title: Phospho-BAD BH3 mimicry protects β cells and restores functional β cell mass in diabetes.
abstract: Strategies that simultaneously enhance the survival and glucose responsiveness of insulin-producing β cells will greatly augment β cell replacement therapies in type 1 diabetes (T1D). We show that genetic and pharmacologic mimetics of the phosphorylated BCL-2 homology 3 (BH3) domain of BAD impart β-cell-autonomous protective effects in the face of stress stimuli relevant to β cell demise in T1D. Importantly, these benefits translate into improved engraftment of donor islets in transplanted diabetic mice, increased β cell viability in islet grafts, restoration of insulin release, and diabetes reversal. Survival of β cells in this setting is not merely due to the inability of phospho-BAD to suppress prosurvival BCL-2 proteins but requires its activation of the glucose-metabolizing enzyme glucokinase. Thus, BAD phospho-BH3 mimetics may prove useful in the restoration of functional β cell mass in diabetes.
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Sanda
authors: S
authors: Ljubicic
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Klaudia
authors: K
authors: Polak
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Accalia
authors: A
authors: Fu
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Jessica
authors: J
authors: Wiwczar
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Benjamin
authors: B
authors: Szlyk
authors: Division of Endocrinology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors: Yigang
authors: Y
authors: Chang
authors: Diabetes, Obesity and Metabolism Institute, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Juan C
authors: JC
authors: Alvarez-Perez
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA.
authors: Gregory H
authors: GH
authors: Bird
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA.
authors: Loren D
authors: LD
authors: Walensky
authors: Diabetes, Obesity and Metabolism Institute, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Adolfo
authors: A
authors: Garcia-Ocaña
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nika_danial@dfci.harvard.edu.
authors: Nika N
authors: NN
authors: Danial
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005941:Glucokinase / Q000378:metabolism; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D051381:Rats; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: D051025:bcl-Associated Death Protein; D005941:Glucokinase
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