Glucagon cell hyperplasia and neoplasia: a recently recognized endocrine receptor disease

in Endocrine-Related Cancer
Authors:
Bence Sipos Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tubingen, Tübingen, Germany
ENETS Center of Excellence, University Hospital Tübingen, Tübingen, Germany

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https://orcid.org/0000-0002-7311-3343
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Günter Klöppel Department of Pathology, Technical University Munich, Munich, Germany

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Correspondence should be addressed to B Sipos: bence.sipos@med.uni-tuebingen.de

This paper is part of a themed collection celebrating the Discovery of Insulin and Glucagon. The Guest Editors for this collection were Günter Klöppel and Wouter de Herder.

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Glucagon cell hyperplasia and neoplasia (GCHN) is the name of an endocrine receptor disease, whose morphology was first described in 2006. Three years later, this rare disease was found to be to be caused by an inactivating mutation of the glucagon receptor (GCGR) gene. Functionally, the genetic defect mainly affects glucagon signaling in the liver with changes in the metabolism of glycogen, fatty acids and amino acids. Recent results of several studies in GCGR knockout mice suggested that elevated serum amino acid levels probably stimulate glucagon cell hyperplasia with subsequent transformation into glucagon cell neoplasia. This process leads over time to numerous small and some large pancreatic neuroendocrine tumors which are potentially malignant. Despite high glucagon serum levels, the patients develop no glucagonoma syndrome. In 2015, GCHN was identified as an autosomal recessive hereditary disorder.

Abstract

Glucagon cell hyperplasia and neoplasia (GCHN) is the name of an endocrine receptor disease, whose morphology was first described in 2006. Three years later, this rare disease was found to be to be caused by an inactivating mutation of the glucagon receptor (GCGR) gene. Functionally, the genetic defect mainly affects glucagon signaling in the liver with changes in the metabolism of glycogen, fatty acids and amino acids. Recent results of several studies in GCGR knockout mice suggested that elevated serum amino acid levels probably stimulate glucagon cell hyperplasia with subsequent transformation into glucagon cell neoplasia. This process leads over time to numerous small and some large pancreatic neuroendocrine tumors which are potentially malignant. Despite high glucagon serum levels, the patients develop no glucagonoma syndrome. In 2015, GCHN was identified as an autosomal recessive hereditary disorder.

Introduction

Glucagon cell hyperplasia and neoplasia (GCHN) of the endocrine pancreas is a rare disease, with only a few patients reported so far. Soon after its morphological description in 2006, its genetic background, an inactivating mutation of the glucagon receptor gene (GCGR), was found in 2009. Since this discovery coincided with an interest in inhibiting the glucagon receptor as a way to find a treatment for type 2 diabetes (Guzman et al. 2017), there were mouse models available and further developed, including GCGR knock-out mice (Gelling et al. 2003, for review see Yu 2018). According to these well-characterized mouse models, GCGR inactivation probably interrupts glucagon signaling in the liver, whereby the metabolism of glycogen, fatty acids and amino acids is disturbed. The net result of the altered function of the liver cells is hyperplastic changes of the glucagon cells of the pancreatic islets, followed by hyperglucagonemia and the development of multiple glucagon-producing neuroendocrine tumors.

History and histology

The first well-documented cases of GCHN were published in 2006 by Martin Anlauf and colleagues in an article on microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome (Anlauf et al. 2006). Among 37 cases of multiple pancreatic endocrine neoplasms were 4 patients who had no hormonal symptoms and showed no association with mutations in the von Hippel–Lindau (VHL) or multiple endocrine neoplasia 1 (MEN1) genes. Histology and immunohistochemistry revealed that the four pancreata contained a few neuroendocrine macrotumors and many unevenly distributed microtumors all expressing almost exclusively glucagon and only occasionally a pancreatic polypeptide cell. In addition, there were normal islets besides many big islets with glucagon cell hyperplasia (Fig. 1). The tumors showed a Ki67 index below 1%.

Figure 1
Figure 1

(A) Multiple hyperplastic islets and microtumors (×100, HE) that express predominantly glucagon (B). (C) Only single cells are insulin positive. (D) The physiologic distribution of glucagon (alpha) and insulin (beta) cells is completely abrogated (green – glucagon, red – insulin, bar marks 20 µm).

