Hypermethylator Phenotype and Ectopic GIP Receptor in GNAS Mutation-Negative Somatotropinomas

Abstract Context Besides GNAS gene mutations, the molecular pathogenesis of somatotroph adenomas responsible for gigantism and acromegaly remains elusive. Objective To investigate alternative driver events in somatotroph tumorigenesis, focusing on a subgroup of acromegalic patients with a paradoxical increase in growth hormone (GH) secretion after oral glucose, resulting from ectopic glucose-dependent insulinotropic polypeptide receptor (GIPR) expression in their somatotropinomas. Design, Setting, and Patients We performed combined molecular analyses, including array-comparative genomic hybridization, RNA/DNA fluorescence in situ hybridization, and RRBS DNA methylation analysis on 41 somatotropinoma samples from 38 patients with acromegaly and three sporadic giants. Ten patients displayed paradoxical GH responses to oral glucose. Results GIPR expression was detected in 13 samples (32%), including all 10 samples from patients with paradoxical GH responses. All GIPR-expressing somatotropinomas were negative for GNAS mutations. GIPR expression occurred through transcriptional activation of a single allele of the GIPR gene in all GIPR-expressing samples, except in two tetraploid samples, where expression occurred from two alleles per nucleus. In addition to extensive 19q duplications, we detected in four samples GIPR locus microamplifications in a certain proportion of nuclei. We identified an overall hypermethylator phenotype in GIPR-expressing samples compared with GNAS-mutated adenomas. In particular, we observed hypermethylation in the GIPR gene body, likely driving its ectopic expression. Conclusions We describe a distinct molecular subclass of somatotropinomas, clinically revealed by a paradoxical increase of GH to oral glucose related to pituitary GIPR expression. This ectopic GIPR expression occurred through hypomorphic transcriptional activation and is likely driven by GIPR gene microamplifications and DNA methylation abnormalities.

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

Neuroendocrinology ◽

10.1159/000497214 ◽

2019 ◽

Vol 108 (3) ◽

pp. 244-255 ◽

Cited By ~ 1

Author(s):

Mirella Hage ◽

Peter Kamenický ◽

Philippe Chanson

Keyword(s):

Growth Hormone ◽

Ectopic Expression ◽

Oral Glucose ◽

Glucose Load ◽

Physiological Basis ◽

Gh Secretion ◽

Glucose Levels ◽

Chronic Hyperglycemia ◽

Acute Elevation ◽

Underlying Mechanisms

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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GROWTH HORMONE RESPONSES TO FRUCTOSE IN DIABETES MELLITUS

Acta Endocrinologica ◽

10.1530/acta.0.0750497 ◽

1974 ◽

Vol 75 (3) ◽

pp. 497-502

Author(s):

Mayer B. Davidson ◽

Roger M. Steele

Keyword(s):

Diabetes Mellitus ◽

Growth Hormone ◽

Fasting Glucose ◽

Area Under The Curve ◽

Oral Glucose ◽

Gh Secretion ◽

Significant Difference ◽

Duration Of Disease ◽

Hormone Responses

ABSTRACT Since fructose is normally metabolized in diabetics and has recently been shown to stimulate GH secretion, it was used to assess GH responses in diabetics. Fourteen diabetics (9 on insulin) and 8 controls matched for weight were studied. Fructose, infused over 10 min, was compared to arginine, infused over 30 min, both at 0.5 g/kg. Samples were collected at 0, 30, 60, 90 and 120 min and GH responses assessed as area under the curve minus the fasting area. There was no significant difference between the GH responses in diabetics and controls to either agent. Responses to arginine and fructose were significantly correlated (r = 0.60, P < 0.01) in all subjects, but not related to therapy, duration of disease or fasting glucose (75–287 mg/100 ml) in the diabetics. Oral glucose blunted the GH response to fructose in 2 controls. It is concluded that 1) fructose can stimulate GH secretion in male diabetics; 2) however, fructose-stimulated GH responses are not increased in diabetes mellitus.

