title: Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers.
abstract: Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes. Restoration of insulin production in type 1 diabetes is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation. Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display 'somatostatin-to-insulin' δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.
authors.affiliation: Department of Genetic Medicine &Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Chera
authors.affiliation: Department of Genetic Medicine &Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
authors.forename: Delphine
authors.initials: D
authors.lastname: Baronnier
authors.affiliation: Department of Genetic Medicine &Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
authors.forename: Luiza
authors.initials: L
authors.lastname: Ghila
authors.affiliation: Department of Genetic Medicine &Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cigliola
authors.affiliation: Novo Nordisk A/S, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark.
authors.forename: Jan N
authors.initials: JN
authors.lastname: Jensen
authors.affiliation: Cell and Developmental Biology, Vanderbilt University Medical Center, 465 21st Av. South, Nashville, Tennessee 37232, USA.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Gu
authors.affiliation: Department of Genetic Medicine &Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Furuyama
authors.affiliation: Department of Genetic Medicine &Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Thorel
authors.affiliation: Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.affiliation: Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Department of Genetic Medicine &Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D054337:Cell Dedifferentiation; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D003921:Diabetes Mellitus, Experimental / Q000473:pathology* / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000628:therapy; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D012038:Regeneration; D012741:Sexual Maturation; D013004:Somatostatin / Q000096:biosynthesis / Q000378:metabolism; D019864:Somatostatin-Secreting Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D013004:Somatostatin