Citation: Endocrine-Related Cancer 30, 8; 10.1530/ERC-23-0032

In 2008, the first clinically well-characterized case of GCHN was described by the group of Run Yu at Cedars-Sinai Medical Center in Los Angeles (Yu et al. 2008). The patient was a 60-year-old woman with abdominal pain and sometimes mild hypoglycemia but without signs of a glucagonoma syndrome such as hyperglycemia, skin rash, stomatitis, weight loss or thromboembolism, although markedly elevated glucagon levels were detected. In the head of the pancreas, there was a 4 cm large neuroendocrine tumor associated with two microtumors. In the surrounding tissue, there was marked hyperplasia of the endocrine islets with the predominance of glucagon-expressing cells. The neuroendocrine tumor expressed no glucagon or pancreatic polypeptide. Yu and colleagues named the disorder ‘Mahvash’ disease after the patient’s first name (Yu 2018).

In 2009, Henopp et al. further characterized four patients (including the first three cases from the publication of Anlauf et al. 2006) and demonstrated in addition to multiple micro- and macro-neuroendocrine tumors with glucagon expression the presence of diffuse glucagon cell hyperplasia in the islets that increased with the size of the islets to the point that it eventually imperceptibly passed into glucagon cell microtumors (Henopp et al. 2009).

In the same year, the group of Yu (Zhou et al. 2009) sequenced the GCGR in the patient reported in 2008 and detected a homozygous point mutation (P86S, exon 4) in the extracellular domain. In vitro functional assays revealed that this mutation abrogated glucagon binding but not the localization of the receptor in the plasma membrane.

In 2015, we reported a series of six patients with GCHN (Sipos et al. 2015). Three of them harbored deleterious mutations in the GCGR gene, while the other cases revealed a wildtype GCGR gene by Sanger and pyrosequencing. The pancreatic changes of the mutation carriers were more pronounced in terms of the number and size of glucagon-positive tumors. This finding suggested that GCHN, as we called the disease (Sipos et al. 2015), seems to be caused by two different pathomechanisms, of which one is associated with a GCGR gene mutation, while the other is not and lacks so far any known genetic alteration or explanation. As to the inheritance of the GCGR mutation, we found an autosomal recessive trait in one index patient and his parents. We also detected lymph node micrometastases in one GCHN patient with wildtype GCGR, indicating that GCHN has the potential to metastasize (Sipos et al. 2015). In 2017, GCHN has been included in the WHO Classification of Tumours of Endocrine Organs in the chapter of inherited tumor syndromes (WHO 2018).

Clinical presentation and course

Patients are mostly middle-aged adults who present with non-specific symptoms such as abdominal pain, fatigue, diabetes or acute pancreatitis. Despite very high serum glucagon levels, none of the GCHN patients with GCGR mutations showed a glucagonoma syndrome, most probably owing to the receptor’s deficient signaling. The only reported patient with a glucagonoma syndrome harbored a wildtype GCGR (Otto et al. 2011, Sipos et al. 2015), a constellation that still needs explanation as to the underlying GCHN. Elevated amino acid levels were found in the only pediatric patient (Li et al. 2018) and in one adult patient (Larger et al. 2016) reported so far. The pancreatic neuroendocrine tumours (NET) can be visualized by somatostatin receptor imaging, since the glucagon-producing cells express the somatostatin receptor SSTR2 (Henopp et al. 2009).

GCHN follows a benign clinical course for most patients. However, follow-up of the patients is suggested, as the tumors have a metastatic potential. Glucagon serum level may serve as tumor marker for monitoring patients during surveillance. Some anecdotal GCHN cases with liver metastasis are known in the scientific community, but none of these cases has been published so far (Yu 2018).

Genetics and pathogenesis

GCHN in patients with mutated GCGR follows an autosomal recessive inheritance (Sipos et al. 2015). The GCGR gene is located on chromosome 17q25. The reported GCGR gene germline mutations are either homozygous GCGR sequence variants or two compound heterozygous variants leading to premature stop codons or most probably deficient protein expression (Table 1). The functional characterization of D63N, P86S, R225H, V368M point mutations revealed impaired receptor signaling function (Zhou et al. 2009, van der Velden et al. 2022).

Table 1

Characteristics of GCGR mutations in GCHN cases.