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Rare and novel GNAS gene mutations in Chinese patients with thyroid cancer

Precision Medical Sciences ◽

10.1002/prm2.12039 ◽

2021 ◽

Author(s):

Zhuo Wang ◽

Changwen Jing ◽

Haixia Cao ◽

Jianzhong Wu ◽

Rong Ma

Keyword(s):

Thyroid Cancer ◽

Gene Mutations ◽

Chinese Patients ◽

Gnas Gene

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Evaluation of selective transsphenoidal adenomectomy by endocrinological testing and somatomedin-C measurement in acromegaly

Journal of Neurosurgery ◽

10.3171/jns.1989.70.4.0561 ◽

1989 ◽

Vol 70 (4) ◽

pp. 561-567 ◽

Cited By ~ 44

Author(s):

Marco Losa ◽

Reinhard Oeckler ◽

Jochen Schopohl ◽

O. Albrecht Müller ◽

Julia Alba-Lopez ◽

...

Keyword(s):

Tolerance Test ◽

Oral Glucose ◽

Slow Increase ◽

Insulin Hypoglycemia ◽

Somatomedin C ◽

Content Type ◽

Gh Secretion ◽

Effective Form ◽

Transsphenoidal Adenomectomy ◽

Favorable Prognostic Factor

✓ A series of 29 previously untreated patients with acromegaly underwent transsphenoidal adenomectomy. Pre- and postoperative evaluation consisted of measuring growth hormone (GH) secretory dynamics during an oral glucose tolerance test (OGTT), the insulin hypoglycemia test, and the thyrotropin- and gonadotropin-releasing hormone (TRH/GnRH) test, and by obtaining the basal somatomedin-C level. After surgery, clinical and biochemical amelioration was achieved in all but two patients. In the whole group, basal GH and somatomedin-C levels decreased from a mean (± standard error of the mean) of 52.3 ± 12.7 to 11.1 ± 6.3 ng/ml and from 7.6 ± 0.7 to 2.5 ± 0.5 U/ml, respectively. Application of different criteria of cure revealed that 19 patients (66%) had basal GH levels below 5 ng/ml, 17 patients (59%) had normal somatomedin-C values, 16 patients (55%) had complete GH suppression (< 1 ng/ml) during OGTT, and 13 patients (45%) met the above-mentioned criteria with disappearance of the paradoxical GH response to TRH/GnRH test. Evaluation of GH secretion by insulin hypoglycemia testing was useless in assessing the outcome after neurosurgery. When only patients with a normal somatomedin-C level and complete GH suppressibility during OGTT were considered “cured,” the main favorable prognostic factor was intrasellar tumor localization, since 15 (75%) of 20 patients were “cured,” as opposed to only one (11%) of nine with extrasellar extension of the adenoma. During the follow-up period, no tumor recurrence was detected in any of the “cured” patients. In these subjects somatomedin-C levels remained stable in all except two patients, who showed a slow increase within the normal range of somatomedin-C concentration. These data confirm that transsphenoidal surgery is the most effective form of treatment in previously untreated acromegalic patients and that normalization of somatomedin-C levels reflects normal GH secretion. Measurement of somatomedin-C could replace more extensive endocrinological testing during monitoring of treated acromegalic patients.

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Ghrelin test for the assessment of GH status in successfully treated patients with acromegaly

Acta Endocrinologica ◽

10.1530/eje.1.02148 ◽

2006 ◽

Vol 154 (5) ◽

pp. 659-666 ◽

Cited By ~ 9

Author(s):

S Pekic ◽

M Doknic ◽

D Miljic ◽

M Joksimovic ◽

J Glodic ◽

...

