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Open access

Zimin Song, Meng Gao, Jun Lv, Canqing Yu, Yu Guo, Zheng Bian, Yuxia Wei, Ling Yang, Huaidong Du, Yiping Chen, Jianqiang Zhang, Jvying Yao, Junshi Chen, Zhengming Chen, Tao Huang, Liming Li, and the China Kadoorie Biobank (CKB) Collaborative Group

Objectives

To prospectively assess the association of metabolic health status and its transition with incident diabetes risk across BMI categories.

Design

Cohort study based on the China Kadoorie Biobank (CKB).

Methods

The CKB study enrolled 512 715 adults aged 30–79 years from ten diverse areas in China during 2004–2008. After exclusion, 432 763 participants were cross-classified by BMI categories and the metabolic status was followed up for incident diabetes disease. The changes in BMI and metabolic health status were defined from baseline to the second resurvey.

Results

Type 2 diabetes risk is higher for metabolically healthy obese (MHO) subjects than metabolically healthy normal weight (MHN) individuals (HR: 3.97, 95% CI: 3.64–3.66), and it is highest for those affected by metabolically unhealthy obese (MUO) (HR: 6.47, 95% CI: 6.17–6.79). About 15.26% of participants with MHN converted to metabolically healthy overweight or obesity (MHOO), whereas 48.40% of MHOO remained unconverted throughout the follow-up. In obese or overweight people, the conversion from metabolically healthy to unhealthy might increase the chances of developing diabetes as compared to those with a stable metabolic healthy state (HR: 3.70, 95% CI: 2.99–4.59), while those with persistent metabolic disorders are most likely to have diabetes (HR: 8.32, 95% CI: 7.08–9.78).

Conclusions

Metabolic healthy is a transient state, and individuals converted from metabolically healthy status to unhealthy phenotypes across all BMI categories might raise the risk of diabetes.

Restricted access

Sailimai Man, Yongxiang Gao, Jun Lv, Mingkun Tong, Jianchun Yin, Bo Wang, Yi Ning, and Liming Li

Objective

The risk of gallstones among metabolically healthy obesity (MHO) individuals is largely unexplored. Therefore, the present study investigated the association between MHO and gallstones in a health check-up cohort of Chinese adults.

Design

A prospective cohort study.

Methods

Participants included 58 862 individuals from the MJ health check-up cohort aged ≥ 18 years without a history of gallstones at baseline. Gallstones were diagnosed using abdominal B-type ultrasound. Metabolically healthy was defined as not having any one of the components of metabolic syndrome. Obesity was identified by BMI and waist circumference (WC). Participants were cross-classified at baseline by metabolic health and obesity. Adjusted hazard ratios (HRs) and 95% CIs of gallstones across BMI or WC categories were estimated with Cox proportional hazard regression models.

Results

During a median follow-up of 3.0 years (interquartile range, 1.6–6.1), 1269 participants developed gallstones. Individuals with MHO (HR: 1.95, 95% CI: 1.23, 3.09 for BMI criteria; HR: 1.74, 95% CI: 1.37, 2.21 for WC criteria) had a significantly higher risk of gallstones than those with metabolically healthy normal weight. In metabolically healthy individuals, BMI and WC both displayed linear dose–response relationships with gallstones (P for non-linearity >0.05). The association between MHO and gallstones remained unchanged when using different criteria for metabolic health and obesity.

Conclusions

MHO was significantly associated with gallstones, suggesting that obesity can independently contribute to gallstones development, even among metabolically healthy individuals. These findings emphasize that metabolically healthy individuals may still benefit from maintaining normal body weight to prevent gallstones.

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Ranyao Yang, Yue Hu, Chi Ho Lee, Yan Liu, Candela Diaz-Canestro, Carol Ho Yi Fong, Huige Lin, Kenneth K Y Cheng, Aparna Padmanabhan Pravelil, Erfei Song, Karen S L Lam, and Aimin Xu

Objective

Peptidase M20 domain containing 1 (PM20D1), a secreted enzyme catalysing condensation of fatty acids and amino acids into the bioactive lipids N-acyl amino acids (NAAA), induces uncoupling protein 1 (UCP1)-independent adaptive thermogenesis in brown/beige adipocytes in mice. This study aimed to explore the associations of the circulating levels of PM20D1 and major NAAA with obesity-related metabolic complications in humans.

Design and methods

Serum concentrations of PM20D1 and NAAA (C18:1-Leu and C18:1-Phe) in 256 Chinese subjects, including 78 lean and 178 overweight/obese individuals with or without diabetes, were measured with immunoassays and liquid chromatography–mass spectrometry, respectively. The impact of sulfonylurea and rosiglitazone on their circulating levels was examined in 62 patients with type 2 diabetes.