Mutation Exon Domain Function Method Patient Reference
R8STOP 2 First extracellular Loss, premature termination of translation In silico Female, 43 years Sipos et al. (2015)
IVS3-1G > T 4 splice site First extracellular Loss, premature termination of translation In silico More family members Tang & Yu (2016)
D63N 4 First extracellular Reduced glucagon binding, reduced G protein binding In vitro More family members Yu et al. (2016), van der Velden et al. (2022)
W83Lfs*35 4 First extracellular Loss, premature termination of translation In silico Male, 25 years Sipos et al. (2015)
P86S 4 First extracellular Reduced glucagon binding, reduced G protein binding In vitro Female, 65 years Zhou et al. (2009), van der Velden et al. (2022)
R225H 8 Beginning of extracellular loop 3 Reduced G protein binding In silico, in vitro Male, 58 years Sipos et al. (2015), van der Velden (2022)
IVS9-1G > A 9, splice site Second extracellular loop and part of the fifth transmembrane domain Missense translation of the sequence encoded by exons 10–13, and introduction of a stop codon after amino acid 327. In vitro Male, 51 years Larger et al. (2016)
Phe320del 11 Fifth transmembrane domain Probably altered G protein binding In vitro Female, 7 years Li et al. (2018)
Q327STOP 11 Third intracellular loop Loss, premature termination of translation In silico Female, 43 years Sipos et al. (2015)
V368M 12 Sixth transmembrane domain Reduced G protein binding In silico, in vitro Male, 58 years Sipos et al. (2015), Lin et al. (2020), van der Velden (2022)

The GCGR is expressed in humans predominantly in the liver. Its activation by glucagon which is mainly secreted in response to hypoglycemia and elevated amino acid serum levels (Janah et al. 2019, van der Velden et al. 2022) suppresses glycolysis and increases gluconeogenesis and glycogenolysis in hepatocytes. Glucagon also increases hepatic amino acid turnover and thus lowers postprandial serum amino acid levels. In addition, glucagon promotes increased beta-oxidation, decreased fatty acid synthesis and very-low-density lipoprotein (VLDL) release.

Of these glucagon effects, the disturbed amino acid metabolism plays the most important role in the development of GCHN, as several studies in GCGR knockout mice have shown (Solloway et al. 2015, Kim et al. 2019, Capozzi et al. 2022). Impaired glucagon signaling in the liver results in constantly elevated serum amino acid levels which stimulate the secretion and proliferation of glucagon cells, leading to hyperglucagonemia, glucagon cell hyperplasia and finally neuroendocrine tumors. This proliferative effect on glucagon cells is most probably mediated by amino acid transporters (e.g. slc38a5 in mice, slc38a4 in humans), which react to several amino acids, that were found to be elevated in GCHN. These amino acid transporters are coupled with downstream mechanistic targets of rapamycin signaling, which leads to glucagon cell proliferation, but not to an increase in glucagon secretion (Kim et al. 2017, 2019). Since the diagnosis of GCHN in humans was mostly made postoperatively, only few data on increased amino acid levels in GCHN patients are available. However, these data that come from the only pediatric patient and from one adult patient (Larger et al. 2016) suggest that the pathomechanisms of glucagon cell proliferation in mouse models and humans with an inactive GCGR are probably comparable.

Conclusions

GCHN is a receptor disease, in which changes in the glucagon cells follow a hyperplasia–neoplasia sequence. The molecular mechanisms underlying GCHN tumorigenesis are unique among the neuroendocrine tumors of the pancreas. The first step, the glucagon cell hyperplasia, has been well explained in recent years by the inactivating mutation of the GCGR gene that leads to disturbed glucagon signaling in the liver cells and elevated amino acid levels in the serum, with a stimulating effect on glucagon cell secretion and proliferation. The second step, the transformation of hyperplastic glucagon cells into neoplastic glucagon cells, has yet to be elucidated but might be explained by the activation of one of the driver genes in pancreatic neuroendocrine tumorigenesis. The proliferative activity and the metastatic potential of the neoplastic glucagon cells seem to be low. However, since only a small number of GCHN cases have been described and studied so far, future investigations with long-term follow-up in a larger number of GCHN cases will probably give new insights into the course and the spectrum of the disease. Of great interest in this respect is the question regarding the pathomechanism of GCHN cases with wildtype GCGR. As possible mechanisms can be hypothesized alterations in amino acid transporters, in downstream signaling or epigenetic modifications in GCGR.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • Anlauf M, Schlenger R, Perren A, Bauersfeld J, Koch CA, Dralle H, Raffel A, Knoefel WT, Weihe E, Ruszniewski P, et al.2006 Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. American Journal of Surgical Pathology 30 560574. (https://doi.org/10.1097/01.pas.0000194044.01104.25)