Keyword(s):

Gh Deficiency ◽

Provocation Test ◽

Tolerance Test ◽

Oral Glucose ◽

Provocative Test ◽

Gh Secretion ◽

Control Subjects ◽

Igf I ◽

Secretory Capacity ◽

Igfbp 3

Objective: Posttreatment assessment of disease activity and definition of cure of acromegaly, using measurement of GH secretion, remains problematic. Furthermore, with our efforts to achieve tight biochemical control of the disease it is foreseeable that a proportion of patients may be rendered GH deficient, thus requiring testing for GH deficiency. The aim of our study was to evaluate residual GH secretion in cured patients with acromegaly. Design and methods: At baseline, circulating GH, IGF-I, IGFBP-3, leptin and lipid (cholesterol and tri-glycerides) levels were measured in 33 acromegalic patients nine years after treatment with surgery of whom 6 were additionally irradiated. Two tests were performed: the GH suppression test - oral glucose tolerance test (OGTT) and the GH provocation test - ghrelin test (1 μg/kg i.v. bolus) and the results were compared with 11 age- and sex-matched control subjects. Results: According to the consensus criteria (normal IGF-I levels and post-OGTT GH nadir <1 μg/l), 21 treated acromegalic patients were cured, 6 had discordant IGF-I and GH nadir values during OGTT, while 6 had persistent acromegaly. After the GH provocative test with ghrelin (cut-off for severe GH deficiency is GH <3 μg/l), we detected 9 severely GH deficient patients (GHD) among 21 cured acromegalic patients. Mean GH peak (±s.e.m.) response to the ghrelin test in GHD acromegalics was significantly lower compared with acromegalics with sufficient GH secretory capacity and control subjects (1.2 ± 0.2 μg/l vs 20.1 ± 2.4 μg/l vs 31.1 ± 2.5 μg/l respectively, P<0.0001). Mean IGF-I and IGFBP-3 levels were not different between GHD and GH-sufficient cured acromegalics. Leptin levels and body mass index (BMI) were significantly higher in GHD male acromegalics compared with GH-sufficient male acromegalics. GHD female acromegalics tended to have higher BMIs while leptin levels were not different. Conclusions: The assessment of residual GH secretory capacity by the GH provocation test is necessary in the long-term follow-up of successfully treated acromegalics since a large proportion of these patients are rendered GH deficient.

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Sitagliptin decreases visceral fat and blood glucoses in women with polycystic ovarian syndrome

10.1101/19001685 ◽

2019 ◽

Author(s):

Jessica K. Devin ◽

Hui Nian ◽

Jorge E. Celedonio ◽

Patricia Wright ◽

Nancy J. Brown

Keyword(s):

Body Composition ◽

Half Life ◽

Vascular Function ◽

Polycystic Ovarian Syndrome ◽

Interpulse Interval ◽

Oral Glucose ◽

Insulinogenic Index ◽

Glucose Response ◽

Gh Secretion ◽

Ovarian Syndrome

ContextWomen with polycystic ovarian syndrome (PCOS) have decreased growth hormone (GH), which can increase visceral adiposity (VAT) and impair vascular function. GH releasing hormone, a dipeptidyl peptidase-4 (DPP4) substrate, stimulates GH secretion.ObjectiveWe tested the hypothesis that DPP4 inhibition increases GH and improves glucose levels and vascular function in women with PCOS.MethodsEighteen women with PCOS participated in a double-blinded, cross-over study. They received sitagliptin 100 mg vs. placebo daily for one month separated by an eight-week washout. During each treatment, women underwent a 75-gram oral glucose tolerance test (OGTT), assessment of vascular function and body composition. Overnight GH secretion was assessed via venous sampling every 10 minutes for 12 hours and analyzed using an automated deconvolution algorithm.ResultsDuring OGTT, sitagliptin increased GLP-1 (p<0.001), early insulin secretion (from mean insulinogenic index 1.9±1.2 (SD) to 3.2±3.1; p=0.02) and decreased peak glucose (mean −17.2 mg/dL [95% CI −27.7, −6.6]; p<0.01). At one month, sitagliptin decreased VAT (from 1141.9±700.7 to 1055.1±710.1 g; p=0.02) but did not affect vascular function. Sitagliptin increased GH half-life (from 13.9±3.6 to 17.0±6.8 min, N=16; p=0.04) and interpulse interval (from 53.2±20.0 to 77.3±38.2 min, N=16; p<0.05) but did not increase mean overnight GH (p=0.92 vs. placebo).ConclusionsSitagliptin decreased the maximal glucose response to OGTT and VAT. Sitagliptin did not increase overnight GH but increased GH half-life and the interpulse interval.PrecisSitagliptin improved body composition and blood glucoses following oral glucose load in women with PCOS. Sitagliptin potentiated GH half-life but did not increase overnight GH levels.

