Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis

Katrine D. Galsgaard; Marie Winther-Sørensen; Cathrine Ørskov; Hannelouise Kissow; Steen S. Poulsen; Hendrik Vilstrup; Cornelia Prehn; Jerzy Adamski; Sara L. Jepsen; Bolette Hartmann; Jenna Hunt; Maureen J Charron; Jens Pedersen; Nicolai J. Wewer Albrechtsen; Jens J. Holst

doi:10.1152/ajpendo.00198.2017

Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis

Katrine D. Galsgaard, Marie Winther-Sørensen, Cathrine Ørskov, Hannelouise Kissow, Steen S. Poulsen, Hendrik Vilstrup, Cornelia Prehn, Jerzy Adamski, Sara L. Jepsen, Bolette Hartmann, Jenna Hunt, Maureen J Charron, Jens Pedersen, Nicolai J. Wewer Albrechtsen, Jens J. Holst

37 Citations (Scopus)

Abstract

Glucagon secreted from the pancreatic alpha-cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolism by promoting ureagenesis. We hypothesized that disruption of glucagon receptor signaling would lead to an increased plasma concentration of amino acids, which in a feedback manner stimulates the secretion of glucagon, eventually associated with compensatory proliferation of the pancreatic alpha-cells. To address this, we performed plasma profiling of glucagon receptor knockout ( Gcgr-/-) mice and wild-type (WT) littermates using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, and tissue biopsies from the pancreas were analyzed for islet hormones and by histology. A principal component analysis of the plasma metabolome from Gcgr-/- and WT littermates indicated amino acids as the primary metabolic component distinguishing the two groups of mice. Apart from their hyperaminoacidemia, Gcgr-/- mice display hyperglucagonemia, increased pancreatic content of glucagon and somatostatin (but not insulin), and alpha-cell hyperplasia and hypertrophy compared with WT littermates. Incubating cultured α-TC1.9 cells with a mixture of amino acids (Vamin 1%) for 30 min and for up to 48 h led to increased glucagon concentrations (~6-fold) in the media and cell proliferation (~2-fold), respectively. In anesthetized mice, a glucagon receptor-specific antagonist (Novo Nordisk 25-2648, 100 mg/kg) reduced amino acid clearance. Our data support the notion that glucagon secretion and hepatic amino acid metabolism are linked in a close feedback loop, which operates independently of normal variations in glucose metabolism.

Original language	English
Journal	American Journal of Physiology: Endocrinology and Metabolism
Volume	314
Issue number	1
Pages (from-to)	E93-E103
ISSN	0193-1849
DOIs	https://doi.org/10.1152/ajpendo.00198.2017
Publication status	Published - Jan 2018

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Journal Article

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Galsgaard, K. D., Winther-Sørensen, M., Ørskov, C., Kissow, H., Poulsen, S. S., Vilstrup, H., Prehn, C., Adamski, J., Jepsen, S. L., Hartmann, B., Hunt, J., Charron, M. J., Pedersen, J., Albrechtsen, N. J. W., & Holst, J. J. (2018). Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis. American Journal of Physiology: Endocrinology and Metabolism, 314(1), E93-E103. https://doi.org/10.1152/ajpendo.00198.2017

Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis. / Galsgaard, Katrine D.; Winther-Sørensen, Marie ; Ørskov, Cathrine et al.
In: American Journal of Physiology: Endocrinology and Metabolism, Vol. 314, No. 1, 01.2018, p. E93-E103.

Research output: Contribution to journal › Journal article › Research › peer-review

Galsgaard, KD , Winther-Sørensen, M , Ørskov, C , Kissow, H , Poulsen, SS, Vilstrup, H, Prehn, C, Adamski, J, Jepsen, SL , Hartmann, B, Hunt, J, Charron, MJ, Pedersen, J , Albrechtsen, NJW & Holst, JJ 2018, 'Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis', American Journal of Physiology: Endocrinology and Metabolism, vol. 314, no. 1, pp. E93-E103. https://doi.org/10.1152/ajpendo.00198.2017