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    • Search Google Scholar
    • Export Citation
  • Capozzi ME, D'Alessio DA & & Campbell JE 2022 The past, present, and future physiology and pharmacology of glucagon. Cell Metabolism 34 16541674. (https://doi.org/10.1016/j.cmet.2022.10.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, Obici S, Tang B, Holst JJ, Fledelius C, et al.2003 Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice. Proceedings of the National Academy of Sciences of the United States of America 100 14381443. (https://doi.org/10.1073/pnas.0237106100)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guzman CB, Zhang XM, Liu R, Regev A, Shankar S, Garhyan P, Pillai SG, Kazda C, Chalasani N, & Hardy TA.2017 Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. Diabetes, Obesity and Metabolism 19 15211528. (https://doi.org/10.1111/dom.12958)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henopp T, Anlauf M, Schmitt A, Schlenger R, Zalatnai A, Couvelard A, Ruszniewski P, Schaps KP, Jonkers YM, Speel EJ, et al.2009 Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas. Journal of Clinical Endocrinology and Metabolism 94 213217. (https://doi.org/10.1210/jc.2008-1300)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Janah L, Kjeldsen S, Galsgaard KD, Winther-Sørensen M, Stojanovska E, Pedersen J, Knop FK, Holst JJ & & Wewer Albrechtsen NJ 2019 Glucagon receptor signaling and glucagon resistance. International Journal of Molecular Sciences 20 3314. (https://doi.org/10.3390/ijms20133314)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kim J, Dominguez Gutierrez G, Xin Y, Cavino K, Sung B, Sipos B, Kloeppel G, Gromada J & & Okamoto H 2019 Increased SLC38A4 amino acid transporter expression in human pancreatic α-cells after glucagon receptor inhibition. Endocrinology 160 979988. (https://doi.org/10.1210/en.2019-00022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kim J, Okamoto H, Huang Z, Anguiano G, Chen S, Liu Q, Cavino K, Xin Y, Na E, Hamid R, et al.2017 Amino acid transporter Slc38a5 controls glucagon receptor inhibition-induced pancreatic α cell hyperplasia in mice. Cell Metabolism 25 13481361.e8. (https://doi.org/10.1016/j.cmet.2017.05.006)

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    • Search Google Scholar
    • Export Citation
  • Larger E, Wewer Albrechtsen NJ, Hansen LH, Gelling RW, Capeau J, Deacon CF, Madsen OD, Yakushiji F, De Meyts P, Holst JJ, et al.2016 Pancreatic α-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation. Endocrinology, Diabetes and Metabolism Case Reports 2016 160081. (https://doi.org/10.1530/EDM-16-0081)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li H, Zhao L, Singh R, Ham JN, Fadoju DO, Bean LJH, Zhang Y, Xu Y, Xu HE & & Gambello MJ 2018 The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine. Molecular Genetics and Metabolism Reports 17 4652. (https://doi.org/10.1016/j.ymgmr.2018.09.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin G, Liu Q, Dai A, Cai X, Zhou Q, Wang X, Chen Y, Ye C, Li J, Yang D & Wang MW 2020 Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders. Biochemical Journal47725812594. (https://doi.org/10.1042/bcj20200235)

    • PubMed
    • Export Citation
  • Otto AI, Marschalko M, Zalatnai A, Toth M, Kovacs J, Harsing J, Tulassay Z & & Karpati S 2011 Glucagon cell adenomatosis: a new entity associated with necrolytic migratory erythema and glucagonoma syndrome. Journal of the American Academy of Dermatology 65 458459. (https://doi.org/10.1016/j.jaad.2010.04.010)

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    • Search Google Scholar
    • Export Citation
  • Sipos B, Sperveslage J, Anlauf M, Hoffmeister M, Henopp T, Buch S, Hampe J, Weber A, Hammel P, Couvelard A, et al.2015 Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. Journal of Clinical Endocrinology and Metabolism 100 E783E788. (https://doi.org/10.1210/jc.2014-4405)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Solloway MJ, Madjidi A, Gu C, Eastham-Anderson J, Clarke HJ, Kljavin N, Zavala-Solorio J, Kates L, Friedman B, Brauer M, et al.2015 Glucagon couples hepatic amino acid catabolism to mTOR-dependent regulation of α-cell Mass. Cell Reports 12 495510. (https://doi.org/10.1016/j.celrep.2015.06.034)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tang L & & Yu R 2016 A novel hereditary pancreatic neuroendocrine tumor syndrome associated with biallelic inactivation of the glucagon receptor. Neuroendocrinology 103(Suppl 1) abstract B11. (https://doi.org/10.1159/000448725)

