Dual role of proapoptotic BAD in insulin secretion and beta cell survival

Nika N. Danial; Loren D. Walensky; Chen Yu Zhang; Cheol Soo Choi; Jill K. Fisher; Anthony J.A. Molina; Sandeep Robert Datta; Kenneth L. Pitter; Gregory H. Bird; Jakob D. Wikstrom; Jude T. Deeney; Kirsten Robertson; Joel Morash; Ameya Kulkarni; Susanne Neschen; Sheene Kim; Michael E. Greenberg; Barbara E. Corkey; Orian S. Shirihai; Gerald I. Shulman; Bradford B. Lowell; Stanley J. Korsmeyer

doi:10.1038/nm1717

Dual role of proapoptotic BAD in insulin secretion and beta cell survival

Nika N. Danial, Loren D. Walensky, Chen Yu Zhang, Cheol Soo Choi, Jill K. Fisher, Anthony J.A. Molina, Sandeep Robert Datta, Kenneth L. Pitter, Gregory H. Bird, Jakob D. Wikstrom, Jude T. Deeney, Kirsten Robertson, Joel Morash, Ameya Kulkarni, Susanne Neschen, Sheene Kim, Michael E. Greenberg, Barbara E. Corkey, Orian S. Shirihai, Gerald I. ShulmanBradford B. Lowell, Stanley J. Korsmeyer

Research output: Contribution to journal › Article › peer-review

273 Scopus citations

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.

Original language	English
Pages (from-to)	144-153
Number of pages	10
Journal	Nature Medicine
Volume	14
Issue number	2
DOIs	https://doi.org/10.1038/nm1717
State	Published - 1 Feb 2008
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm1717

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Danial, N. N., Walensky, L. D., Zhang, C. Y., Choi, C. S., Fisher, J. K., Molina, A. J. A., Datta, S. R., Pitter, K. L., Bird, G. H., Wikstrom, J. D., Deeney, J. T., Robertson, K., Morash, J., Kulkarni, A., Neschen, S., Kim, S., Greenberg, M. E., Corkey, B. E., Shirihai, O. S., ... Korsmeyer, S. J. (2008). Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nature Medicine, 14(2), 144-153. https://doi.org/10.1038/nm1717

@article{d46bdc6b35f44a4ab5bbbf36c9190800,

title = "Dual role of proapoptotic BAD in insulin secretion and beta cell survival",

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.",

author = "Danial, {Nika N.} and Walensky, {Loren D.} and Zhang, {Chen Yu} and Choi, {Cheol Soo} and Fisher, {Jill K.} and Molina, {Anthony J.A.} and Datta, {Sandeep Robert} and Pitter, {Kenneth L.} and Bird, {Gregory H.} and Wikstrom, {Jakob D.} and Deeney, {Jude T.} and Kirsten Robertson and Joel Morash and Ameya Kulkarni and Susanne Neschen and Sheene Kim and Greenberg, {Michael E.} and Corkey, {Barbara E.} and Shirihai, {Orian S.} and Shulman, {Gerald I.} and Lowell, {Bradford B.} and Korsmeyer, {Stanley J.}",

note = "Funding Information: We thank M. Godes and C. Gramm for technical assistance, R. Pasquier and B. Szlyk for islet isolation and animal husbandry, G. Weir (Joslin Diabetes Center, Boston, MA) for antibody to glucokinase, B. Spiegelman, B. Malynn, M. Vander Heiden, A. Schinzel, J. Labelle, G. Verdine, F. Bernal, A. Saghatelian, A.-M. Richards and G. Yaney for helpful discussion and E. Smith for manuscript preparation. N.N.D. and L.D.W. are recipients of the Burroughs Wellcome Fund Career Award in Biomedical Sciences. This work was supported by US National Institute of Health grants K01CA10659 (N.N.D.), 5R01CA50239 and 5R01DK68781 (S.J.K.), 5K08HL074049 (L.D.W.) and by Charles E. Culpeper Scholarship in Medical Science (L.D.W.).",

year = "2008",

month = feb,

day = "1",

doi = "10.1038/nm1717",

language = "English",

volume = "14",

pages = "144--153",

journal = "Nature Medicine",

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Danial, NN, Walensky, LD, Zhang, CY, Choi, CS, Fisher, JK, Molina, AJA, Datta, SR, Pitter, KL, Bird, GH, Wikstrom, JD, Deeney, JT, Robertson, K, Morash, J, Kulkarni, A, Neschen, S, Kim, S, Greenberg, ME, Corkey, BE, Shirihai, OS, Shulman, GI, Lowell, BB & Korsmeyer, SJ 2008, 'Dual role of proapoptotic BAD in insulin secretion and beta cell survival', Nature Medicine, vol. 14, no. 2, pp. 144-153. https://doi.org/10.1038/nm1717

TY - JOUR

T1 - Dual role of proapoptotic BAD in insulin secretion and beta cell survival

AU - Danial, Nika N.

AU - Walensky, Loren D.

AU - Zhang, Chen Yu

AU - Choi, Cheol Soo

AU - Fisher, Jill K.

AU - Molina, Anthony J.A.

AU - Datta, Sandeep Robert

AU - Pitter, Kenneth L.

AU - Bird, Gregory H.

AU - Wikstrom, Jakob D.

AU - Deeney, Jude T.

AU - Robertson, Kirsten

AU - Morash, Joel

AU - Kulkarni, Ameya

AU - Neschen, Susanne

AU - Kim, Sheene

AU - Greenberg, Michael E.

AU - Corkey, Barbara E.

AU - Shirihai, Orian S.

AU - Shulman, Gerald I.

AU - Lowell, Bradford B.

AU - Korsmeyer, Stanley J.

N1 - Funding Information: We thank M. Godes and C. Gramm for technical assistance, R. Pasquier and B. Szlyk for islet isolation and animal husbandry, G. Weir (Joslin Diabetes Center, Boston, MA) for antibody to glucokinase, B. Spiegelman, B. Malynn, M. Vander Heiden, A. Schinzel, J. Labelle, G. Verdine, F. Bernal, A. Saghatelian, A.-M. Richards and G. Yaney for helpful discussion and E. Smith for manuscript preparation. N.N.D. and L.D.W. are recipients of the Burroughs Wellcome Fund Career Award in Biomedical Sciences. This work was supported by US National Institute of Health grants K01CA10659 (N.N.D.), 5R01CA50239 and 5R01DK68781 (S.J.K.), 5K08HL074049 (L.D.W.) and by Charles E. Culpeper Scholarship in Medical Science (L.D.W.).

PY - 2008/2/1

Y1 - 2008/2/1

N2 - 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.

AB - 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.

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U2 - 10.1038/nm1717

DO - 10.1038/nm1717

M3 - Article

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AN - SCOPUS:38949140180

SN - 1078-8956

VL - 14

SP - 144

EP - 153

JO - Nature Medicine

JF - Nature Medicine

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ER -

Dual role of proapoptotic BAD in insulin secretion and beta cell survival

Abstract

ASJC Scopus subject areas

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