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Adrenocortical Overexpression of Gastric Inhibitory Polypeptide Receptor Underlies Food-Dependent Cushing’s Syndrome¹

Division of Endocrinology and Department of Medicine, Research Center, Campus Hôtel-Dieu, Centre Hospitalier de l’Université de Montréal, Montreal, Canada H2W 1T8; and the Department of Internal Medicine, University Hospital Rotterdam (W.W.D.H.), Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: André Lacroix, M.D., Division of Endocrinology, Research Center, Pavillon Hôtel-Dieu, Centre Hospitalier de l’Université de Montréal, 3850 St. Urbain Street, Montreal, Quebec, Canada H2W 1T8. E-mail: lacroixa{at}ere.umontreal.ca

	Abstract

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Abnormal responsiveness of adrenocortical cells to gastric inhibitory polypeptide (GIP) in food-dependent Cushing’s syndrome suggested that adrenal expression of ectopic, overexpressed, or mutated GIP receptor (GIPR) underlies this syndrome. The expression of GIPR was studied by RT-PCR in human adrenal tissues from two patients with GIP-dependent Cushing’s syndrome (adenoma, bilateral hyperplasia), five fetal or adult controls, one patient with Cushing’s disease, and four patients with non-food-dependent cortisol-secreting adenomas or bilateral hyperplasias and compared to that in normal pancreas. Hybridization of the RT-PCR-amplified ribonucleic acids with the human GIPR complementary DNA showed an overexpression of GIPR in the adrenals of the two GIP-dependent Cushing’s syndrome patients compared to that in normal adrenal tissues (2–3 orders of magnitude) or pancreas (10-fold); no signal could be seen in adrenal adenomas or macronodular hyperplasia from cases of non-food-dependent Cushing’s syndrome. No mutation of the GIPR was identified by sequencing the full-length receptor in GIP-dependent adrenal tissue. New alternative spliced isoforms of the GIPR were found, but are identical in GIP-dependent and normal adrenal tissues. Incubation of adrenal cells with GIP stimulates cortisol secretion in GIP-dependent, but not in normal fetal, adult, or non-food-dependent Cushing’s syndrome, adrenals. We conclude that the GIPR overexpression and its coupling to steroidogenesis underlie GIP-dependent Cushing’s syndrome.

	Introduction

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CORTICOTROPIN-INDEPENDENT Cushing’s syndrome is usually secondary to cortisol-secreting adrenal adenomas or carcinomas (1), which are essentially of unknown pathophysiology. Rare cases of corticotropin-independent bilateral adrenal hyperplasia have been reported (1, 2), and their pathophysiology is diverse. Primary pigmented nodular adrenocortical disease can be familial, associated with other tumors (Carney complex), and linked to an unknown gene on chromosome 2 (3). In McCune-Albright syndrome, activating mutations of G_s in adrenal nodules induce constitutive steroidogenesis (4). Recently, we (5) and others (6, 7) identified food-dependent cortisol production and Cushing’s syndrome in three women with corticotropin-independent bilateral adrenal hyperplasia and two patients with adrenal adenomas (8, 9). Abnormal adrenal regulation of cortisol production by gastric inhibitory polypeptide (GIP; also known as glucose-dependent insulinotropic polypeptide) in vivo (5, 6, 9) or in vitro (5) suggested that this new etiology of Cushing’s syndrome may be secondary to either ectopic expression or an activating mutation of GIP receptors (GIPR) not normally expressed or functional in adrenal cortical tissues; this hypothesis could not be studied directly at the time of the initial reports (5, 6, 7), as the GIPR was not yet well characterized. The GIPR complementary DNA (cDNA) has now been cloned from rat (10), hamster (11), and human (12, 13, 14) sources; the human GIPR is about 13.8 kb long and consists of 14 exons (13). GIPR was expressed predominantly in pancreatic ß-cells in the hamster, as shown by Northern blot analysis (11); however, by using RT-PCR in rats, it was found to be distributed in several tissues, including the brain, pituitary, gut, fat, heart, vascular endothelium, and adrenals (10, 15). In situ hybridization studies indicated that the GIPR was localized in the inner layers of the rat adrenal cortex (10); it is unknown, however, whether GIP regulates steroidogenesis or adrenal growth in the rat. This study demonstrates that GIP-dependent Cushing’s syndrome in humans is secondary to the adrenal overexpression of the GIPR that is able to be coupled efficiently to steroidogenesis.

	Subjects and Methods

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Patient’s tissues

Adrenal tissues were obtained at the time of surgery from two women with previously reported GIP-dependent Cushing’s syndrome (5, 9). One had bilateral macronodular adrenal hyperplasia (5), and another had an adrenal adenoma (9). Tissues were collected rapidly in liquid nitrogen and were stored at -80 C until analysis. Several other control adrenal cortical tissues were obtained from 1) three normal human fetuses and two normal adult multiple organ transplant donors; 2) one woman with pituitary Cushing’s disease; and 3) three patients with ACTH-independent, non-food-dependent Cushing’s syndrome: one with an adrenal adenoma (62-yr-old woman) and two others with macronodular adrenal hyperplasia secondary to ectopic adrenal ß-adrenergic receptor (56-yr-old man) (16) and to increased V1-vasopressin receptor response (36-yr-old woman) (17), respectively. Normal pancreas was obtained from a woman undergoing a distal pancreatectomy for a benign pancreatic cyst. The study protocol was approved by the local institutional review committee, and informed consent was obtained from all subjects.

Ribonucleic acid (RNA) preparation and RT-PCR

Total RNA was extracted from adrenals by the guanidium-phenol chloroform method (18). First strand cDNA synthesis was carried out with 2 µg total RNA and random primers (hexamers) using Moloney murine leukemia virus reverse transcriptase (Life Technologies, Burlington, Canada) as recommended by the manufacturer. In control reactions, reverse transcriptase was omitted to ensure that the PCR amplification did not result from contaminating genomic DNA. The PCR reaction contained 10 mM Tris-HCl (pH 8.3), 1.5 mM MgCl₂, 50 mM KCl, 0.2 mM each of deoxy-NTP, 10 pmol each of sense and antisense primers specific for the human GIPR (GeneBank no. U39231), one fifth of the RT reaction, and 2.5 U Taq DNA polymerase. Two sets of primers were used to amplify the full-length GIPR cDNA: 5'-GGGACAGGCCTGATCGCCCCT-3' (-50 to -30) and 5'-TGTAGCCGCCTGAACAAACTC-3' (532–551); and 5'-TGCTAGCCCTGCTCATCTTGA-3' (513–533) and 5'-ACACGGGGATCCCGCCCCCTA-3'(1453–1474). The amplification was achieved with 30 and 35 cycles (94 C for 30 s, 48 C for 30 s, and 72 C for 30 s). The PCR products were separated on agarose gel. The RNA samples were also amplified (94 C for 30 s, 51 C for 30 s, and 72 C for 30 s) with a pair of primers specific for the human ß-actin cDNA (5'-GATTCCTATGTGGGCGA-3' and 5'-GATTCCTATGTGGGCGA-3').

DNA sequencing

The RT-PCR products were subcloned in Bluescript SK⁺ (Stratagene, Aurora, Canada). Sequencing of the cDNA inserts was performed on double stranded DNA using the chain termination reaction technique (19) with Circumvent (New England Biolabs, Mississauga, Canada).

Hybridization on RT-PCR products and quantification

RT-PCR products from three independent PCR reactions were hybridized with the full-length GIPR cDNA under high stringency conditions. Filters were prehybridized at 42 C for 2–4 h in a solution containing 50% formamide, 5 x Denhardt’s (1 x Denhardt’s is 0.02% polyvinylpyrrolidone, Ficoll 400, and BSA), 6 x SSC (1 x SSC is 150 mmol/L NaCl and 15 mmol/L Na₃ citrate, pH 7.0), and 100 µg/mL salmon sperm DNA. Hybridization was performed for 16 h at 42 C with 2 x 10⁵ cpm/mL cDNA probe labeled by random priming (Life Technologies). The filters were washed twice for 15 min each time at room temperature with a solution containing 2 x SSC and 0.1% SDS and then once for 30 min at 65 C with a solution containing 0.1 x SSC and 0. 5% SDS.

Quantification of RT-PCR products was performed with the ImageQuant program (1988–1992, Molecular Dynamics, Sunnyvale, CA). Each experiment (n = 3) was analyzed twice. Only the 30 cycle amplification products were quantified, as the most accurate results were obtained when the amplification rates of specific RNA were identical within exponential phase. The 546- and 453-bp bands were both analyzed.

