Autophagy Regulates Pancreatic Beta Cell Death in Response to Pdx1 Deficiency and Nutrient Deprivation

There are three types of cell death; apoptosis, necrosis, and autophagy. The possibility that activation of the macroautophagy (autophagy) pathway may increase beta cell death is addressed in this study. Increased autophagy was present in pancreatic islets from Pdx1+/− mice with reduced insulin secretion and beta cell mass. Pdx1 expression was reduced in mouse insulinoma 6 (MIN6) cells by delivering small hairpin RNAs using a lentiviral vector. The MIN6 cells died after 7 days of Pdx1 deficiency, and autophagy was evident prior to the onset of cell death. Inhibition of autophagy prolonged cell survival and delayed cell death. Nutrient deprivation increased autophagy in MIN6 cells and mouse and human islets after starvation. Autophagy inhibition partly prevented amino acid starvation-induced MIN6 cell death. The in vivo effects of reduced autophagy were studied by crossing Pdx1+/− mice to Becn1+/− mice. After 1 week on a high fat diet, 4-week-old Pdx1+/− Becn1+/− mice showed normal glucose tolerance, preserved beta cell function, and increased beta cell mass compared with Pdx1+/− mice. This protective effect of reduced autophagy had worn off after 7 weeks on a high fat diet. Increased autophagy contributes to pancreatic beta cell death in Pdx1 deficiency and following nutrient deprivation. The role of autophagy should be considered in studies of pancreatic beta cell death and diabetes and as a target for novel therapeutic intervention. There are three types of cell death; apoptosis, necrosis, and autophagy. The possibility that activation of the macroautophagy (autophagy) pathway may increase beta cell death is addressed in this study. Increased autophagy was present in pancreatic islets from Pdx1+/− mice with reduced insulin secretion and beta cell mass. Pdx1 expression was reduced in mouse insulinoma 6 (MIN6) cells by delivering small hairpin RNAs using a lentiviral vector. The MIN6 cells died after 7 days of Pdx1 deficiency, and autophagy was evident prior to the onset of cell death. Inhibition of autophagy prolonged cell survival and delayed cell death. Nutrient deprivation increased autophagy in MIN6 cells and mouse and human islets after starvation. Autophagy inhibition partly prevented amino acid starvation-induced MIN6 cell death. The in vivo effects of reduced autophagy were studied by crossing Pdx1+/− mice to Becn1+/− mice. After 1 week on a high fat diet, 4-week-old Pdx1+/− Becn1+/− mice showed normal glucose tolerance, preserved beta cell function, and increased beta cell mass compared with Pdx1+/− mice. This protective effect of reduced autophagy had worn off after 7 weeks on a high fat diet. Increased autophagy contributes to pancreatic beta cell death in Pdx1 deficiency and following nutrient deprivation. The role of autophagy should be considered in studies of pancreatic beta cell death and diabetes and as a target for novel therapeutic intervention. Normal pancreatic beta cell function is essential for normal glucose tolerance, and abnormal beta cell function leads to glucose intolerance and diabetes. A progressive reduction in beta cell mass has been shown to occur in the evolution of diabetes (1Butler P.C. Meier J.J. Butler A.E. Bhushan A. Nat. Clin. Pract. Endocrinol. Metab. 2007; 3: 758-768Crossref PubMed Scopus (224) Google Scholar). Thus understanding the mechanisms responsible for the reduction in beta cell mass is important for understanding the pathogenesis of diabetes and in developing novel approaches to prevention and treatment. There are three types of cell death; apoptosis, necrosis, and autophagy (2Scarlatti F. Granata R. Meijer A.J. Codogno P. Cell Death Differ. 2009; 16: 12-20Crossref PubMed Scopus (221) Google Scholar). Previous studies have focused on apoptosis as the mechanism underlying beta cell death (1Butler P.C. Meier J.J. Butler A.E. Bhushan A. Nat. Clin. Pract. Endocrinol. Metab. 2007; 3: 758-768Crossref PubMed Scopus (224) Google Scholar, 3Johnson J.D. Ahmed N.T. Luciani D.S. Han Z. Tran H. Fujita J. Misler S. Edlund H. Polonsky K.S. J. Clin. Invest. 2003; 111: 1147-1160Crossref PubMed Scopus (303) Google Scholar, 4Johnson J.D. Bernal-Mizrachi E. Alejandro E.U. Han Z. Kalynyak T.B. Li H. Beith J.L. Gross J. Warnock G.L. Townsend R.R. Permutt M.A. Polonsky K.S. Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 19575-19580Crossref PubMed Scopus (172) Google Scholar, 5Li Y. Cao X. Li L.X. Brubaker P.L. Edlund H. Drucker D.J. Diabetes. 2005; 54: 482-491Crossref PubMed Scopus (187) Google Scholar). The possibility that activation of the macroautophagy (hereafter referred to as autophagy) pathway may increase beta cell death has not been systematically studied. Autophagy is a regulated lysosomal pathway leading to the degradation and recycling of long-lived proteins and organelles. During autophagy, cytoplasmic constituents are sequestered into autophagosomes with double membranes and fused to lysosomes (autolysosomes), where degradation occurs. Under certain circumstances such as in response to nutrient deprivation, autophagy may function as a pro-survival pathway by mediating cellular turnover of proteins and organelles (6Klionsky D.J. Nat. Rev. Mol. Cell Biol. 2007; 8: 931-937Crossref PubMed Scopus (1583) Google Scholar, 7Levine B. Kroemer G. Cell. 2008; 132: 27-42Abstract Full Text Full Text PDF PubMed Scopus (5647) Google Scholar, 8Mortimore G.E. Pösö A.R. Annu. Rev. Nutr. 1987; 7: 539-564Crossref PubMed Google Scholar). On the other hand, an increase in autophagy can cause autophagic cell death distinct from apoptosis (9Shimizu S. Kanaseki T. Mizushima N. Mizuta T. Arakawa-Kobayashi S. Thompson C.B. Tsujimoto Y. Nat. Cell Biol. 2004; 6: 1221-1228Crossref PubMed Scopus (1196) Google Scholar, 10Yu L. Alva A. Su H. Dutt P. Freundt E. Welsh S. Baehrecke E.H. Lenardo M.J. Science. 2004; 304: 1500-1502Crossref PubMed Scopus (1108) Google Scholar). It has been suggested that autophagy plays a key role in the turnover of insulin secretory granules and of mitochondria within the beta cell, thereby regulating insulin secretion (11Marsh B.J. Soden C. Alarcón C. Wicksteed B.L. Yaekura K. Costin A.J. Morgan G.P. Rhodes C.J. Mol. Endocrinol. 2007; 21: 2255-2269Crossref PubMed Scopus (152) Google Scholar, 12Twig G. Elorza A. Molina A.J. Mohamed H. Wikstrom J.D. Walzer G. Stiles L. Haigh S.E. Katz S. Las G. Alroy J. Wu M. Py B.F. Yuan J. Deeney J.T. Corkey B.E. Shirihai O.S. EMBO J. 2008; 27: 433-446Crossref PubMed Scopus (2230) Google Scholar). 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PubMed Scopus Google Scholar, H. K. P.L. C.B. Diabetes. PubMed Google Scholar). studies were to nutrient deprivation leads to a increase in autophagy in the beta cell as in other cells and G.E. Pösö A.R. Annu. Rev. Nutr. 1987; 7: 539-564Crossref PubMed Google Scholar). insulinoma MIN6 insulinoma 1 hairpin cells were in with and 1 and amino acid deprivation, the were to amino amino acid and MIN6 cells were in with and cells were in with of the cells were in an of and mouse insulinoma 6 1 small hairpin MIN6 and cells and islets were in cell 1 1 1 and of were by and were with Pdx1 Cell Cell and the of and were to the After this the MIN6 cells were three with and with for cells by The of cell death was as the of the of by islets were by using and as J.D. Ahmed N.T. Luciani D.S. Han Z. Tran H. Fujita J. Misler S. Edlund H. Polonsky K.S. J. Clin. Invest. 2003; 111: 1147-1160Crossref PubMed Scopus (303) Google and human islets were by the in The islets were in with with and and expression were as S. P. Polonsky K.S. J. Biol. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). The was to the of in the and The was by of in the Pdx1 were using the a of the target was that to Pdx1 target was into the of mouse and were from lentiviral were by cells with the and was to the on days 1 and by on days and The autophagy were on days and 7 The of autophagosomes in MIN6 cells islets was using MIN6 cells were with for by with of the mice were and the with The was and the of autophagy, the of in cell was in from is as a of the and thereby the of lysosomal in autophagy A. Y. T. Y. R. Y. Cell PubMed Scopus Google Scholar). reduced Pdx1 expression in MIN6 cells autophagic 1 was to the prior to the of the treatment. 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Invest. 