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ResearchIn-Press PreviewCell biologyMetabolism Open Access | 10.1172/JCI200951

Manganese availability determines hepatic insulin sensitivity by enhancing Akt activity

Jennifer R. Gamarra,1 Sei Higuchi,2 Timothy L. Yuan,1 Yuke Xie,1 Cong Liu,1 Niroshan Shanmugarajah,1 Hang Yang,1 Meredith O. Kelly,1 Sarah A. Hannou,3 Kathrin Schilling,4 Ana Navas-Acien,4 Eunhee Choi,5 Anum Glasgow,6 Inna I. Astapova,7 Mark A. Herman,7 and Rebecca A. Haeusler1

1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

Find articles by Glasgow, A. in: PubMed | Google Scholar

1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

Find articles by Herman, M. in: PubMed | Google Scholar |

1Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

2Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, Queens, United States of America

3Duke Molecular Physiology Institute, Duke University, Durham, United States of America

4Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States of America

5Department of Pathology and Cell Biology, Columbia University, New York, United States of America

6Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States of America

7Department of Medicine, Baylor College of Medicine, Houston, United States of America

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Published October 14, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI200951.
Copyright © 2026, Gamarra et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 14, 2026 - Version history
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Abstract

Insulin signaling is a critical determinant of metabolic health, and impairments in insulin action contribute to the development of type 2 diabetes. The kinase Akt is a central mediator of insulin signaling and is required for insulin’s suppression of hepatic glucose output. Although the regulation of Akt by the insulin receptor-PI3K pathway is well understood, there are instances in which signaling downstream of Akt is dissociated from proximal insulin signaling, for example in insulin resistance. Nonetheless, little is known about PI3K-independent mechanisms of Akt regulation. Here, we discovered that hepatocyte manganese concentrations are a key determinant of PI3K-independent Akt function in vivo. We further demonstrated that manganese increases Akt’s catalytic efficiency, and quantitative phosphoproteomics revealed that manganese and insulin act additively to enhance Akt activity. Moreover, we uncovered that hepatic manganese concentrations fluctuate during fasting and feeding via carbohydrate-dependent transcriptional regulation of the manganese efflux transporter Slc30a10. This dynamic metal–signaling axis provides a mechanistic link between nutrient status and Akt activation, and suggests a molecular explanation for the glucose-lowering effects of manganese observed in humans. Our findings establish manganese as a physiologically regulated cofactor for Akt and position metal bioavailability as a previously unrecognized layer of insulin signaling control.

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  • Version 1 (October 14, 2026): In-Press Preview
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