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Open access

Shared etiology of type 1 diabetes and Hashimoto’s thyroiditis: a population-based twin study

Jakob Skov, Ralf Kuja-Halkola, Patrik K E Magnusson, Soffia Gudbjörnsdottir, Olle Kämpe, and Sophie Bensing

Objective

Type 1 diabetes and Hashimoto’s thyroiditis frequently cluster in individuals and in families, indicating shared origins. The objective of this study was to investigate familial co-aggregation of these diseases and to quantify shared genetic and environmental factors.

Design

This study is a twin cohort study.

Methods

National health registers were used to identify cases among 110 814 Swedish twins. Co-aggregation was calculated as risk ratios for type 1 diabetes among co-twins of individuals with Hashimoto’s thyroiditis, and vice-versa. Variance explained by genetics (i.e. heritability), and the proportions thereof shared between the diseases, was estimated by contrasting associations in monozygotic and dizygotic twins using structural equation models.

Results

Individuals with one disease were at a high risk for the other disease (adjusted risk ratio: 11.4 (95% CI: 8.5–15.3)). Co-aggregation was more common in monozygotic than in dizygotic pairs, with adjusted risk ratios of 7.0 (95% CI: 3.2–15.1) and 1.7 (95% CI: 0.7–4.1), respectively. Genetic effects shared across diseases accounted for 11% of the variance for type 1 diabetes and 9% of the variance for Hashimoto’s thyroiditis, while environmental factors unique to individual twins, but shared across diseases, accounted for 10% of the variance for type 1 diabetes and 18% of the variance for Hashimoto’s thyroiditis.

Conclusions

Both genes and environment unique to individual twins contribute to considerable etiologic overlap between type 1 diabetes and Hashimoto’s thyroiditis. These findings add to the current knowledge on the mechanisms behind autoimmune disease clustering and could guide future research aimed at identifying pathophysiological mechanisms and intervention targets.

Free access

THERAPY OF ENDOCRINE DISEASE: Amylin and calcitonin – physiology and pharmacology

David S Mathiesen, Asger Lund, Jens J Holst, Filip K Knop, Thomas A Lutz, and Jonatan I Bagger

Type 2 diabetes is a common manifestation of metabolic dysfunction due to obesity and constitutes a major burden for modern health care systems, in concert with the alarming rise in obesity worldwide. In recent years, several successful pharmacotherapies improving glucose metabolism have emerged and some of these also promote weight loss, thus, ameliorating insulin resistance. However, the progressive nature of type 2 diabetes is not halted by these new anti-diabetic pharmacotherapies. Therefore, novel therapies promoting weight loss further and delaying diabetes progression are needed. Amylin, a beta cell hormone, has satiating properties and also delays gastric emptying and inhibits postprandial glucagon secretion with the net result of reducing postprandial glucose excursions. Amylin acts through the six amylin receptors, which share the core component with the calcitonin receptor. Calcitonin, derived from thyroid C cells, is best known for its role in humane calcium metabolism, where it inhibits osteoclasts and reduces circulating calcium. However, calcitonin, particularly of salmon origin, has also been shown to affect insulin sensitivity, reduce the gastric emptying rate and promote satiation. Preclinical trials with agents targeting the calcitonin receptor and the amylin receptors, show improvements in several parameters of glucose metabolism including insulin sensitivity and some of these agents are currently undergoing clinical trials. Here, we review the physiological and pharmacological effects of amylin and calcitonin and discuss the future potential of amylin and calcitonin-based treatments for patients with type 2 diabetes and obesity.

Open access

Transcriptome in paraffin samples for the diagnosis and prognosis of adrenocortical carcinoma

Anne Jouinot, Juliane Lippert, Mathilde Sibony, Florian Violon, Lindsay Jeanpierre, Daniel De Murat, Roberta Armignacco, Amandine Septier, Karine Perlemoine, Franck Letourneur, Brigitte Izac, Bruno Ragazzon, Karen Leroy, Eric Pasmant, Marie-Odile North, Sébastien Gaujoux, Bertrand Dousset, Lionel Groussin, Rossella Libe, Benoit Terris, Martin Fassnacht, Cristina L Ronchi, Jérôme Bertherat, and Guillaume Assie

Design

Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas ‘C2’ from carcinomas, and identify two groups of carcinomas ‘C1A’ and ‘C1B’, of poor and better prognosis respectively. However, many ACT cannot be profiled because of improper or absent freezing procedures, a mandatory requirement so far. The main aim was to determine transcriptome profiles on formalin-fixed paraffin-embedded (FFPE) samples, using the new 3’-end RNA-sequencing technology. A secondary aim was to demonstrate the ability of this technique to explore large FFPE archives, by focusing on the rare oncocytic ACT variants.