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    • Search Google Scholar
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  • van der Velden WJC, Lindquist P, Madsen JS, Stassen RHMJ, Wewer Albrechtsen NJ, Holst JJ, Hauser AS & & Rosenkilde MM 2022 Molecular and in vivo phenotyping of missense variants of the human glucagon receptor. Journal of Biological Chemistry 298 101413. (https://doi.org/10.1016/j.jbc.2021.101413)

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    • Search Google Scholar
    • Export Citation
  • WHO Classification of Tumours of Endocrine Organs 2018 WHO/IARC Classification of Tumours, 4th ed. Eds. Lloyd RV, , Osamura RY, , Klöppel G, , Rosai J, & Yu R. Lyon, France: IARC Publications.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu R, Nissen NN, Dhall D & & Heaney AP 2008 Nesidioblastosis and hyperplasia of alpha cells, microglucagonoma, and nonfunctioning islet cell tumor of the pancreas: review of the literature. Pancreas 36 428431. (https://doi.org/10.1097/MPA.0b013e31815ceb23)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu R, Zhou C & Chen CR 2016 Characterization and rescue of a pathogenic D63N mutant human glucagon receptor that causes a pancreatic neuroendocrine tumor syndrome (Mahvash disease). Neuroendocrinology 103(Suppl 1) abstract B13. (https://doi.org/10.1159/000448725)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu R 2018 Mahvash disease: 10 years after discovery. Pancreas 47 511515. (https://doi.org/10.1097/mpa.0000000000001044)

  • Zhou C, Dhall D, Nissen NN, Chen CR & & Yu R 2009 Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor. Pancreas 38 941946. (https://doi.org/10.1097/MPA.0b013e3181b2bb03)

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  • Figure 1

    (A) Multiple hyperplastic islets and microtumors (×100, HE) that express predominantly glucagon (B). (C) Only single cells are insulin positive. (D) The physiologic distribution of glucagon (alpha) and insulin (beta) cells is completely abrogated (green – glucagon, red – insulin, bar marks 20 µm).

  • Anlauf M, Schlenger R, Perren A, Bauersfeld J, Koch CA, Dralle H, Raffel A, Knoefel WT, Weihe E, Ruszniewski P, et al.2006 Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. American Journal of Surgical Pathology 30 560574. (https://doi.org/10.1097/01.pas.0000194044.01104.25)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Capozzi ME, D'Alessio DA & & Campbell JE 2022 The past, present, and future physiology and pharmacology of glucagon. Cell Metabolism 34 16541674. (https://doi.org/10.1016/j.cmet.2022.10.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, Obici S, Tang B, Holst JJ, Fledelius C, et al.2003 Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice. Proceedings of the National Academy of Sciences of the United States of America 100 14381443. (https://doi.org/10.1073/pnas.0237106100)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guzman CB, Zhang XM, Liu R, Regev A, Shankar S, Garhyan P, Pillai SG, Kazda C, Chalasani N, & Hardy TA.2017 Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. Diabetes, Obesity and Metabolism 19 15211528. (https://doi.org/10.1111/dom.12958)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Henopp T, Anlauf M, Schmitt A, Schlenger R, Zalatnai A, Couvelard A, Ruszniewski P, Schaps KP, Jonkers YM, Speel EJ, et al.2009 Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas. Journal of Clinical Endocrinology and Metabolism 94 213217. (https://doi.org/10.1210/jc.2008-1300)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Janah L, Kjeldsen S, Galsgaard KD, Winther-Sørensen M, Stojanovska E, Pedersen J, Knop FK, Holst JJ & & Wewer Albrechtsen NJ 2019 Glucagon receptor signaling and glucagon resistance. International Journal of Molecular Sciences 20 3314. (https://doi.org/10.3390/ijms20133314)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kim J, Dominguez Gutierrez G, Xin Y, Cavino K, Sung B, Sipos B, Kloeppel G, Gromada J & & Okamoto H 2019 Increased SLC38A4 amino acid transporter expression in human pancreatic α-cells after glucagon receptor inhibition. Endocrinology 160 979988. (https://doi.org/10.1210/en.2019-00022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kim J, Okamoto H, Huang Z, Anguiano G, Chen S, Liu Q, Cavino K, Xin Y, Na E, Hamid R, et al.2017 Amino acid transporter Slc38a5 controls glucagon receptor inhibition-induced pancreatic α cell hyperplasia in mice. Cell Metabolism 25 13481361.e8. (https://doi.org/10.1016/j.cmet.2017.05.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Larger E, Wewer Albrechtsen NJ, Hansen LH, Gelling RW, Capeau J, Deacon CF, Madsen OD, Yakushiji F, De Meyts P, Holst JJ, et al.2016 Pancreatic α-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation. Endocrinology, Diabetes and Metabolism Case Reports 2016 160081. (https://doi.org/10.1530/EDM-16-0081)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li H, Zhao L, Singh R, Ham JN, Fadoju DO, Bean LJH, Zhang Y, Xu Y, Xu HE & & Gambello MJ 2018 The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine. Molecular Genetics and Metabolism Reports 17 4652. (https://doi.org/10.1016/j.ymgmr.2018.09.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin G, Liu Q, Dai A, Cai X, Zhou Q, Wang X, Chen Y, Ye C, Li J, Yang D & Wang MW 2020 Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders. Biochemical Journal47725812594. (https://doi.org/10.1042/bcj20200235)

