title: Oxidative and energetic stresses mediate beta-cell dysfunction induced by PGC-1α.
abstract: OBJECTIVE
  Alteration of functional beta-cell mass in adults can be programmed by adverse events during fetal life. Previously, it was demonstrated that high glucocorticoid (GC) levels during fetal life participate in this programming by inhibition of beta-cell development. More specifically, GC levels stimulate expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a transcriptional co-regulator of the GC receptor (GR), which per se impairs beta-cell mass and function when overexpressed. As PGC-1α is also a potent inducer of mitochondrial biogenesis, our study aimed to determine how PGC-1α modifies mitochondrial function in beta cells and how it might regulate insulin secretion.
  
  
  METHODS
  Beta-cell function was studied in mice overexpressing PGC-1α specifically in beta cells and in MIN6 cells overexpressing PGC-1α in vitro.
  
  
  RESULTS
  PGC-1α overexpression in beta cells in vivo leads to a reduced beta-cell mass early in fetal life, whereas PGC-1α overexpression in vitro stimulates mitochondrial biogenesis and respiratory activity without improving ATP production, while increasing oxidative stress and impairing insulin secretion in response to glucose. While oxidative stress with PGC-1α overexpression in beta cells activates AMPK, it has also been revealed that blocking such oxidative stress or AMPK activation restores insulin secretion.
  
  
  CONCLUSIONS
  PGC-1α induces oxidative stress, which disrupts insulin secretion by AMPK activation. Thus, control of oxidative or energetic stress in beta cells may help to restore insulin secretion.
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Sorbonne Université, UPMC, University Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Besseiche
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Sorbonne Université, UPMC, University Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; AP-HP, Hôpital Lariboisière, Department of Diabetes and Endocrinology, University Paris 7 Denis-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Riveline
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Sorbonne Université, UPMC, University Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Delavallée
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Sorbonne Université, UPMC, University Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Foufelle
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Sorbonne Université, UPMC, University Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; AP-HP, Hôpital Lariboisière, Department of Diabetes and Endocrinology, University Paris 7 Denis-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Gautier
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Sorbonne Université, UPMC, University Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France. Electronic address: bertrand.blondeau@upmc.fr.
authors.forename: B
authors.initials: B
authors.lastname: Blondeau
mesh_terms: D000818:Animals; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000235:genetics*; D010101:Oxygen Consumption / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics* / Q000378:metabolism*
chemical_list: D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse
keywords: Beta cell; Energetic stress; Insulin secretion; Oxidative stress; PGC-1