Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2

Amber Lockridge; Seokwon Jo; Eric Gustafson; Niklas Damberg; Ramkumar Mohan; Miranda Olson; Juan E. Abrahante; Emilyn U. Alejandro

doi:10.1016/j.celrep.2020.107609

Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2

Amber Lockridge, Seokwon Jo, Eric Gustafson, Niklas Damberg, Ramkumar Mohan, Miranda Olson, Juan E. Abrahante, Emilyn U. Alejandro

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

20 Scopus citations

Abstract

During early obesity, pancreatic β cells compensate for increased metabolic demand through a transient phase of insulin hypersecretion that stabilizes blood glucose and forestalls diabetic progression. We find evidence that β cell O-GlcNAcylation, a nutrient-responsive post-translational protein modification regulated by O-GlcNAc transferase (OGT), is critical for coupling hyperlipidemia to β cell functional adaptation during this compensatory prediabetic phase. In mice, islet O-GlcNAcylation rises and falls in tandem with the timeline of secretory potentiation during high-fat feeding while genetic models of β-cell-specific OGT loss abolish hyperinsulinemic responses to lipids, in vivo and in vitro. We identify the endoplasmic reticulum (ER) Ca²⁺ ATPase SERCA2 as a β cell O-GlcNAcylated protein in mice and humans that is able to rescue palmitate-stimulated insulin secretion through pharmacological activation. This study reveals an important physiological role for β cell O-GlcNAcylation in sensing and responding to obesity, with therapeutic implications for managing the relationship between type 2 diabetes and its most common risk factor.

Original language	English (US)
Article number	107609
Journal	Cell reports
Volume	31
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2020.107609
State	Published - May 5 2020

Bibliographical note

Funding Information:
We thank Drs. David Bernlohr, Ernesto Bernal-Mizrachi, James D. Johnson, Alessandro Bartolomucci, and Robert Sorenson for feedback and discussion and Dr. Ron Regal for consultation on the analysis of human islet data. We thank Mr. Tom McBrien, Daniel Baumann, Brian Akhaphong, Ms. Kinsley Kehlenbeck, and Alicia Wong for technical support. Microscope and imaging support were provided by the University of Minnesota Imaging Center and the Department of Integrative Biology and Physiology. This work was supported by National Institutes of Health grant NIDDK ( K01-DK-103823 , R21-DK-112144 , R03-DK114465 , and R01 DK115720 to E.U.A. and 1F31DK113694 to A.L.). Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH grant no. 2UC4DK098085 .

Funding Information:
We thank Drs. David Bernlohr, Ernesto Bernal-Mizrachi, James D. Johnson, Alessandro Bartolomucci, and Robert Sorenson for feedback and discussion and Dr. Ron Regal for consultation on the analysis of human islet data. We thank Mr. Tom McBrien, Daniel Baumann, Brian Akhaphong, Ms. Kinsley Kehlenbeck, and Alicia Wong for technical support. Microscope and imaging support were provided by the University of Minnesota Imaging Center and the Department of Integrative Biology and Physiology. This work was supported by National Institutes of Health grant NIDDK (K01-DK-103823, R21-DK-112144, R03-DK114465, and R01 DK115720 to E.U.A. and 1F31DK113694 to A.L.). Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH grant no. 2UC4DK098085. Developed the Study, A.L.; Designed Experiments, Generated and Analyzed Data, Assisted with Manuscript Preparation, and Approved the Final Version, A.L. S.J. E.G. N.D. R.M. M.O. J.E.A. and E.U.A.; Interpreted the Data and Wrote and Edited the Manuscript, A.L. E.G. and E.U.A.; Analyzed Data Involving RNA-Seq, J.E.A.; Conceived the Study and in Charge of Overall Direction and Guarantor of This Work, E.U.A. The authors declare no conflicts of interest.