Methods

We included 131 ACT: a training cohort from Cochin hospital and an independent validation cohort from Wuerzburg hospital. The 3’ transcriptome was generated from FFPE samples using QuantSeq (Lexogen, Vienna, Austria) and NextSeq500 (Illumina, San Diego, CA, USA).

Results

In the training cohort, unsupervised clustering identified three groups: ‘C1A’ aggressive carcinomas (n = 28, 29%), ‘C1B’ more indolent carcinomas (n = 28, 29%), and ‘C2’ adenomas (n = 39, 41%). The prognostic value of FFPE transcriptome was confirmed in the validation cohort (5-year OS: 26% in ‘C1A’ (n = 26) and 100% in ‘C1B’ (n = 10), P  = 0.003). FFPE transcriptome was an independent prognostic factor in a multivariable model including tumor stage and Ki-67 (OS HR: 7.5, P  = 0.01). Oncocytic ACT (n = 19) did not form any specific cluster. Oncocytic carcinomas (n = 6) and oncocytic ACT of uncertain malignant potential (n = 4) were all in ‘C1B’.

Conclusions

The 3’ RNA-sequencing represents a convenient solution for determining ACT molecular class from FFPE samples. This technique should facilitate routine use and large retrospective studies.

Free access

True unilateral primary aldosteronism exists, and unilateral adrenalectomy saves lives

Martin Reincke and Tracy Ann Williams

Open access

Biallelic POC1A variants cause syndromic severe insulin resistance with muscle cramps

Veronica Mericq, Isabel Huang-Doran, Dhekra Al-Naqeb, Javiera Basaure, Claudia Castiglioni, Christiaan de Bruin, Yvonne Hendriks, Enrico Bertini, Fowzan S Alkuraya, Monique Losekoot, Khalid Al-Rubeaan, Robert K Semple, and Jan M Wit

Objective

To describe clinical, laboratory, and genetic characteristics of three unrelated cases from Chile, Portugal, and Saudi Arabia with severe insulin resistance, SOFT syndrome, and biallelic pathogenic POC1A variants.

Design

Observational study.

Methods

Probands’ phenotypes, including short stature, dysmorphism, and insulin resistance, were compared with previous reports.

Results

Cases 1 (female) and 3 (male) were homozygous for known pathogenic POC1A variants: c.649C>T, p.(Arg217Trp) and c.241C>T, p.(Arg81*), respectively. Case 2 (male) was compound heterozygous for p.(Arg217Trp) variant and the rare missense variant c.370G>A, p.(Asp124Asn). All three cases exhibited severe insulin resistance, acanthosis nigricans, elevated serum triglycerides and decreased HDL, and fatty liver, resembling three previously reported cases. All three also reported severe muscle cramps. Aggregate analysis of the six known cases with biallelic POC1A variants and insulin resistance showed decreased birth weight and length mean (s.d.): −2.8 (0.9) and −3.7 (0.9) SDS, respectively), severe short stature mean (s.d.) height: −4.9 (1.7) SDS) and moderate microcephaly (mean occipitofrontal circumference −3.0 (range: −4.7 to −1.2)). These findings were similar to those reported for patients with SOFT syndrome without insulin resistance. Muscle biopsy in Case 3 showed features of muscle involvement secondary to a neuropathic process.

Conclusions

Patients with SOFT syndrome can develop severe dyslipidaemic insulin resistance, independent of the exonic position of the POC1A variant. They also can develop severe muscle cramps. After diagnosis, patients should be regularly screened for insulin resistance and muscle complaints.

Free access

Can the treatment of polycystic ovary syndrome with spironolactone prevent severe COVID infection?