2003; 111: 1147-1160Crossref PubMed Scopus (303) Google Scholar). of the in this using were by the were by The were considered The are as the S.E. reduced Pdx1 expression autophagy, a to an to MIN6 cells a mouse insulinoma cell to of of MIN6 cells with this reduced Pdx1 to of on A in Pdx1 was on 6 and an increase in cell death was on 7 as by and cells a and of MIN6 cells with a not cause cell and the Pdx1 not cause death in mouse cells that not Pdx1 not Thus the increase in cell death after lentiviral is to a in Pdx1 expression and not cellular of autophagy is present in MIN6 cells with reduced Pdx1 of 1 were on Pdx1 MIN6 cells cell death evident and on 7 cell death was were increased Pdx1 MIN6 cells with the of lysosomal in autophagy to reduced Pdx1 expression in MIN6 cells autophagic Pdx1 expression in the of 1 resulted in of in with the of in Pdx1 MIN6 cells on 7 that autophagic is increased in MIN6 a of in the of autophagy Y. Mizushima N. Ueno T. A. T. T. Kominami E. Y. T. 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G. Thompson C.B. M. R. Y. Ueno T. T. P. Z. G. J. G. T. L. Z. M. X. X. 2008; PubMed Scopus Google studied the effects of expression of in MIN6 and are key of S. M. K. B. H. B. PubMed Scopus Google Scholar, A. M. M. A. H. T. Y. T. Mizushima N. 2004; PubMed Scopus Google Scholar). is the of the and a of the in S. M. K. B. H. B. PubMed Scopus Google Scholar). in MIN6 cells to an increase in and this was with a increase in the death of the with of cells of cell death were to expression in Pdx1 MIN6 cells by and expression in cells reduced MIN6 cell death as by the of cells that from in cells to and 7 in cells in expression had been reduced by and On the other expression was reduced by the of cells increased to that a of autophagy is for MIN6 cell survival and are with the in the beta Atg7 mouse that a of Atg7 is with the activation of in islets and an increase in beta cell death (13Ebato C. Uchida T. Arakawa M. Komatsu M. Ueno T. Komiya K. Azuma K. Hirose T. Tanaka K. Kominami E. Kawamori R. Y. H. Cell Metab. 2008; 8: Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Komatsu M. Tanaka K. Han J. Cell Metab. 2008; 8: Full Text Full Text PDF PubMed Scopus Google Scholar). on the was to autophagy in Inhibition of autophagy by prevented Pdx1 MIN6 cell death on cells on with the with 1 Pdx1 MIN6 cells reduced Pdx1 expression is with autophagy in studied Pdx1+/− mouse Pdx1+/− beta cells the for that is of autophagy of a increase in the of in Pdx1+/− beta cells compared with The of and the were increased in Pdx1+/− islets compared with islets by that autophagy is increased in islets from Pdx1+/− mice. into the present in Pdx1+/− the of beta cells was by cells be from cells of the of a small by a J. Cell Biol. PubMed Scopus Google as shown in normal beta cells from islets and in Pdx1+/− beta cells a in beta in Pdx1+/− beta cells and not in beta mice with to reduced Pdx1 expression in beta cells autophagic in resulted in an increase in the of in Pdx1+/− beta cells compared with mice with after suggesting that autophagic is increased in Pdx1+/− beta that autophagy is in Pdx1+/− beta cells in the of increased autophagy in Pdx1+/− beta Pdx1+/− mice were to Becn1+/− mice to autophagy in Pdx1+/− mice. a high fat autophagy in beta cells (13Ebato C. Uchida T. Arakawa M. Komatsu M. Ueno T. Komiya K. Azuma K. Hirose T. Tanaka K. Kominami E. Kawamori R. Y. H. Cell Metab. 2008; 8: Full Text Full Text PDF PubMed Scopus Google mice on a high fat from weeks of After 1 week on the high fat diet, Pdx1+/− Becn1+/− mice showed glucose after the of glucose compared with Pdx1+/− mice. Becn1+/− and mice had glucose A and This was by in and insulin after glucose in Pdx1+/− Becn1+/− mice compared with Pdx1+/− mice autophagy and apoptosis were in Pdx1+/− Becn1+/− mice. were in Pdx1+/− Becn1+/− beta cells compared with beta cells from Pdx1+/− was not suggesting of autophagy in Pdx1+/− Becn1+/− beta have increased apoptosis in Pdx1+/− islets by reduced beta cell mass J.D. Ahmed N.T. Luciani D.S. Han Z. Tran H. Fujita J. Misler S. Edlund H. Polonsky K.S. J. Clin. Invest. 