Phospho-BAD BH3 Mimicry Protects β Cells and Restores Functional β Cell Mass in Diabetes
Sanda Ljubicic,
Klaudia Polak,
Accalia Fu,
Jessica Wiwczar,
Benjamin Szlyk,
Yigang Chang,
Juan C. Alvarez-Perez,
Gregory H. Bird,
Loren D. Walensky,
Adolfo Garcia-Ocaña,
Nika N. Danial
Affiliations
Sanda Ljubicic
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Klaudia Polak
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Accalia Fu
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Jessica Wiwczar
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Benjamin Szlyk
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Yigang Chang
Division of Endocrinology, University of Pittsburgh, Pittsburgh, PA 15260, USA
Juan C. Alvarez-Perez
Diabetes, Obesity and Metabolism Institute, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Gregory H. Bird
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, MA 02115, USA
Loren D. Walensky
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, MA 02115, USA
Adolfo Garcia-Ocaña
Diabetes, Obesity and Metabolism Institute, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Nika N. Danial
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
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.