Publisher Copyright:
© 2020 The Author(s)

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

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@article{d358e5c4be6f40a2a01ee4ee348c4ddf,

title = "Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2",

abstract = "During early obesity, pancreatic β cells compensate for increased metabolic demand through a transient phase of insulin hypersecretion that stabilizes blood glucose and forestalls diabetic progression. We find evidence that β cell O-GlcNAcylation, a nutrient-responsive post-translational protein modification regulated by O-GlcNAc transferase (OGT), is critical for coupling hyperlipidemia to β cell functional adaptation during this compensatory prediabetic phase. In mice, islet O-GlcNAcylation rises and falls in tandem with the timeline of secretory potentiation during high-fat feeding while genetic models of β-cell-specific OGT loss abolish hyperinsulinemic responses to lipids, in vivo and in vitro. We identify the endoplasmic reticulum (ER) Ca2+ ATPase SERCA2 as a β cell O-GlcNAcylated protein in mice and humans that is able to rescue palmitate-stimulated insulin secretion through pharmacological activation. This study reveals an important physiological role for β cell O-GlcNAcylation in sensing and responding to obesity, with therapeutic implications for managing the relationship between type 2 diabetes and its most common risk factor.",

author = "Amber Lockridge and Seokwon Jo and Eric Gustafson and Niklas Damberg and Ramkumar Mohan and Miranda Olson and Abrahante, {Juan E.} and Alejandro, {Emilyn U.}",

note = "Funding Information: We thank Drs. David Bernlohr, Ernesto Bernal-Mizrachi, James D. Johnson, Alessandro Bartolomucci, and Robert Sorenson for feedback and discussion and Dr. Ron Regal for consultation on the analysis of human islet data. We thank Mr. Tom McBrien, Daniel Baumann, Brian Akhaphong, Ms. Kinsley Kehlenbeck, and Alicia Wong for technical support. Microscope and imaging support were provided by the University of Minnesota Imaging Center and the Department of Integrative Biology and Physiology. This work was supported by National Institutes of Health grant NIDDK ( K01-DK-103823 , R21-DK-112144 , R03-DK114465 , and R01 DK115720 to E.U.A. and 1F31DK113694 to A.L.). Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH grant no. 2UC4DK098085 . Funding Information: We thank Drs. David Bernlohr, Ernesto Bernal-Mizrachi, James D. Johnson, Alessandro Bartolomucci, and Robert Sorenson for feedback and discussion and Dr. Ron Regal for consultation on the analysis of human islet data. We thank Mr. Tom McBrien, Daniel Baumann, Brian Akhaphong, Ms. Kinsley Kehlenbeck, and Alicia Wong for technical support. Microscope and imaging support were provided by the University of Minnesota Imaging Center and the Department of Integrative Biology and Physiology. This work was supported by National Institutes of Health grant NIDDK (K01-DK-103823, R21-DK-112144, R03-DK114465, and R01 DK115720 to E.U.A. and 1F31DK113694 to A.L.). Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH grant no. 2UC4DK098085. Developed the Study, A.L.; Designed Experiments, Generated and Analyzed Data, Assisted with Manuscript Preparation, and Approved the Final Version, A.L. S.J. E.G. N.D. R.M. M.O. J.E.A. and E.U.A.; Interpreted the Data and Wrote and Edited the Manuscript, A.L. E.G. and E.U.A.; Analyzed Data Involving RNA-Seq, J.E.A.; Conceived the Study and in Charge of Overall Direction and Guarantor of This Work, E.U.A. The authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2020 The Author(s) Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = may,

day = "5",

doi = "10.1016/j.celrep.2020.107609",

language = "English (US)",

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T1 - Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2

AU - Lockridge, Amber

AU - Jo, Seokwon

AU - Gustafson, Eric

AU - Damberg, Niklas

AU - Mohan, Ramkumar

AU - Olson, Miranda

AU - Abrahante, Juan E.

AU - Alejandro, Emilyn U.