2003; 111: 1147-1160Crossref PubMed Scopus (303) Google Scholar). cells in islets were in Pdx1+/− Becn1+/− mice compared with Pdx1+/− mice that inhibition of autophagy in Pdx1+/− islets cell was studied by with beta cells were increased in Pdx1+/− Becn1+/− mice and Becn1+/− mice compared with Pdx1+/− mice and a of beta cell the by beta cells within pancreatic was and as a of the shown in the beta cell was in Pdx1+/− Becn1+/− mice in Pdx1+/− mice and was to the in and Becn1+/− mice. Thus after 1 week on a high fat diet, compared with Pdx1+/− Pdx1+/− Becn1+/− mice inhibition of autophagy, reduced activation of and increased of beta cells This in increased insulin secretion and preserved glucose and beta cell cell autophagy, apoptosis, and mass in pancreatic islets from mice after 1 week on a high fat diet. were in the mouse in the of was from in Pdx1+/− beta cells to in Pdx1+/− Becn1+/− beta cells The of in beta cells from and Becn1+/− mice were and the of cells for was reduced in islets from Pdx1+/− Becn1+/− mice compared with Pdx1+/− mice The of cells for was in islets from Becn1+/− and mice the of beta cells islet was increased in Pdx1+/− Becn1+/− and Becn1+/− mice compared with Pdx1+/− and Pdx1+/− Becn1+/− Becn1+/− beta cell 1 week after high fat was using insulin as and to the were from Pdx1+/− Becn1+/− beta cell was preserved compared with that of Pdx1+/− and with that in and Becn1+/− mice the of were in on a high fat for 7 this Pdx1+/− Becn1+/− and Pdx1+/− mice of A and of insulin secretion in and in beta cell On the other 7 weeks on a high fat diet, was increased in Pdx1+/− Becn1+/− mice compared with Pdx1+/− mice and the of was reduced suggesting that autophagy is in Pdx1+/− Becn1+/− beta cells this that the activation of autophagy that in Pdx1+/− beta cells is the onset of cell death is delayed of activation of an increase in autophagy is a response to nutrient deprivation, nutrient deprivation autophagy in beta cells as in other cell and G.E. Pösö A.R. Annu. Rev. Nutr. 1987; 7: 539-564Crossref PubMed Google Scholar, N. A. M. T. Y. Mol. Biol. Cell. 2004; PubMed Scopus Google Scholar). MIN6 cells for in in amino and amino an increase in compared with normal and the of amino in amino starvation-induced response to nutrient deprivation, the of evident by nutrient deprivation was by 1 increase in was in human islets in in amino acid for compared with normal and this increase was by 1 (13Ebato C. Uchida T. Arakawa M. Komatsu M. Ueno T. Komiya K. Azuma K. Hirose T. Tanaka K. Kominami E. Kawamori R. Y. H. Cell Metab. 2008; 8: Full Text Full Text PDF PubMed Scopus Google that autophagy in beta and not autophagy in islets in Thus mice for and islets with The was in the of islet beta cells from of of a increase in the of in beta cells from for compared with in the that autophagy in the beta cell in and in Inhibition of autophagy using Atg7 small prevented cell death in increased cell death in L. H. F. J. G. J. Biol. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). Thus the increase in autophagy by amino acid deprivation cell survival leads to cell death in MIN6 A progressive increase in MIN6 cell death was a in amino MIN6 of reduced not the increase in cell death by amino acid deprivation suggesting that the increase in cell death is by autophagy in MIN6 were increased in amino MIN6 cells that apoptosis is to the in MIN6 of in amino cells to an increase in cell death and compared with and Thus the effects of autophagy inhibition on amino acid starvation-induced cell death in cell The present addressed the role of autophagy in beta cell survival and death. The possibility that an increase in autophagy a role in the pathogenesis of diabetes has and is not autophagy contributes to pancreatic beta cell death and reduced beta cell mass. (11Marsh B.J. Soden C. Alarcón C. Wicksteed B.L. Yaekura K. Costin A.J. Morgan G.P. Rhodes C.J. Mol. Endocrinol. 2007; 21: 2255-2269Crossref PubMed Scopus (152) Google have suggested that the of within the insulin secretory the of turnover of and this is an important mechanism for that the of insulin secretory granules is to the of the for with beta of Atg7 showed degradation of islets and impaired insulin secretion of abnormal turnover and function of cellular organelles (13Ebato C. Uchida T. Arakawa M. Komatsu M. Ueno T. Komiya K. Azuma K. Hirose T. Tanaka K. Kominami E. Kawamori R. Y. H. Cell Metab. 2008; 8: Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Komatsu M. Tanaka K. Han J. Cell Metab. 2008; 8: Full Text Full Text PDF PubMed Scopus Google Scholar). cells in and mice that had been a high fat showed of increased insulin by high (13Ebato C. Uchida T. Arakawa M. Komatsu M. Ueno T. Komiya K. Azuma K. Hirose T. Tanaka K. Kominami E. Kawamori R. Y. H. Cell Metab. 2008; 8: Full Text Full Text PDF PubMed Scopus Google Scholar). Autophagy has been in high of proteins into cytoplasmic in a M. H. M. A. Diabetes. 