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Cell Metab. 2017 Jun 6;25(6):1362-1373.e5. doi: 10.1016/j.cmet.2017.05.011.

Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation.

Author information

1
Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
2
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
3
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
4
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
5
Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Health System, Ann Arbor, MI 48103, USA.
6
Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27701, USA.
7
REMD Biotherapeutics, Camarillo, CA 93012, USA.
8
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami, Miami, FL 33146, USA.
9
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
10
Amgen, Thousand Oaks, CA 91320, USA.
11
Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; VA Tennessee Valley Healthcare, Nashville, TN 37212, USA. Electronic address: al.powers@vanderbilt.edu.

Abstract

Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to α cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for α cell proliferation, we used transcriptomics/proteomics/metabolomics in three models of interrupted glucagon signaling and found that proliferation of mouse, zebrafish, and human α cells was mTOR and FoxP transcription factor dependent. Changes in hepatic amino acid (AA) catabolism gene expression predicted the observed increase in circulating AAs. Mimicking these AA levels stimulated α cell proliferation in a newly developed in vitro assay with L-glutamine being a critical AA. α cell expression of the AA transporter Slc38a5 was markedly increased in mice with interrupted glucagon signaling and played a role in α cell proliferation. These results indicate a hepatic α islet cell axis where glucagon regulates serum AA availability and AAs, especially L-glutamine, regulate α cell proliferation and mass via mTOR-dependent nutrient sensing.

KEYWORDS:

Slc38a5; alpha cell; amino acid; amino acid transport; glucagon; glucagon receptor; glutamine; liver; pancreatic islet; proliferation

PMID:
28591638
PMCID:
PMC5572896
DOI:
10.1016/j.cmet.2017.05.011
[Indexed for MEDLINE]
Free PMC Article

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