Phospho-BAD BH3 mimicry protects ? cells and restores functional ? cell mass in diabetes.

ABSTRACT: Strategies that simultaneously enhance the survival and glucose responsiveness of insulin-producing ? cells will greatly augment ? 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 ?-cell-autonomous protective effects in the face of stress stimuli relevant to ? cell demise in T1D. Importantly, these benefits translate into improved engraftment of donor islets in transplanted diabetic mice, increased ? cell viability in islet grafts, restoration of insulin release, and diabetes reversal. Survival of ? 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 ? cell mass in diabetes.

SUBMITTER: Ljubicic S 

PROVIDER: S-EPMC4991214 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature