Browse

You are looking at 31 - 40 of 20,470 items for

  • Refine by Access: All content x
Clear All
Restricted access

Marja-Riitta Taskinen, Niina Matikainen, Elias Björnson, Sanni Söderlund, Mari Ainola, Antti Hakkarainen, Nina Lundbom, Carina Sihlbom, Annika Thorsell, Linda Andersson, Martin Adiels, Bolette Hartmann, Carolyn F Deacon, Jens J Holst, Chris J Packard, and Jan Borén

Objective

Incretins are known to influence lipid metabolism in the intestine when administered as pharmacologic agents. The aggregate influence of endogenous incretins on chylomicron production and clearance is less clear, particularly in light of opposing effects of co-secreted hormones. Here, we tested the hypothesis that physiological levels of incretins may impact on production or clearances rates of chylomicrons and VLDL.

Design and methods

A group of 22 overweight/obese men was studied to determine associations between plasma levels of glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) after a fat-rich meal and the production and clearance rates of apoB48- and apoB100-containing triglyceride-rich lipoproteins. Subjects were stratified by above- and below-median incretin response (area under the curve).

Results

Stratification yielded subgroups that differed about two-fold in incretin response. There were neither differences in apoB48 production rates in chylomicrons or VLDL fractions nor in apoB100 or triglyceride kinetics in VLDL between men with above- vs below-median incretin responses. The men with above-median GLP-1 and GLP-2 responses exhibited higher postprandial plasma and chylomicron triglyceride levels, but this could not be related to altered kinetic parameters. No differences were found between incretin response subgroups and particle clearance rates.

Conclusion

We found no evidence for a regulatory effect of endogenous incretins on contemporaneous chylomicron or VLDL metabolism following a standardised fat-rich meal. The actions of incretins at pharmacological doses may not be reflected at physiological levels of these hormones.

Restricted access

Wesley Jim Goedegebuure, Manouk Van der Steen, Carolina Catharina Johanna Smeets, Gerthe Femke Kerkhof, and Anita Charlotte Suzanne Hokken-Koelega

Background

Catch-up in weight-for-length in the first year of life results in more insulin resistance, an adverse lipid profile and more fat mass (FM) in 21-year-old adults born small for gestational age (SGA-CU) compared to peers born SGA without catch-up and those born appropriate for gestational age (AGA). The aim of present study was to investigate if the adverse metabolic health profile in the SGA-CU group would worsen or remain stable over the years and to determine the cardiometabolic health at 32 years between the SGA and AGA groups.

Methods

We longitudinally investigated 287 adults, 170 SGA with catch-up growth (SGA-CU) or persistent short stature (SGA-S) and 117 AGA at ages 21 and 32 years. Insulin sensitivity (Si) and β-cell function were measured by frequently sampled i.v. glucose tolerance test, body composition by dual-energy X-ray absorptiometry (DXA) scan, and abdominal adipose tissue and liver fat fraction by MRI scan. Also, fasting serum lipid levels and blood pressure were measured.

Results

At age 32 years, SGA-CU had lower Si than AGA (P  = 0.030), while SGA-S had similar Si than AGA. FM and trunk fat were higher in SGA-CU than AGA (P  = 0.033, P  = 0.024, respectively), while SGA-S had lower lean body mass than SGA-CU and AGA (P  = 0.001 and P  < 0.001, respectively). SGA-CU had significantly higher levels of adverse lipids than AGA. Beta-cell function, visceral fat, liver fat fraction and blood pressure were similar in all groups. Metabolic health parameters in SGA-CU and SGA-S did not worsen compared to AGA during 11 years of follow-up. Gain in weight SDS from birth to age 32 years was associated with a higher risk of developing metabolic syndrome at age 32 years.

Conclusion

At age 32 years, SGA-CU adults had insulin resistance, higher FM with central adiposity and an adverse lipid profile. Postnatal catch-up growth increases the cardiometabolic risk; therefore, accelerated gain in weight should be prevented in SGA-born children.

Restricted access

Dongyun Zhang, Willy Hugo, Marvin Bergsneider, Marilene B Wang, Won Kim, Harry V Vinters, and Anthony P Heaney

Objective

Provide insights into the defective POMC processing and invasive behavior in silent pituitary corticotroph tumors.

Design and methods

Single-cell RNAseq was used to compare the cellular makeup and transcriptome of silent and active corticotroph tumors.

Results

A series of transcripts related to hormone processing peptidases and genes involved in the structural organization of secretory vesicles were reduced in silent compared to active corticotroph tumors. Most relevant to their invasive behavior, silent corticotroph tumors exhibited several features of epithelial-to-mesenchymal transition, with increased expression of mesenchymal genes along with the loss of transcripts that regulate hormonal biogenesis and secretion. Silent corticotroph tumor vascular smooth muscle cell and pericyte stromal cell populations also exhibited plasticity in their mesenchymal features.

Conclusions

Our findings provide novel insights into the mechanisms of impaired POMC processing and invasion in silent corticotroph tumors and suggest that a common transcriptional reprogramming mechanism simultaneously impairs POMC processing and activates tumor invasion.

Restricted access

Magdalena Stefanowicz, Agnieszka Nikołajuk, Natalia Matulewicz, Marek Strączkowski, and Monika Karczewska-Kupczewska

Objective

Skeletal muscle is the major site of insulin action. There are limited data on the relationship between insulin action and skeletal muscle myogenic/regenerative potential. RUNX1 is a transcription factor which plays a role in muscle development and regeneration. The aim of our study was to assess the role of skeletal muscle myogenic/regenerative potential in the development of insulin resistance through the studies on RUNX1 transcription factor.

Design

This study is a cross-sectional study. Experimental part with myoblast cell line culture.

Methods

We examined 41 young healthy volunteers, 21 normal weight and 20 with overweight or obesity. Hyperinsulinemic-euglycemic clamp and vastus lateralis muscle biopsy were performed. In L6 myoblast and human skeletal muscle myoblasts (hSkMM) cell cultures, RUNX1 was silenced at two stages of development. Cell growth, the expression of markers of myogenesis, nuclei fusion index, Akt phosphorylation and glucose uptake were measured.

Results

Skeletal muscle RUNX1 expression was decreased in overweight/obese individuals in comparison with normal-weight individuals and was positively related to insulin sensitivity, independently of BMI. Runx1 loss-of-function at the stage of myoblast inhibited myoblast proliferation and differentiation and reduced insulin-stimulated Akt phosphorylation and insulin-stimulated glucose uptake. In contrast, Runx1 knockdown in myotubes did not affect Akt phosphorylation, glucose uptake and other parameters studied.

Conclusions

Myogenic/regenerative potential of adult skeletal muscle may be an important determinant of insulin action. Our data suggest that muscle RUNX1 may play a role in the modulation of insulin action through its effect on myogenesis.

Open access

Treena Cranston, Hannah Boon, Mie K Olesen, Fiona J Ryan, Deborah Shears, Rosemary London, Hussam Rostom, Taha Elajnaf, Rajesh V Thakker, and Fadil M Hannan

Objective

The autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disorder characterised by immune dysregulation and autoimmune endocrine gland destruction. APS-1 is caused by biallelic mutations affecting the autoimmune regulator (AIRE) gene on chromosome 21q22.3, which facilitates immunological self-tolerance. The objective was to investigate >300 probands with suspected APS-1 or isolated hypoparathyroidism for AIRE abnormalities.

Methods

Probands were assessed by DNA sequence analysis. Novel variants were characterised using 3D modelling of the AIRE protein. Restriction enzyme and microsatellite analysis were used to investigate for uniparental isodisomy.

Results

Biallelic AIRE mutations were identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. These included a novel homozygous p.(His14Pro) mutation, predicted to disrupt the N-terminal caspase activation recruitment domain of the AIRE protein. Furthermore, an apparently homozygous AIRE mutation, p.Leu323fs, was identified in an APS-1 proband, who is the child of non-consanguineous asymptomatic parents. Microsatellite analysis revealed that the proband inherited two copies of the paternal mutant AIRE allele due to uniparental isodisomy. Hypoparathyroidism was the most common endocrine manifestation in AIRE mutation-positive probands and >45% of those harbouring AIRE mutations had at least two diseases out of the triad of candidiasis, hypoparathyroidism, and hypoadrenalism. In contrast, type 1 diabetes and hypothyroidism occurred more frequently in AIRE mutation-negative probands with suspected APS-1. Around 30% of AIRE mutation-negative probands with isolated hypoparathyroidism harboured mutations in other hypoparathyroid genes.

Conclusions

This study of a large cohort referred for AIRE mutational analysis expands the spectrum of genetic abnormalities causing APS-1.

Free access

Anders Sundin

The increasing use of cross-sectional imaging, mainly CT, results in an accelerating number of incidental findings, for instance of adrenal tumours. Although most ‘adrenal incidentalomas’ are benign, it is important to identify the malignant and the hormone producing (functional) tumours. For a small fraction of adrenal incidentalomas, the diagnosis is apparent on imaging, but the large majority requires radiological characterisation. To this end, a previous joint European Society of Endocrinology and European Network for the Study of Adrenal Tumours publication in this jounal, recommends CT measurements of the native (non-contrast) tumour attenuation ≤10 Hounsfield units, consistent with a lipid-rich benign adrenocortical adenoma, and imaging at least 6 months apart, on which unchanged tumour size implies a benign tumour. Because of weak evidence, calculation of CT contrast medium washout was not recommended as a means for tumour characterisation, but this technique has nevertheless still been applied in several countries. The recent article by Schloetelburg et al. in this journal is important because, in the largest study to date, the authors confirm that calculation of CT contrast medium washout with established thresholds is insufficient to reliably characterise adrenal tumours. Their results are therefore expected to impact the management of these patients.

Restricted access

Fidéline Bonnet-Serrano, Jonathan Poirier, Anna Vaczlavik, Christelle Laguillier-Morizot, Benoît Blanchet, Stephanie Baron, Laurence Guignat, Laura Bessiène, Léopoldine Bricaire, Lionel Groussin, Guillaume Assié, Jean Guibourdenche, and Jérôme Bertherat

Introduction: Osilodrostat is a new 11 ß-hydroxylase inhibitor with a mode of action analogue to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated by either Osilodrostat or Metyrapone for ACTH-dependent Cushing’s Syndrome (CS).

Methods: Patients followed in Cochin hospital Endocrinology department between March 2019 and December 2021 for an ACTH-dependent CS, controlled by either Osilodrostat or Metyrapone were included. A serum profile of 5 steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined using UPLC – tandem mass spectrometry (UPLC-MS/MS).

Results: Nineteen patients treated by Osilodrostat, 8 patients treated by Metyrapone and 6 patients treated by consecutive Metyrapone then Osilodrostat were included. Hypocortisolism (basal cortisol < 100 nmol/L) was found in 48% of patients treated by Osilodrostat and 7% of patients treated by Metyrapone. 11-deoxycortisol and androstenedione levels were higher in patients treated by Metyrapone (respectively, 80.9 [2.2-688.4] and 14.9 [2.5-54.3] nmol/L) than in patients treated by Osilodrostat (10.3 [0.5-71.9] and 4.0 [0.3-13.3] nmol/L) (p=0.0009 and p=0.0005). Testosterone level in women was also higher in Metyrapone group (3.3 [0.93-4.82] nmol/L vs 1.31[0.13-5.09] nmol/L, p=0.0146). CYP11B1 activity (11-deoxycortisol/cortisol) was not significantly different between the two groups. CYP21A2 activity, (17OHprogesterone/11-deoxycortisol) and CYP17A1 activity (17OHprogesterone/androstenedione) were decreased in Osilodrostat group (p<0.0001).

Conclusion: In patients with ACTH-dependent CS, the use of CYP11B1 inhibitors in routine care suggests that Osilodrostat has a less specific effect on the inhibition of steroidogenic enzymes than Metyrapone. This might explain a smaller increase in 11-deoxycortisol and androgens levels in patients treated by Osilodrostat.

Restricted access

Esra Dülger, Melike Mut, Tomris Erbas, Levent Sahiner, Naciye Vardar Yağlı, and Sevil Bilgin

Objective

The pituitary gland is responsible for hormonal balance in the body, and disruption of hormonal balance in patients with pituitary adenoma (PA) indirectly affects the quality of life. This study aimed to examine the effects of yoga and combined aerobic and strength training (A+ST) on quality of life and related parameters such as sleep, fatigue, emotional state, sexual function, and cognitive status in women with PA.

Design

Ten women with PA were included in this randomized crossover study. Group 1 (n = 5, mean age: 52 ± 13.5 years) received A+ST for the first 6 weeks, a 2-week washout period, and yoga for the second 6 weeks. Group 2 (n = 5, mean age: 41.8 ± 14 years) received the yoga program first, followed by the A+ST program.

Methods

Participants were assessed using the following tools before and after each exercise intervention: Functional Assessment of Cancer Therapy–Brain (FACT-Br) (quality of life), Pittsburg Sleep Quality Index, Fatigue Severity Scale (FSS), Female Sexual Function Index (FSFI), Hospital Anxiety and Depression Scale (HADS), and Montreal Cognitive Assessment Scale (MOCA).

Results

FACT-Br scores were higher after the yoga program, HADS anxiety score was lower after the A+ST program, and MOCA scores increased after both exercise programs (P  < 0.05). FSS score decreased after both exercise programs, but not significantly. In addition, nonsignificant decreases in HADS anxiety and depression scores and increased FSFI scores were observed after the yoga program.

Conclusion

A+ST and yoga have positive effects on the quality of life in PA. We recommend yoga and A+ST as a supportive therapy for this population that may face comorbidities after surgical and medical treatment. Our results indicate these patients may benefit from physiotherapist-guided exercise programs.

Open access

Steven G Waguespack, Alexander Drilon, Jessica J Lin, Marcia S Brose, Ray McDermott, Mohammed Almubarak, Jessica Bauman, Michela Casanova, Anuradha Krishnamurthy, Shivaani Kummar, Serge Leyvraz, Do-Youn Oh, Keunchil Park, Davendra Sohal, Eric Sherman, Ricarda Norenberg, Josh D Silvertown, Nicoletta Brega, David S Hong, and Maria E Cabanillas

Objective

Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).

Methods

We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020.

Results

Twenty-nine patients (median age: 60; range: 6–80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51–87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64–97) for PTC/FTC and 29% (95% CI 4–71) for ATC. Median time to response was 1.87 months (range 1.64–3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1–2.

Conclusion

In TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy.

Significance statement

NTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing.

Free access

Sabina Ruiz, Federico Vázquez, Silvia Pellitero, and Manel Puig-Domingo

Obesity, the growing pandemic of the 21st century, is associated with multiple organ dysfunction, either by a direct increase in fatty organ content or by indirect modifications related to general metabolic changes driven by a specific increase in biologic products. The pituitary gland is not protected against such a situation. Different hypothalamic–pituitary axes experience functional modifications initially oriented to an adaptive situation that, with years of obesity, turn to maladaptive dynamics that contribute to perpetuating obesity and specific symptoms of their hormonal nature. This paper reviews the recent knowledge on obesity-related pituitary dysfunction and its pathogenic mechanisms and discusses potential therapeutic actions aimed at contributing to ameliorating the complex treatment of severe cases of obesity.