Decio Armanini, Chiara Sabbadin, Luigi De Marco, and Luciana Bordin

In a recent paper, Subramanian and collaborators reported a 52% increased risk of COVID-19 infection in women with polycystic ovary syndrome (PCOS) and an incidence nearly twice that of women without PCOS. The authors focused, as important factors of the increased prevalence of infection, both the inflammatory characteristic of PCOS and the increase in androgens that facilitate the entry of the virus into the cells of the target organs. We asked 200 consecutive, unvaccinated women with PCOS who had been followed with spironolactone for more than 4 months, about COVID-19 infection and found only four patients who were infected. None of the infected patients were hospitalized and only one had fever and other manifestations of the syndrome, but these symptoms resolved in a few days. The other three reported only mild or minimal symptoms. This observation needs confirmation with specific studies, considering the possibility that many other patients may have been infected by being asymptomatic and not swabbing for COVID-19. Spironolactone can increase the circulating angiotensin-converting enzyme 2 and antagonize the androgen receptor, preventing activation of transmembrane protease serine 2 in cells of the respiratory tract and other tissues. Drug also has potent anti-inflammatory and antithrombotic actions by antagonizing the mineralocorticoid receptor in target tissues and inflammatory cells. From Subramanian's study and reported observations, a proper evaluation of the use of spironolactone in COVID-19 in both PCOS and the general population is urged.

Free access

Controversies about the systematic preoperative pharmacological treatment before pheochromocytoma or paraganglioma surgery

Frederic Castinetti, Jean-Baptiste De Freminville, Carole Guerin, Erika Cornu, Gabrielle Sarlon, and Laurence Amar

The question of systematic use of a pharmacological treatment before surgery in patients diagnosed with pheochromocytoma and paraganglioma (PPGL) remains highly controversial. While recent guidelines suggest that this should be used in all patients, some experienced teams consider it unnecessary in some cases, provided the surgery is performed in a dedicated center that has expert endocrinologists, cardiologists, surgeons, and anesthetists. This controversy is aimed at shedding light on the potential benefits and risks of such a treatment, focusing specifically on alpha blockers which are considered as the first-line medical treatments in patients with PPGL. After discussing the rationale for alpha blockers, hemodynamic instability, tolerance, and acute cardiac complications will then be discussed in the first part of the manuscript, defending a systematic use. The second section will focus on blood pressure control, tolerance of alpha blockers, and also the management of normotensive PPGL, examining the daily risks of PPGL and arguing against the systematic use of a preoperative pharmacological treatment before surgery. Finally, we will discuss the concept of expert centers and define the patients in whom the risk/benefit profile would favor the use of this preoperative treatment.

Restricted access

Effects of dapagliflozin on postprandial lipid metabolism in type 2 diabetes mellitus

Benjamin Burggraaf, Nadine M C Pouw, Salvador Fernández Arroyo, Leonie C van Vark-van der Zee, Gert-Jan M van de Geijn, Erwin Birnie, Jeannine Huisbrink, Ellen M van der Zwan, Wouter W de Herder, Monique T Mulder, Patrick C N Rensen, and Manuel Castro Cabezas

Objectives

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) modulate lipid metabolism and improve cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The exact cardioprotective mechanism of SGLT2i is unclear. We evaluated the effects of SGLT2i on postprandial lipids, lipoprotein concentrations, glucose and fatty acids.

Design

A placebo-controlled randomized, proof-of-concept study.

Methods

Fourteen male patients with T2DM on intensive insulin regimen were randomly and double-blind allocated to 12 weeks dapagliflozin (10 mg) or placebo. Postprandial effects were assessed with an 8-h standardized oral fat loading test.

Results

Mean glycated A1c did not change by dapagliflozin, but the mean daily insulin dose was significantly reduced. Although dapagliflozin did not affect fasting or postprandial levels of glucose and insulin, it increased the postprandial levels of glucagon. While fasting levels of free fatty acids and beta-hydroxybutyrate (bHBA) were unchanged, dapagliflozin significantly increased the postprandial bHBA response. This was seen in the context of increased postprandial glucagon levels by dapagliflozin, without influencing postprandial insulin or glucose levels. Dapagliflozin did not affect fasting or postprandial plasma cholesterol and triglycerides nor postprandial inflammatory markers. Fasting apolipoprotein B48 was decreased without affecting the postprandial response. Markers of inflammation and vascular function did not change.

