Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells

Sharona Tornovsky-Babeay; Daniela Dadon; Oren Ziv; Elhanan Tzipilevich; Tehila Kadosh; Rachel Schyr-Ben Haroush; Ayat Hija; Miri Stolovich-Rain; Judith Furth-Lavi; Zvi Granot; Shay Porat; Louis H. Philipson; Kevan C. Herold; Tricia R. Bhatti; Charles Stanley; Frances M. Ashcroft; Peter In'T Veld; Ann Saada; Mark A. Magnuson; Benjamin Glaser; Yuval Dor

doi:10.1016/j.cmet.2013.11.007

Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells

Sharona Tornovsky-Babeay, Daniela Dadon, Oren Ziv, Elhanan Tzipilevich, Tehila Kadosh, Rachel Schyr-Ben Haroush, Ayat Hija, Miri Stolovich-Rain, Judith Furth-Lavi, Zvi Granot, Shay Porat, Louis H. Philipson, Kevan C. Herold, Tricia R. Bhatti, Charles Stanley, Frances M. Ashcroft, Peter In'T Veld, Ann Saada, Mark A. Magnuson, Benjamin GlaserYuval Dor

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

124 Scopus citations

Abstract

Summary β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (K_ATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via K_ATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.

Original language	English
Pages (from-to)	109-121
Number of pages	13
Journal	Cell Metabolism
Volume	19
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2013.11.007
State	Published - 7 Jan 2014
Externally published	Yes

Bibliographical note

Funding Information:
This work was funded by grants from the Beta Cell Biology Consortium, JDRF, ERC, EU/FP7 (BetaCellTherapy, grant 241883), the Helmsley trust, the Dutch friends of Hebrew University, and the I-CORE Program of The Israel Science Foundation #41.11 (to Y.D.). This work was supported in part by a grant from USAID’s American Schools and Hospitals Abroad Program for the upgrading of the Hebrew University Medical School Flow Cytometry laboratory. This study was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a JDRF-sponsored collaborative T1D research project. Organ Procurement Organizations (OPO) partnering with nPOD are listed at www.jdrfnpod.org/our-partners.php . O.Z. is a New York Stem Cell Foundation-Druckenmiller Fellow. M.S.-R. was supported by a postdoctoral fellowship from Novo Nordisk and A.H. by a fellowship from Mr. Alan Harper. We thank Norma Kidess-Bassir for excellent technical assistance, Donald K. Scott for the gift of rat glucokinase cDNA, Orr Spiegel for advice with statistical analysis, and Christian Broberger, Muli Ben-Sasson, and Ittai Ben-Porath for insightful discussions.

Funding

This work was funded by grants from the Beta Cell Biology Consortium, JDRF, ERC, EU/FP7 (BetaCellTherapy, grant 241883), the Helmsley trust, the Dutch friends of Hebrew University, and the I-CORE Program of The Israel Science Foundation #41.11 (to Y.D.). This work was supported in part by a grant from USAID’s American Schools and Hospitals Abroad Program for the upgrading of the Hebrew University Medical School Flow Cytometry laboratory. This study was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a JDRF-sponsored collaborative T1D research project. Organ Procurement Organizations (OPO) partnering with nPOD are listed at www.jdrfnpod.org/our-partners.php . O.Z. is a New York Stem Cell Foundation-Druckenmiller Fellow. M.S.-R. was supported by a postdoctoral fellowship from Novo Nordisk and A.H. by a fellowship from Mr. Alan Harper. We thank Norma Kidess-Bassir for excellent technical assistance, Donald K. Scott for the gift of rat glucokinase cDNA, Orr Spiegel for advice with statistical analysis, and Christian Broberger, Muli Ben-Sasson, and Ittai Ben-Porath for insightful discussions.

Funders	Funder number
Beta Cell Biology Consortium
Dutch friends of Hebrew University
Helmsley Trust
National Institute of Diabetes and Digestive and Kidney Diseases	P30DK020595
United States Agency for International Development
Juvenile Diabetes Research Foundation United States of America
European Commission
Israel Science Foundation	41.11
Novo Nordisk
Seventh Framework Programme	241883
Israeli Centers for Research Excellence

UN SDGs

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

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10.1016/j.cmet.2013.11.007

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Tornovsky-Babeay, S., Dadon, D., Ziv, O., Tzipilevich, E., Kadosh, T., Schyr-Ben Haroush, R., Hija, A., Stolovich-Rain, M., Furth-Lavi, J., Granot, Z., Porat, S., Philipson, L. H., Herold, K. C., Bhatti, T. R., Stanley, C., Ashcroft, F. M., In'T Veld, P., Saada, A., Magnuson, M. A., ... Dor, Y. (2014). Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells. Cell Metabolism, 19(1), 109-121. https://doi.org/10.1016/j.cmet.2013.11.007

