You are hereRecent Publications of Members of the Boston Ithaca Islet Club / Dual role of proapoptotic BAD in insulin secretion and beta cell survival
Dual role of proapoptotic BAD in insulin secretion and beta cell survival
| Title | Dual role of proapoptotic BAD in insulin secretion and beta cell survival |
| Publication Type | Journal Article |
| Year of Publication | 2008 |
| Authors | |
| Journal | Nat Med |
| Volume | 14 |
| Issue | 2 |
| Pagination | 144-53 |
| Date Published | Feb |
| Publication Language | eng |
| ISBN Number | 1546-170X (Electronic) |
| Accession Number | 18223655 |
| Key Words | Glucokinase/metabolism, Diet, Cell Survival/drug effects, Cell Count, Calcium/metabolism, Blood Glucose, Animals, Amino Acid Sequence, bcl-Associated Death Protein/chemistry/deficiency/*metabolism, Protein Structure, Tertiary, Phosphoserine/metabolism, Peptides/pharmacology, Molecular Sequence Data, Models, Genetic, Mice, Membrane Potential, Mitochondrial/drug effects, Insulin-Secreting Cells/*cytology/drug effects/enzymology/*secretion, Insulin/*secretion, Hydrocarbons/pharmacology, Humans, Glucose/pharmacology |
| Abstract | The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion. |
| Notes | 5K08HL074049/HL/NHLBI NIH HHS/United States5R01CA50239/CA/NCI NIH HHS/United States5R01DK68781/DK/NIDDK NIH HHS/United StatesK01CA10659/CA/NCI NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tUnited States |
| URL | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18223655 |
| Citation Key | 318 |
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- Amino Acid Sequence
- Animals
- bcl-Associated Death Protein/chemistry/deficiency/*metabolism
- Blood Glucose
- Calcium/metabolism
- Cell Count
- Cell Survival/drug effects
- Diet
- Glucokinase/metabolism
- Glucose/pharmacology
- Humans
- Hydrocarbons/pharmacology
- Insulin-Secreting Cells/*cytology/drug effects/enzymology/*secretion
- Insulin/*secretion
- Membrane Potential, Mitochondrial/drug effects
- Mice
- Models, Genetic
- Molecular Sequence Data
- Peptides/pharmacology
- Phosphoserine/metabolism
- Protein Structure, Tertiary