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Low temperature triggers genome-wide hypermethylation of transposable elements and centromeres in maize

10.1101/573915 ◽

2019 ◽

Cited By ~ 1

Author(s):

Zeineb Achour ◽

Johann Joets ◽

Martine Leguilloux ◽

Hélène Sellier ◽

Jean-Philippe Pichon ◽

...

Keyword(s):

Dna Methylation ◽

Transposable Elements ◽

Transcriptional Activation ◽

Gene Expression Regulation ◽

Environmental Cues ◽

Specific Response ◽

Genome Wide ◽

A Genome ◽

Response To Stress ◽

Context Specific

ABSTRACTCharacterizing the molecular processes developed by plants to respond to environmental cues is a major task to better understand local adaptation. DNA methylation is a chromatin mark involved in the transcriptional silencing of transposable elements (TEs) and gene expression regulation. While the molecular bases of DNA methylation regulation are now well described, involvement of DNA methylation in plant response to environmental cues remains poorly characterized. Here, using the TE-rich maize genome and analyzing methylome response to prolonged cold at the chromosome and feature scales, we investigate how genomic architecture affects methylome response to stress in a cold-sensitive genotype. Interestingly, we show that cold stress induces a genome-wide methylation increase through the hypermethylation of TE sequences and centromeres. Our work highlights a cytosine context-specific response of TE methylation that depends on TE types, chromosomal location and proximity to genes. The patterns observed can be explained by the parallel transcriptional activation of multiple DNA methylation pathways that methylate TEs in the various chromatin locations where they reside. Our results open new insights into the possible role of genome-wide DNA methylation in phenotypic response to stress.

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decapentaplegic is a direct target of dTcf repression in the Drosophila visceral mesoderm

Development ◽

10.1242/dev.127.17.3695 ◽

2000 ◽

Vol 127 (17) ◽

pp. 3695-3702 ◽

Cited By ~ 1

Author(s):

X. Yang ◽

M. van Beest ◽

H. Clevers ◽

T. Jones ◽

D.A. Hursh ◽

...

Keyword(s):

Gene Expression ◽

Reporter Gene ◽

Transforming Growth Factor Beta ◽

Transcriptional Activation ◽

Binding Sites ◽

Transforming Growth Factor ◽

Ectopic Expression ◽

Reporter Gene Expression ◽

Enhancer Element ◽

Visceral Mesoderm

Drosophila T cell factor (dTcf) mediates transcriptional activation in the presence of Wingless signalling and repression in its absence. Wingless signalling is required for the correct expression of decapentaplegic (dpp), a Transforming Growth Factor (beta) family member, in parasegments 3 and 7 of the Drosophila visceral mesoderm. Here we demonstrate that a dpp enhancer element, which directs expression of a reporter gene in the visceral mesoderm in a pattern indistinguishable from dpp, has two functional dTcf binding sites. Mutations that reduce or eliminate Wingless signalling abolish dpp reporter gene expression in parasegment 3 and reduce it in parasegment 7 while ectopic expression of Wingless signalling components expand reporter gene expression anteriorly in the visceral mesoderm. However, mutation of the dTcf binding sites in the dpp enhancer results in ectopic expression of reporter gene expression throughout the visceral mesoderm, with no diminution of expression in the endogenous sites of expression. These results demonstrate that the primary function of dTcf binding to the dpp enhancer is repression throughout the visceral mesoderm and that activation by Wingless signalling is probably not mediated via these dTcf binding sites to facilitate correct dpp expression in the visceral mesoderm.

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