Conclusion

Treatment with dapagliflozin of patients with T2DM led to a reduction of fasting chylomicron remnants and increased postprandial ketone bodies compared to placebo suggesting enhanced hepatic fatty acid oxidation. The latter may have been caused by decreasing the insulin–glucagon ratio. The beneficial clinical effects seen in the trials using dapagliflozin most likely are not due to effects on postprandial inflammation nor postprandial lipemia.

Restricted access

Frequency, determinants and costs of thyroid function testing in a laboratory serving a large population

Usman Javaid, David Kennedy, Caroline Addison, Vasileios Tsatlidis, and Salman Razvi

Objective

To assess the rationale and frequency of thyroid function testing and to analyse factors that influence serum thyrotropin (TSH) levels.

Patients, design and main outcome measures

Serum TSH levels were evaluated in a hospital laboratory serving a population of 604 000 in 2018. Patients on medications or with conditions affecting thyroid function were excluded. Frequency of thyroid function testing by age and sex was assessed and the relationship between serum TSH with potential predictor variables was analysed using ordinary least square regression analysis allowing for potential non-linearity.

Results

Twenty-eight percent of the local population had their thyroid function tested at least once in 2018 with significant differences by sex (28.2% women vs 23.4% men) and by age groups, with less than 2% of <16-year-old people and more than 50% of >80-year-old people being tested. Most of the symptoms commonly attributed to thyroid dysfunction were not higher in the thyroid dysfunction groups. Serum TSH levels were higher in older people particularly after the age of 60 years, in women (by 0.1 mIU/L), during the early hours of the morning, and in winter and spring seasons. There was remarkable uniformity in the frequency of subclinical thyroid dysfunction, as well as substantial cost savings, if TSH reference intervals were recalculated across sexes, age groups, time-periods and seasons.

Conclusions

Serum TSH is frequently tested in the population but is not a good discriminant of symptoms attributed to thyroid dysfunction. Furthermore, considering the influence of factors on TSH reference limits could significantly impact patient care and resource utilisation.

Restricted access

Hemithyroidectomy and ipsilateral central neck dissection for T1 low-risk papillary thyroid cancer: single-institution retrospective observational study

Davide Giordano, Cecilia Botti, Simonetta Piana, Andrea Castellucci, Andrea Frasoldati, Michele Zini, Martina Fornaciari, Francesco Maria Crocetta, and Angelo Ghidini

Objective

The aim of this study was to report the rationale and selection criteria for hemithyroidectomy and ipsilateral central neck dissection in patients with selected papillary thyroid cancer and to report the surgical and oncological outcomes.

Design

Single-institution retrospective observational study.

Methods

The clinical records of patients with a histopathological diagnosis of low-risk pT1 papillary thyroid cancer who underwent hemithyroidectomy with or without ipsilateral central neck dissection between March 2000 and April 2018 at a tertiary referral center were retrospectively reviewed. Demographic, clinical, and histopathological data were collected.

Results

During the study period, 176 patients underwent hemithyroidectomy for PTC. Thirteen patients (13/176, 7.39%) were lost to follow-up and 74 patients (74/163 45.40%) underwent completion thyroidectomy within 1 month because they were classified intermediate ATA initial risk based on definitive pathology. The final study group was composed of 89 patients, who had a median follow-up of 5.3 years. The mean follow-up was 6.3 years (range: 36–207 months). Eighty-four patients (94.38%) did not experience recurrence in the follow-up period. A total of 5/89 patients (5.62%) underwent delayed completion thyroidectomy with or without neck dissection for recurrent malignancy in the residual lobe (3/5) or regional lymph nodes (2/5). The median time from surgery to recurrence was 24.8 months (range: 6–60). The follicular variant was an independent risk factor for recurrence.

Conclusions

Hemithyroidectomy with or without prophylactic ipsilateral central neck dissection is a valuable treatment option in selected low-risk papillary thyroid cancers and ensures a low risk of recurrence. Prophylactic ipsilateral central compartment dissection could have a role in improving cancer staging, and accurate ultrasonographic follow-up is essential to identify local recurrence.