    • PubMed
    • Export Citation
  • Otto AI, Marschalko M, Zalatnai A, Toth M, Kovacs J, Harsing J, Tulassay Z & & Karpati S 2011 Glucagon cell adenomatosis: a new entity associated with necrolytic migratory erythema and glucagonoma syndrome. Journal of the American Academy of Dermatology 65 458459. (https://doi.org/10.1016/j.jaad.2010.04.010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sipos B, Sperveslage J, Anlauf M, Hoffmeister M, Henopp T, Buch S, Hampe J, Weber A, Hammel P, Couvelard A, et al.2015 Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. Journal of Clinical Endocrinology and Metabolism 100 E783E788. (https://doi.org/10.1210/jc.2014-4405)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Solloway MJ, Madjidi A, Gu C, Eastham-Anderson J, Clarke HJ, Kljavin N, Zavala-Solorio J, Kates L, Friedman B, Brauer M, et al.2015 Glucagon couples hepatic amino acid catabolism to mTOR-dependent regulation of α-cell Mass. Cell Reports 12 495510. (https://doi.org/10.1016/j.celrep.2015.06.034)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tang L & & Yu R 2016 A novel hereditary pancreatic neuroendocrine tumor syndrome associated with biallelic inactivation of the glucagon receptor. Neuroendocrinology 103(Suppl 1) abstract B11. (https://doi.org/10.1159/000448725)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • van der Velden WJC, Lindquist P, Madsen JS, Stassen RHMJ, Wewer Albrechtsen NJ, Holst JJ, Hauser AS & & Rosenkilde MM 2022 Molecular and in vivo phenotyping of missense variants of the human glucagon receptor. Journal of Biological Chemistry 298 101413. (https://doi.org/10.1016/j.jbc.2021.101413)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • WHO Classification of Tumours of Endocrine Organs 2018 WHO/IARC Classification of Tumours, 4th ed. Eds. Lloyd RV, , Osamura RY, , Klöppel G, , Rosai J, & Yu R. Lyon, France: IARC Publications.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu R, Nissen NN, Dhall D & & Heaney AP 2008 Nesidioblastosis and hyperplasia of alpha cells, microglucagonoma, and nonfunctioning islet cell tumor of the pancreas: review of the literature. Pancreas 36 428431. (https://doi.org/10.1097/MPA.0b013e31815ceb23)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu R, Zhou C & Chen CR 2016 Characterization and rescue of a pathogenic D63N mutant human glucagon receptor that causes a pancreatic neuroendocrine tumor syndrome (Mahvash disease). Neuroendocrinology 103(Suppl 1) abstract B13. (https://doi.org/10.1159/000448725)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu R 2018 Mahvash disease: 10 years after discovery. Pancreas 47 511515. (https://doi.org/10.1097/mpa.0000000000001044)

  • Zhou C, Dhall D, Nissen NN, Chen CR & & Yu R 2009 Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor. Pancreas 38 941946. (https://doi.org/10.1097/MPA.0b013e3181b2bb03)

    • PubMed
    • Search Google Scholar
    • Export Citation