In vitro stimulation of steroidogenesis by GIP in adrenal cells

Adrenal cells were dispersed from portions of freshly obtained adrenal tissues as reported previously (5, 9). The dispersed cells were incubated in DMEM (Life Technologies) without serum at a concentration of 1 x 10⁶ cells/mL; 1-mL aliquots were incubated with human GIP (Bachem Fine Chemicals, Torrance, CA) in duplicate for 2 h at 37 C under 5% carbon dioxide-95% air. After the incubation, the medium was collected, stored at -20 C until measurement of cortisol concentrations using either a commercial RIA kit or an immunofluorometric assay (Technicon Immuno I System, Miles Diagnostics, Elkhart, IN). Each experiment was performed the day of the surgery. The results are expressed as a percentage of the response in the unstimulated condition.

	Results

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The expression of GIPR in adrenals was examined by RT-PCR using the first set of primers corresponding to nucleotides -50 to -30 and 532–551. Two fragments of 546 and 453 bp, corresponding to the extracellular domain of the GIPR, were amplified from the adrenals of the two patients with GIP-dependent Cushing’s syndrome (Fig. 1A). The same two bands were revealed by ethidium bromide staining in normal adult pancreas, but not in normal fetal and adult adrenals or in adrenal adenoma or bilateral hyperplasia from patients with non-food-dependent Cushing’s syndrome. Hybridization with the human GIPR cDNA showed weak expression in normal fetal and adult adrenals (2–3 orders of magnitude less than GIP-dependent Cushing’s patient adrenals). No signal could be seen in adrenal adenomas or macronodular hyperplasias from patients with non-food-dependent Cushing’s syndrome (Fig. 1B). ß-Actin bands of the expected size were similar in all tissues examined (Fig. 1C).

View larger version (61K): [in this window] [in a new window]   Figure 1. Analysis of GIPR expression. GIPR was amplified by RT-PCR from 2 µg total RNA of human and pathologic adrenals as described in Subjects and Methods (A); the PCR products were run on a 1.5% agarose gel and stained by ethidium bromide. The analysis of the RT-PCR products was performed by hybridization of the full-length GIPR cDNA after 35-cycle amplification (B). The faint signal in the two border lanes corresponds to nonspecific hybridization of the probe with the DNA ladder. Procedures are described in Subjects and Methods. ß-Actin was amplified as an internal control (C). Lane 1, GIP-dependent adrenal hyperplasia; lane 2, GIP-dependent adrenal adenoma; lanes 3–5, human fetal adrenals; lanes 6 and 7, human fasciculata cells and whole adult adrenal; lanes 8–11, non-food-dependent Cushing’s adrenals; lane 8, adrenal hyperplasia secondary to increased activity of V1-vasopressin receptor; lane 9, ectopic ß-adrenergic receptor; lane 10, pituitary Cushing’s disease; lane 11, adrenal adenoma; lane 12, normal pancreas.

View larger version (15K): [in this window] [in a new window]   Figure 2. Schematic representation of the three adrenal cDNAs; cDNAs were inserted in the SmaI site of Bluescript SK+. Open boxes represent the coding exons, and the dotted box represents the noncoding first exon. Arrows represent the oligonucleotides used for the amplification of the full-length cDNA.

We have previously found that the incubation of adrenal cells with GIP resulted in a dose-dependent stimulation of steroidogenesis in cells from patients with GIP-dependent Cushing’s syndrome (5, 9) (Table 1); GIP did not stimulate cortisol production in adrenal cells dispersed from normal adult or fetal adrenals, Cushing’s disease, non-food-dependent cortisol-secreting adrenal adenomas, or hyperplasias. Incubation with ACTH-(1–24) stimulated cortisol secretion in all adrenal cells studied (not shown).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The presence of GIPR in the adrenals of these two patients with GIP-dependent Cushing’s syndrome was suggested both in vivo, by the bilateral adrenal uptake of [¹²³I]GIP (5), and in vitro, where GIP stimulated cortisol secretion from dispersed adrenal cells (5, 7, 9). The present study confirmed, at the molecular level, the presence of GIPR messenger RNA (mRNA) in the adrenals of two patients with GIP-dependent Cushing’s syndrome. GIPR expression was previously demonstrated by in situ hybridization in the adrenal adenoma of the patient with GIP-dependent Cushing’s syndrome, whereas it was not present in a non-food-dependent cortisol-secreting adrenal adenoma (9); however, normal human adrenal tissues were not studied in that initial report. The absence of functional GIPR in normal adult or fetal human adrenals was previously suggested by the lack of steroidogenic response to GIP in vivo (5, 6) and in vitro (5, 7), and is confirmed in this study. The low level of GIPR demonstrated by RT-PCR in normal fetal and adult adrenal tissues or in the hyperplastic adrenals of a pituitary Cushing’s disease patient is not coupled to regulation of steroidogenesis by GIP in vivo (5, 6) or in vitro (5). Thus, this study indicates that an important overexpression of GIPR and its effective coupling to steroidogenesis are responsible for GIP-dependent Cushing’s syndrome. We had initially suggested that this syndrome could result from the ectopic or aberrant expression of the GIPR (5); although a faint amount of GIPR mRNA is detectable by large RT-PCR amplification, we propose that the concept of an ectopic receptor, responsible for the physiopathology of this syndrome, remains valid because the small amount of mRNA does not appear to confer biological activity. It also remains to be determined whether the small amount of GIPR is expressed in steroidogenic cells or in others, such as endothelial cells in normal adrenals.