2007; PubMed Scopus Google Scholar). of autophagy by high glucose was by in with and this is to be of autophagy E. Z. 2008; PubMed Scopus Google present is not high glucose autophagy in beta Pdx1 deficiency was as the for studies normal expression of this is essential for beta cell survival and with a Pdx1 a of diabetes J. Nat. PubMed Scopus Google Scholar). for a in Pdx1 as as in the Pdx1 has been in beta cells by insulin secretion J. L. K. Edlund H. PubMed Scopus Google Scholar, J. L. Edlund T. Edlund H. PubMed Scopus Google Scholar, K. PubMed Scopus Google Scholar, H. K. P.L. C.B. Diabetes. PubMed Google and Pdx1 plays an important role in the pro-survival of insulin in the beta cell J.D. Bernal-Mizrachi E. Alejandro E.U. Han Z. Kalynyak T.B. Li H. Beith J.L. Gross J. Warnock G.L. Townsend R.R. Permutt M.A. Polonsky K.S. Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 19575-19580Crossref PubMed Scopus (172) Google Scholar). have an important role for autophagy in regulating the cellular response to reduced Pdx1 expression in vivo in mice and in in MIN6 Pdx1+/− mice after on a high fat diet, and have reduced insulin secretion and pancreatic beta cell mass. Autophagy is increased in with an increase in and the of autophagosomes and autophagy was reduced in Pdx1+/− mice by crossing with Becn1+/− the onset of was delayed in the Pdx1+/− Becn1+/− and preserved insulin secretion and beta cell mass and increased beta cell compared with Pdx1+/− mice. The protective effects on beta cell function of reduced autophagy in the Pdx1+/− Becn1+/− mice were not and after 7 weeks on a high fat the Pdx1+/− Becn1+/− and Pdx1+/− had of of insulin and reduction in beta cell mass. The reduction in autophagy delayed not the of apoptosis in the Pdx1+/− Becn1+/− and this was responsible for the of pancreatic beta cell death and reduced beta cell mass. showed reduced apoptosis and increased beta cell in Pdx1+/− Becn1+/− mice compared with Pdx1+/− mice 1 week after a high fat diet. Pdx1+/− Becn1+/− mice glucose intolerance and reduced beta cell mass by increased Autophagy was in the MIN6 cells autophagosomes the and the increase in and The effects of autophagy were by the MIN6 cells to the autophagy This delayed the onset of cell death not the cells from and cell death was with in Thus autophagy is an of the beta cell response to reduced and the onset and of beta cell death. Nutrient deprivation is a of autophagy G.E. Pösö A.R. Annu. Rev. Nutr. 1987; 7: 539-564Crossref PubMed Google Scholar). mice an increase in in pancreatic of expression of in the mice prevented in pancreatic islets N. A. M. T. Y. Mol. Biol. Cell. 2004; PubMed Scopus Google Scholar). were to the was in beta increase in autophagy was in MIN6 cells in and this effect was by of the cells to and reduced expression as in other cells 2008; Scopus Google Scholar, S. A. 2006; PubMed Scopus Google Scholar). Autophagy was in pancreatic beta cells from mice that had been for and in beta cells of in Autophagy was in human islets of amino The of autophagy is that an response to cell survival in response to such as nutrient deprivation. that this plays a role in the beta have an in the survival of islets and cells and cells autophagy is by genetic and suggesting that circumstances autophagy cell death. The autophagy and apoptosis is the of have been to in the cell 2008; Scopus Google Scholar, S. A. 2006; PubMed Scopus Google and that the in beta Under the studied Pdx1 and nutrient autophagy was increased Inhibition of autophagy delayed the onset of cell death not inhibition of autophagy in MIN6 cells cell death by apoptosis in of the increase in autophagy may the of cell in the have studied apoptosis is the responsible for cell death. Inhibition of autophagy not apoptosis, and inhibition of autophagy may an increase in autophagy is an of the response of beta cells to reduced Pdx1 expression and nutrient deprivation. Autophagy is evident prior to the onset of cell death by and inhibition of autophagy not cell is by The role of autophagy should be considered in studies of pancreatic beta cell death in diabetes and in to novel that target this for prevention and of the for in the expression for the Becn1+/− and Edlund for the Pdx1+/− mice. with

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