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title = "Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells",

abstract = "Summary β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.",

author = "Sharona Tornovsky-Babeay and Daniela Dadon and Oren Ziv and Elhanan Tzipilevich and Tehila Kadosh and {Schyr-Ben Haroush}, Rachel and Ayat Hija and Miri Stolovich-Rain and Judith Furth-Lavi and Zvi Granot and Shay Porat and Philipson, {Louis H.} and Herold, {Kevan C.} and Bhatti, {Tricia R.} and Charles Stanley and Ashcroft, {Frances M.} and {In'T Veld}, Peter and Ann Saada and Magnuson, {Mark A.} and Benjamin Glaser and Yuval Dor",

note = "Funding Information: This work was funded by grants from the Beta Cell Biology Consortium, JDRF, ERC, EU/FP7 (BetaCellTherapy, grant 241883), the Helmsley trust, the Dutch friends of Hebrew University, and the I-CORE Program of The Israel Science Foundation #41.11 (to Y.D.). This work was supported in part by a grant from USAID{\textquoteright}s American Schools and Hospitals Abroad Program for the upgrading of the Hebrew University Medical School Flow Cytometry laboratory. This study was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a JDRF-sponsored collaborative T1D research project. Organ Procurement Organizations (OPO) partnering with nPOD are listed at www.jdrfnpod.org/our-partners.php . O.Z. is a New York Stem Cell Foundation-Druckenmiller Fellow. M.S.-R. was supported by a postdoctoral fellowship from Novo Nordisk and A.H. by a fellowship from Mr. Alan Harper. We thank Norma Kidess-Bassir for excellent technical assistance, Donald K. Scott for the gift of rat glucokinase cDNA, Orr Spiegel for advice with statistical analysis, and Christian Broberger, Muli Ben-Sasson, and Ittai Ben-Porath for insightful discussions. ",

year = "2014",

month = jan,

day = "7",

doi = "10.1016/j.cmet.2013.11.007",

language = "אנגלית",

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pages = "109--121",

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Tornovsky-Babeay, S, Dadon, D, Ziv, O, Tzipilevich, E, Kadosh, T, Schyr-Ben Haroush, R, Hija, A, Stolovich-Rain, M, Furth-Lavi, J, Granot, Z, Porat, S, Philipson, LH, Herold, KC, Bhatti, TR, Stanley, C, Ashcroft, FM, In'T Veld, P, Saada, A, Magnuson, MA, Glaser, B & Dor, Y 2014, 'Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells', Cell Metabolism, vol. 19, no. 1, pp. 109-121. https://doi.org/10.1016/j.cmet.2013.11.007

TY - JOUR

T1 - Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells

AU - Tornovsky-Babeay, Sharona

AU - Dadon, Daniela

AU - Ziv, Oren

AU - Tzipilevich, Elhanan

AU - Kadosh, Tehila

AU - Schyr-Ben Haroush, Rachel

AU - Hija, Ayat

AU - Stolovich-Rain, Miri

AU - Furth-Lavi, Judith

AU - Granot, Zvi

AU - Porat, Shay

AU - Philipson, Louis H.

AU - Herold, Kevan C.

AU - Bhatti, Tricia R.

AU - Stanley, Charles

AU - Ashcroft, Frances M.

AU - In'T Veld, Peter

AU - Saada, Ann

AU - Magnuson, Mark A.

AU - Glaser, Benjamin

AU - Dor, Yuval

N1 - Funding Information: This work was funded by grants from the Beta Cell Biology Consortium, JDRF, ERC, EU/FP7 (BetaCellTherapy, grant 241883), the Helmsley trust, the Dutch friends of Hebrew University, and the I-CORE Program of The Israel Science Foundation #41.11 (to Y.D.). This work was supported in part by a grant from USAID’s American Schools and Hospitals Abroad Program for the upgrading of the Hebrew University Medical School Flow Cytometry laboratory. This study was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a JDRF-sponsored collaborative T1D research project. Organ Procurement Organizations (OPO) partnering with nPOD are listed at www.jdrfnpod.org/our-partners.php . O.Z. is a New York Stem Cell Foundation-Druckenmiller Fellow. M.S.-R. was supported by a postdoctoral fellowship from Novo Nordisk and A.H. by a fellowship from Mr. Alan Harper. We thank Norma Kidess-Bassir for excellent technical assistance, Donald K. Scott for the gift of rat glucokinase cDNA, Orr Spiegel for advice with statistical analysis, and Christian Broberger, Muli Ben-Sasson, and Ittai Ben-Porath for insightful discussions.

PY - 2014/1/7

Y1 - 2014/1/7

N2 - Summary β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.

AB - Summary β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.

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Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells

Abstract

Bibliographical note

Funding

UN SDGs

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