Three distinct forms of GIPR, the full-length cDNA, a cDNA without exon 4, and one without exon 9, have been identified in normal adrenals and in those of GIP-dependent Cushing’s syndrome; it is not known whether the latter two are also functional receptors when overexpressed. Two GIPR cDNAs were described recently in human pancreas (12): one lacks exons 9 and 10 and encodes a nonfunctional receptor, whereas the other has an 81-nucleotide insertion at the 3'-end and encodes a functional receptor. In this study, these two forms of GIPR have not been seen in adrenals from either patients or normal subjects. Another potential pathophysiological mechanism of GIP-dependent Cushing’s syndrome, an activating mutation of the GIPR, was excluded by direct sequencing of its full-length cDNA. A recent study reported the presence of a partially inactivating missense mutation of the hGIPR gene in close to 4% of the Japanese population (25); no association with noninsulin-dependent diabetes was found.

The molecular mechanisms regulating tissue-specific expression of GIPR are still unknown, as are those leading to increased adrenal expression; the promoter of the hGIPR has not yet been characterized. Transcriptional regulation is the most plausible mechanism, as the expressions of GIPR isoforms were similar to those of the full-length GIPR. A unilateral GIP-dependent cortisol-secreting adenoma may result from the clonal expansion of one cell in which a somatic mutation inducing the overexpression of GIPR had occurred. In the case of GIP-dependent bilateral macronodular adrenal hyperplasia, where all adrenal cells exhibit hyperplasia, the mutation must have occurred during embryogenesis; genetic transmission has not been demonstrated. The mechanisms by which GIPR expression is decreased in non-GIP-dependent adrenal Cushing’s syndrome, as shown in this and a previous study (9), may also imply transcriptional regulation. It will be of interest to examine whether the GIPR expression is increased in tissues other than the adrenals in patients with bilateral diffuse hyperplasia and whether it results in other pathological conditions. Taking into account the high expression of GIPR in the rat brain (10, 15), it is noteworthy that the patient with bilateral adrenal disease (5) has persisted in presenting significant psychiatric symptoms several years after the correction of hypercortisolism.

The possibility that ectopic expression or abnormal activity of hormone receptors other than for GIP may be functionally coupled to adenylyl cyclase and steroidogenesis and underlies other cases of adrenal Cushing’s syndrome is now supported by recent reports of vasopressin-dependent (17, 26, 27) and ß-adrenergic-dependent Cushing’s syndromes (16). The identification of the abnormal receptors can lead to novel pharmacological approaches to control hypercortisolism and potentially adrenal proliferation with inhibitors of the ligands (6) or antagonists of the ectopic receptors (16).

	Acknowledgments

 
The authors thank Drs. Ted B. Usdin and Tom I. Bonner for providing the human GIPR cDNA; Drs. Nicole Gallo-Payet, Daniel Pharand, Jean-Marie Paquin, and Alfons Pomp for providing the adrenal tissues; and Marie-France Lepage for preparation of the manuscript.

	Footnotes

 
¹ Presented in part at the 79th Annual Meeting of The Endocrine Society, Minneapolis, MN, June 12, 1997. This work was supported by a grant (MT-131–89) from the Medical Research Council of Canada.

Received January 22, 1998.

Revised May 1, 1998.

Accepted May 11, 1998.

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