Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2
Summary: 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 pr...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720305581 |
| _version_ | 1818283732238336000 |
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| author | Amber Lockridge Seokwon Jo Eric Gustafson Niklas Damberg Ramkumar Mohan Miranda Olson Juan E. Abrahante Emilyn U. Alejandro |
| author_facet | Amber Lockridge Seokwon Jo Eric Gustafson Niklas Damberg Ramkumar Mohan Miranda Olson Juan E. Abrahante Emilyn U. Alejandro |
| author_sort | Amber Lockridge |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-13T00:41:35Z |
| format | Article |
| id | doaj.art-c85a91f350514adc99fa3f058ddfc74f |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T00:41:35Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c85a91f350514adc99fa3f058ddfc74f2022-12-22T00:05:07ZengElsevierCell Reports2211-12472020-05-01315Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2Amber Lockridge0Seokwon Jo1Eric Gustafson2Niklas Damberg3Ramkumar Mohan4Miranda Olson5Juan E. Abrahante6Emilyn U. Alejandro7Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USAIntegrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USAIntegrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USAIntegrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USAIntegrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USAIntegrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USASupercomputing Institute, University of Minnesota Medical School, Minneapolis, MN, USAIntegrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124720305581 |
| spellingShingle | Amber Lockridge Seokwon Jo Eric Gustafson Niklas Damberg Ramkumar Mohan Miranda Olson Juan E. Abrahante Emilyn U. Alejandro Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2 Cell Reports |
| title | Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2 |
| title_full | Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2 |
| title_fullStr | Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2 |
| title_full_unstemmed | Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2 |
| title_short | Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2 |
| title_sort | islet o glcnacylation is required for lipid potentiation of insulin secretion through serca2 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720305581 |
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