83Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). Noteworthy is that normal pancreatic islets express both PGC-1α (Yoon et al., 2003Yoon J.C. Xu G. Deeney J.T. Yang S.N. Rhee J. Puigserver P. Levens A.R. Yang R. Zhang C.Y. Lowell B.B. et al.Dev. Cell. 2003; 5: 73-83Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar) and Sirt1 (Moynihan et al., 2005Moynihan K.A. Grimm A.A. Plueger M.M. Bernal-Mizrachi E. Ford E. Cras-Meneur C. Permutt M.A. Imai S. Cell Metab. 2005; 2 (this issue): 105-117Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar) at low levels. Hence, in light of these data and the central role of glucose metabolism in GSIS, the results of the study by Moynihan et al. might at first sight seem unexpected. If one posits that overexpression of Sirt1 in β cells activates PGC-1α, thereby repressing glycolysis, one would expect a decrease in ATP production and, hence, a decreased GSIS. On the contrary, Moynihan and coworkers find an increase, rather than a decrease, in ATP levels in glucose-stimulated BESTO β cells. Assuming no changes or even a reduction in the glycolytic flux, the higher ATP levels could be explained by a more efficient oxidative phosphorylation, which is exactly what Moynihan et al. report. They find that overexpression of Sirt1 in β cells leads to the repression of the uncoupling protein UCP2. UCPs are mitochondrial inner-membrane proteins that during oxidative phosphorylation uncouple the process of oxygen consumption from ATP generation, which also reduces the amount of produced reactive oxygen species (ROS). The finding that Sirt1 overexpression downregulates UCP2 expression is of general importance because the relation between calorie restriction, and thus Sir2 activity, and UCP expression is unclear. Given the role of Sir2 in calorie restriction and longevity and the currently assumed central role of ROS in aging (see Guarente and Picard, 2005Guarente L. Picard F. Cell. 2005; 120: 473-482Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar), the situation becomes rather complex. Downregulation of UCPs would reduce uncoupling and allow a more efficient ATP production under circumstances of limited access to nutrients. On the other hand, upregulation of UCP would suppress production of ROS and thus be favorable because of reduced oxidative damage and “aging” of cells. Since Sirt1 represses UCP2 expression, increasing Sirt1 activity/dosage may also have implications as a potential therapeutic strategy in diabetes. However, downregulation of UCP2 could lead to an increase in ROS production and hence increase the risk of β cell damage, especially under diabetic conditions. Using Sirt1 activity/dosage as a target might therefore be contraindicated and, in any case, needs much more experimental and clinical work for verification. In this context, it remains to be proven whether the observed phenotype of the BESTO mice reflects the “amplification” of function of the endogenous Sirt1 in the pancreatic β cell, as assumed by the authors, or whether overexpression of Sirt1 should rather be interpreted as a “tool” to manipulate β cell function. This is especially interesting in the light of insulin feedback on β cell function (Leibiger et al., 1998Leibiger I. Leibiger B. Moede T. Berggren P.O. Mol. Cell. 1998; 1: 933-938Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, Kulkarni et al., 1999Kulkarni R.N. Bruning J.C. Winnay J.N. Postic C. Magnuson M.A. Kahn C.R. Cell. 1999; 96: 329-339Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar, Uhles et al., 2003Uhles S. Moede T. Leibiger B. Berggren P.O. Leibiger I.B. J. Cell Biol. 2003; 163: 1327-1337Crossref PubMed Scopus (73) Google Scholar). Insulin may activate genes involved in glycolysis (Leibiger et al., 2001Leibiger B. Leibiger I.B. Moede T. Kemper S. Kulkarni R.N. Kahn C.R. de Vargas L.M. Berggren P.O. Mol. Cell. 2001; 7: 570-581Abstract Full Text Full Text PDF Scopus (209) Google Scholar), and endogenous Sirt1 expression seems to be negatively regulated by insulin (Cohen et al., 2004Cohen H.Y. Miller C. Bitterman K.J. Wall N.R. Hekking B. Kessler B. Howitz K.T. Gorospe M. de Cabo R. Sinclair D.A. Science. 2004; 305: 390-392Crossref PubMed Scopus (1563) Google Scholar). Downregulation of UCP2 expression by Sirt1 in β cells is only the tip of the iceberg. Aside from its role as a histone deacetylase, and its involvement therefore in chromatin remodeling, and the above discussed modulation of PGC-1α, Sirt1 has also been shown to regulate the activity of transcription factors and transcription coregulators such as p53, Ku70, FoxO1, NF-κB, PPARγ, HNF4α, and p300, all of them implicated in regulation of gene expression in the pancreatic β cell (Figure 1). Thus the question as to whether further investigations of sirtuins in β cell function are worthwhile has to be answered: yes, SIRTainly!" @default.
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• W2013806370 title "A SIRTain role in pancreatic β cell function" @default.
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