Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome

Lecoq, Anne-Lise; Stratakis, Constantine A.; Viengchareun, Say; Chaligné, Ronan; Tosca, Lucie; Deméocq, Vianney; Hage, Mirella; Berthon, Annabel; Faucz, Fábio R.; Hanna, Patrick; Boyer, Hadrien-Gaël; Servant, Nicolas; Salenave, Sylvie; Tachdjian, Gérard; Adam, Clovis; Benhamo, Vanessa; Clauser, Éric; Guiochon‐Mantel, Anne; Young, Jacques; Lombès, Marc; Bourdeau, Isabelle; Maiter, Dominique; Tabarin, Antoine; Bertherat, Jérôme; Lefebvre, Henri; Herder, Wouter W. de; Louiset, Estelle; Lacroix, André; Chanson, Philippe; Bouligand, Jérôme; Kamenický, Peter

doi:10.1172/jci.insight.92184

Cited by 45 publications

(17 citation statements)

References 42 publications

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“…An altered interplay between somatostatin and GHRH has been suggested [98] but not well documented. Recently, in analogy to food-dependent Cushing’s syndrome [99-101], a role for ectopic expression of the glucose-dependent insulinotropic polypeptide receptor ( GIPR ) in somatotroph adenomas for mediating the paradoxical GH response to OGTT has been evoked [88, 102]. We have recently shown that among 41 pituitary adenomas, all 10 samples from patients with paradoxical GH responses displayed ectopic GIPR expression [96].…”

Section: Ogtt In the Diagnosis Of Acromegalymentioning

confidence: 99%

Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions

Hage

Kamenický

Chanson³

2019

Neuroendocrinology

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The exact physiological basis of acute growth hormone (GH) suppression by oral glucose is not fully understood. Glucose-mediated increase in hypothalamic somatostatin seems to be the most plausible explanation. Attempts to better understand its underlying mechanisms are compromised by species disparities in the response of GH to glucose load. While in humans, glucose inhibits GH release, the acute elevation of circulating glucose levels in rats has either no effect on GH secretion or may be stimulatory. Likewise, chronic hyperglycemia alters GH release in both humans and rats nonetheless in opposite directions. Several factors influence nadir GH concentrations including, age, gender, body mass index, pubertal age, and the type of assay used. Besides the classical suppressive effects of glucose on GH release, a paradoxical GH increase to oral glucose may be observed in around one third of patients with acromegaly as well as in various other disorders. Though its pathophysiology is poorly characterized, an altered interplay between somatostatin and GH-releasing hormone has been suggested and a link with pituitary ectopic expression of glucose-dependent insulinotropic polypeptide receptor has been recently demonstrated. A better understanding of the dynamics mediating GH response to glucose may allow a more optimal use of the OGTT as a diagnostic tool in various conditions, especially acromegaly.

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Section: Ogtt In the Diagnosis Of Acromegalymentioning

confidence: 99%

Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions

Hage

Kamenický

Chanson³

2019

Neuroendocrinology

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“…Inactivation of ARMC5 does not appear to be associated with specific aberrant receptor phenotypes in BMAH as cortisol responses to upright posture, metoclopramide, and vasopressin were found in some mutated cases; however so far no patients with GIP-dependent BMAH were found to carry ARMC5 mutation, and this was also the case in our patient (46–48). According to a recent study, GIPR over-expression in BMAH occurs from a single allele of the GIPR gene, and in certain unilateral adenoma cases resulted from gene duplication and rearrangement; however such analysis was not performed on this patient's tissues (49).…”

Section: Discussionmentioning

confidence: 98%

Coexistence of Myelolipoma and Primary Bilateral Macronodular Adrenal Hyperplasia With GIP-Dependent Cushing's Syndrome

et al. 2019

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Introduction: Adrenal myelolipomas are usually isolated benign adrenal lesions, but can be adjacent to steroid-secreting adrenocortical tumors. We studied the aberrant regulation of cortisol secretion in a 61 year-old woman with combined bilateral myelolipomas and primary bilateral macronodular adrenal hyperplasia (BMAH) causing Cushing's syndrome. Materials and Methods: Cortisol response was measured during in vivo tests that transiently modulated the levels of ligands for potential aberrant receptors, including GIP. Response to medical therapies decreasing GIP was monitored. Expression of ACTH and of GIP receptors were examined in resected adrenal tissues by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Results: In vivo, cortisol increased in response to mixed meals (+353%), oral 75 g glucose (+71%), GIP infusion (+416%), and hLH IV (+243%). Suppression of GIP by pasireotide improved cortisol secretion but produced hyperglycemia. The left adrenal was predominantly composed of myelolipoma and strands of BMAH, while the right was mainly composed of BMAH with some foci of myelolipoma on pathology. No ACTH was detectable by immunohistochemistry in BMAH or myelolipomas tissue. Ectopic GIP receptor was confirmed by RT-PCR and immunohistochemistry in BMAH tissues but not in the myelolipomas. No germline mutations were identified in the ARMC5 gene of the patient's leucocyte DNA. Conclusion: This is the first report of interspersed myelolipoma and BMAH with GIP-dependent Cushing's syndrome. In contrast with the BMAH tissues, myelolipoma tissue did not express specific GIP receptors. The potential mechanisms responsible for the interspersed growth of those two lesions remain to be identified.

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“…In the CPAs, the duplicated 19q13.32 region was rearranged with other chromosome regions however these chromosome rearrangements did not result in gene fusion but instead placed the GIPR gene in a genomic environment near cis-acting regulatory regions favoring transcriptional activation. In the macronodular BAH sample, a duplication of 19q without chromosome rearrangement was identified (93).…”

Section: Macronodular Adrenocortical Hyperplasiamentioning

confidence: 96%

Molecular Genetic and Genomic Alterations in Cushing’s Syndrome and Primary Aldosteronism

2021

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The genetic alterations that cause the development of glucocorticoid and/or mineralocorticoid producing benign adrenocortical tumors and hyperplasias have largely been elucidated over the past two decades through advances in genomics. In benign aldosterone-producing adrenocortical tumors and hyperplasias, alteration of intracellular calcium signaling has been found to be significant in aldosterone hypersecretion, with causative defects including those in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. In benign cortisol-producing adrenocortical tumors and hyperplasias abnormal cyclic adenosine monophosphate-protein kinase A signaling has been found to play a central role in tumorigenesis, with pathogenic variants in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B being implicated. The role of this signaling pathway in the development of Cushing’s syndrome and adrenocortical tumors was initially discovered through the study of the underlying genetic defects causing the rare multiple endocrine neoplasia syndromes McCune-Albright syndrome and Carney complex with subsequent identification of defects in genes affecting the cyclic adenosine monophosphate-protein kinase A pathway in sporadic tumors. Additionally, germline pathogenic variants in ARMC5, a putative tumor suppressor, were found to be a cause of cortisol-producing primary bilateral macronodular adrenal hyperplasia. This review describes the genetic causes of benign cortisol- and aldosterone-producing adrenocortical tumors.

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Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome

Cited by 45 publications

References 42 publications

Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions

Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions

Coexistence of Myelolipoma and Primary Bilateral Macronodular Adrenal Hyperplasia With GIP-Dependent Cushing's Syndrome

Molecular Genetic and Genomic Alterations in Cushing’s Syndrome and Primary Aldosteronism

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