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

127 Citations (Scopus)

Abstract

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.

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
Publication status	Published - 7 Jan 2014

Keywords

Animals
Biomarkers
Calcineurin
Cell Death
Cell Proliferation
Congenital Hyperinsulinism
DNA Breaks, Double-Stranded
Diabetes Mellitus, Type 2
Disease Models, Animal
Enzyme Activation
Enzyme Induction
Fasting
Glucagon-Like Peptide 1
Glucokinase
Glucose
Humans
Insulin-Secreting Cells
Membrane Potentials
Mice
Transgenes
Tumor Suppressor Protein p53

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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

Tornovsky-Babeay, Sharona ; Dadon, Daniela ; Ziv, Oren ; Tzipilevich, Elhanan ; Kadosh, Tehila ; Schyr-Ben Haroush, Rachel ; Hija, Ayat ; Stolovich-Rain, Miri ; Furth-Lavi, Judith ; Granot, Zvi ; Porat, Shay ; Philipson, Louis H ; Herold, Kevan C ; Bhatti, Tricia R ; Stanley, Charles ; Ashcroft, Frances M ; In 'T Veld, Peter ; Saada, Ann ; Magnuson, Mark A ; Glaser, Benjamin ; Dor, Yuval. / Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells. In: Cell Metabolism. 2014 ; Vol. 19, No. 1. pp. 109-121.

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

abstract = "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.",

keywords = "Animals, Biomarkers, Calcineurin, Cell Death, Cell Proliferation, Congenital Hyperinsulinism, DNA Breaks, Double-Stranded, Diabetes Mellitus, Type 2, Disease Models, Animal, Enzyme Activation, Enzyme Induction, Fasting, Glucagon-Like Peptide 1, Glucokinase, Glucose, Humans, Insulin-Secreting Cells, Membrane Potentials, Mice, Transgenes, Tumor Suppressor Protein p53",

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",

year = "2014",

month = jan,

day = "7",

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

language = "English",

volume = "19",

pages = "109--121",

journal = "Cell Metabolism",

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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

Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells. / Tornovsky-Babeay, Sharona; Dadon, Daniela; Ziv, Oren; Tzipilevich, Elhanan; Kadosh, Tehila; Schyr-Ben Haroush, Rachel; Hija, Ayat; Stolovich-Rain, Miri; Furth-Lavi, Judith; Granot, Zvi; Porat, Shay; Philipson, Louis H; Herold, Kevan C; Bhatti, Tricia R; Stanley, Charles; Ashcroft, Frances M; In 'T Veld, Peter; Saada, Ann; Magnuson, Mark A; Glaser, Benjamin; Dor, Yuval.

In: Cell Metabolism, Vol. 19, No. 1, 07.01.2014, p. 109-121.

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

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

PY - 2014/1/7

Y1 - 2014/1/7

N2 - 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 - 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.

KW - Animals

KW - Biomarkers

KW - Calcineurin

KW - Cell Death

KW - Cell Proliferation

KW - Congenital Hyperinsulinism

KW - DNA Breaks, Double-Stranded

KW - Diabetes Mellitus, Type 2

KW - Disease Models, Animal

KW - Enzyme Activation

KW - Enzyme Induction

KW - Fasting

KW - Glucagon-Like Peptide 1

KW - Glucokinase

KW - Glucose

KW - Humans

KW - Insulin-Secreting Cells

KW - Membrane Potentials

KW - Mice

KW - Transgenes

KW - Tumor Suppressor Protein p53

U2 - 10.1016/j.cmet.2013.11.007

DO - 10.1016/j.cmet.2013.11.007

M3 - Article

C2 - 24332968

VL - 19

SP - 109

EP - 121

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 1

ER -

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

Abstract

Keywords

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