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abstract = "Glucagon secreted from the pancreatic alpha-cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolism by promoting ureagenesis. We hypothesized that disruption of glucagon receptor signaling would lead to an increased plasma concentration of amino acids, which in a feedback manner stimulates the secretion of glucagon, eventually associated with compensatory proliferation of the pancreatic alpha-cells. To address this, we performed plasma profiling of glucagon receptor knockout ( Gcgr-/-) mice and wild-type (WT) littermates using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, and tissue biopsies from the pancreas were analyzed for islet hormones and by histology. A principal component analysis of the plasma metabolome from Gcgr-/- and WT littermates indicated amino acids as the primary metabolic component distinguishing the two groups of mice. Apart from their hyperaminoacidemia, Gcgr-/- mice display hyperglucagonemia, increased pancreatic content of glucagon and somatostatin (but not insulin), and alpha-cell hyperplasia and hypertrophy compared with WT littermates. Incubating cultured α-TC1.9 cells with a mixture of amino acids (Vamin 1%) for 30 min and for up to 48 h led to increased glucagon concentrations (~6-fold) in the media and cell proliferation (~2-fold), respectively. In anesthetized mice, a glucagon receptor-specific antagonist (Novo Nordisk 25-2648, 100 mg/kg) reduced amino acid clearance. Our data support the notion that glucagon secretion and hepatic amino acid metabolism are linked in a close feedback loop, which operates independently of normal variations in glucose metabolism.",

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AU - Ørskov, Cathrine

AU - Kissow, Hannelouise

AU - Poulsen, Steen S.

AU - Vilstrup, Hendrik

AU - Prehn, Cornelia

AU - Adamski, Jerzy

AU - Jepsen, Sara L.

AU - Hartmann, Bolette

AU - Hunt, Jenna

AU - Charron, Maureen J

AU - Pedersen, Jens

AU - Albrechtsen, Nicolai J. Wewer

AU - Holst, Jens J.

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N2 - Glucagon secreted from the pancreatic alpha-cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolism by promoting ureagenesis. We hypothesized that disruption of glucagon receptor signaling would lead to an increased plasma concentration of amino acids, which in a feedback manner stimulates the secretion of glucagon, eventually associated with compensatory proliferation of the pancreatic alpha-cells. To address this, we performed plasma profiling of glucagon receptor knockout ( Gcgr-/-) mice and wild-type (WT) littermates using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, and tissue biopsies from the pancreas were analyzed for islet hormones and by histology. A principal component analysis of the plasma metabolome from Gcgr-/- and WT littermates indicated amino acids as the primary metabolic component distinguishing the two groups of mice. Apart from their hyperaminoacidemia, Gcgr-/- mice display hyperglucagonemia, increased pancreatic content of glucagon and somatostatin (but not insulin), and alpha-cell hyperplasia and hypertrophy compared with WT littermates. Incubating cultured α-TC1.9 cells with a mixture of amino acids (Vamin 1%) for 30 min and for up to 48 h led to increased glucagon concentrations (~6-fold) in the media and cell proliferation (~2-fold), respectively. In anesthetized mice, a glucagon receptor-specific antagonist (Novo Nordisk 25-2648, 100 mg/kg) reduced amino acid clearance. Our data support the notion that glucagon secretion and hepatic amino acid metabolism are linked in a close feedback loop, which operates independently of normal variations in glucose metabolism.

AB - Glucagon secreted from the pancreatic alpha-cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolism by promoting ureagenesis. We hypothesized that disruption of glucagon receptor signaling would lead to an increased plasma concentration of amino acids, which in a feedback manner stimulates the secretion of glucagon, eventually associated with compensatory proliferation of the pancreatic alpha-cells. To address this, we performed plasma profiling of glucagon receptor knockout ( Gcgr-/-) mice and wild-type (WT) littermates using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, and tissue biopsies from the pancreas were analyzed for islet hormones and by histology. A principal component analysis of the plasma metabolome from Gcgr-/- and WT littermates indicated amino acids as the primary metabolic component distinguishing the two groups of mice. Apart from their hyperaminoacidemia, Gcgr-/- mice display hyperglucagonemia, increased pancreatic content of glucagon and somatostatin (but not insulin), and alpha-cell hyperplasia and hypertrophy compared with WT littermates. Incubating cultured α-TC1.9 cells with a mixture of amino acids (Vamin 1%) for 30 min and for up to 48 h led to increased glucagon concentrations (~6-fold) in the media and cell proliferation (~2-fold), respectively. In anesthetized mice, a glucagon receptor-specific antagonist (Novo Nordisk 25-2648, 100 mg/kg) reduced amino acid clearance. Our data support the notion that glucagon secretion and hepatic amino acid metabolism are linked in a close feedback loop, which operates independently of normal variations in glucose metabolism.

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JF - American Journal of Physiology: Endocrinology and Metabolism

IS - 1

ER -

Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis

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