N1 - Funding Information: We thank Drs. David Bernlohr, Ernesto Bernal-Mizrachi, James D. Johnson, Alessandro Bartolomucci, and Robert Sorenson for feedback and discussion and Dr. Ron Regal for consultation on the analysis of human islet data. We thank Mr. Tom McBrien, Daniel Baumann, Brian Akhaphong, Ms. Kinsley Kehlenbeck, and Alicia Wong for technical support. Microscope and imaging support were provided by the University of Minnesota Imaging Center and the Department of Integrative Biology and Physiology. This work was supported by National Institutes of Health grant NIDDK ( K01-DK-103823 , R21-DK-112144 , R03-DK114465 , and R01 DK115720 to E.U.A. and 1F31DK113694 to A.L.). Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH grant no. 2UC4DK098085 . Funding Information: We thank Drs. David Bernlohr, Ernesto Bernal-Mizrachi, James D. Johnson, Alessandro Bartolomucci, and Robert Sorenson for feedback and discussion and Dr. Ron Regal for consultation on the analysis of human islet data. We thank Mr. Tom McBrien, Daniel Baumann, Brian Akhaphong, Ms. Kinsley Kehlenbeck, and Alicia Wong for technical support. Microscope and imaging support were provided by the University of Minnesota Imaging Center and the Department of Integrative Biology and Physiology. This work was supported by National Institutes of Health grant NIDDK (K01-DK-103823, R21-DK-112144, R03-DK114465, and R01 DK115720 to E.U.A. and 1F31DK113694 to A.L.). Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH grant no. 2UC4DK098085. Developed the Study, A.L.; Designed Experiments, Generated and Analyzed Data, Assisted with Manuscript Preparation, and Approved the Final Version, A.L. S.J. E.G. N.D. R.M. M.O. J.E.A. and E.U.A.; Interpreted the Data and Wrote and Edited the Manuscript, A.L. E.G. and E.U.A.; Analyzed Data Involving RNA-Seq, J.E.A.; Conceived the Study and in Charge of Overall Direction and Guarantor of This Work, E.U.A. The authors declare no conflicts of interest. Publisher Copyright: © 2020 The Author(s) Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/5/5

Y1 - 2020/5/5

N2 - During early obesity, pancreatic β cells compensate for increased metabolic demand through a transient phase of insulin hypersecretion that stabilizes blood glucose and forestalls diabetic progression. We find evidence that β cell O-GlcNAcylation, a nutrient-responsive post-translational protein modification regulated by O-GlcNAc transferase (OGT), is critical for coupling hyperlipidemia to β cell functional adaptation during this compensatory prediabetic phase. In mice, islet O-GlcNAcylation rises and falls in tandem with the timeline of secretory potentiation during high-fat feeding while genetic models of β-cell-specific OGT loss abolish hyperinsulinemic responses to lipids, in vivo and in vitro. We identify the endoplasmic reticulum (ER) Ca2+ ATPase SERCA2 as a β cell O-GlcNAcylated protein in mice and humans that is able to rescue palmitate-stimulated insulin secretion through pharmacological activation. This study reveals an important physiological role for β cell O-GlcNAcylation in sensing and responding to obesity, with therapeutic implications for managing the relationship between type 2 diabetes and its most common risk factor.

AB - During early obesity, pancreatic β cells compensate for increased metabolic demand through a transient phase of insulin hypersecretion that stabilizes blood glucose and forestalls diabetic progression. We find evidence that β cell O-GlcNAcylation, a nutrient-responsive post-translational protein modification regulated by O-GlcNAc transferase (OGT), is critical for coupling hyperlipidemia to β cell functional adaptation during this compensatory prediabetic phase. In mice, islet O-GlcNAcylation rises and falls in tandem with the timeline of secretory potentiation during high-fat feeding while genetic models of β-cell-specific OGT loss abolish hyperinsulinemic responses to lipids, in vivo and in vitro. We identify the endoplasmic reticulum (ER) Ca2+ ATPase SERCA2 as a β cell O-GlcNAcylated protein in mice and humans that is able to rescue palmitate-stimulated insulin secretion through pharmacological activation. This study reveals an important physiological role for β cell O-GlcNAcylation in sensing and responding to obesity, with therapeutic implications for managing the relationship between type 2 diabetes and its most common risk factor.

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Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2

Abstract

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Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2

Abstract

Bibliographical note

UN SDGs

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Light Microscopy

Nikon C2 Upright Spectral Confocal and Widefield Imaging System

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