Results

Serum PM20D1 level was significantly elevated in overweight/obese individuals and was closely associated with circulating levels of C18:1-Leu and C18:1-Phe. Furthermore, serum PM20D1, C18:1-Leu and C18:1-Phe concentrations correlated positively with several parameters of adiposity as well as fasting and 2 h postprandial glucose, HbA1c, fasting insulin and HOMA-IR independent of BMI and age. Moreover, a significant elevation in PM20D1, C18:1-Leu and C18:1-Phe concentrations corresponding with increases in the number of components of the metabolic syndrome (MetS) was observed. Treatment with sulfonylurea significantly decreased circulating PM20D1, C18:1-Leu and C18:1-Phe in patients with type 2 diabetes.

Conclusions

Increased serum levels of PM20D1 and its catalytic products NAAA are closely associated with obesity-related glucose dysregulation, insulin resistance and MetS and can be potentially used as clinical biomarkers for diagnosing and monitoring these disorders.

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Theresia Weber, Alicia Poplawski, Christian Vorländer, Cornelia Dotzenrath, Rolf Ringelband, Jochen Schabram, Christian Passler, Andreas Zielke, Nicolas Schlegel, Christoph Nies, Detlef Krenz, Joachim Jähne, Robert Schwab, Detlef K Bartsch, Marcel Binnebösel, Matthias Kemen, Carsten Klinger, Heinz Buhr, and Kerstin Lorenz

Aim

Calcitonin (Ctn) measurement in patients with thyroid disease could potentially increase the detection rates of medullary thyroid carcinoma (MTC) but remains a controversial issue. The aim of this study was to evaluate routine preoperative Ctn measurements.

Methods

All patients with thyroid surgery documented in the prospective StuDoQ|Thyroid registry between March 2017 and September 2020 were included. Cutoff levels for Ctn were determined with receiver-operating characteristic analyses to assess the preoperative diagnosis of MTC in subgroups for females and males.

Findings

In 29 590 of 39 679 patients (75%) participating in the registry, routine preoperative Ctn testing was performed. In 357 patients (227 females and 130 males), histopathology confirmed MTC with a mean tumor size of 14.7 mm (±12.43). Biochemical cure was achieved in 71.4% of the patients. Ctn levels between 11 and 20 pg/mL were seen in 2.6% of the patients, and only 0.7% of the patients had Ctn levels above 21 pg/mL. Cutoff levels for the diagnosis of MTC were 7.9 pg/mL for females and 15 pg/mL for males (P  < 0.001). The sensitivity and specificity for females were 95 and 98%, and 96 and 97% for males, respectively.

Conclusion

Routine Ctn testing is a reliable predictor for MTC and provides the opportunity for earlier thyroidectomy before lymph node metastases occur, resulting in a better prognosis. Females with Ctn levels >7.9 pg/mL and males >15 pg/mL without any other extrathyroidal sources for an elevated Ctn should be monitored. Thyroid surgery should be considered if Ctn levels are increasing or ultrasound detects suspicious thyroid lesions.

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Mingqiang Zhu, Yangxi Li, Guanping Dong, Xuefeng Chen, Ke Huang, Wei Wu, Yangli Dai, Li Zhang, Hu Lin, Sihua Wang, Constantin Polychronakos, and Junfen Fu

Objective

Recessive WFS1 mutations are known to cause Wolfram syndrome, a very rare systemic disorder. However, they were also found in non-syndromic diabetes in Han Chinese misdiagnosed with type 1 diabetes (T1D), a molecular cause that appears to be considerably more common than the fully expressed syndrome. We aimed to better define the incidence and clinical features of non-syndromic diabetes due to recessive WFS1 mutation.

Design

We analyzed the genotype and phenotype of 320 consecutive incident Chinese pediatric diabetic patients diagnosed from 2016 to 2019 to search for non-syndromic diabetic cases due to recessive WFS1 mutation.

Methods

A cohort of 105 pancreatic autoantibody-negative patients were recruited for exome sequencing. All patients tested positive for pathogenic diallelic WFS1 mutations were examined for phenotypic features (fundoscopy, audiogram, and urine density).

Results

We found three cases of non-syndromic diabetes due to recessive WFS1 mutations (incidence = 0.94% (95% CI: 0.25–2.7%)). All three cases only had mild diabetes when diagnosed. All patients had well-conserved fasting C-peptide when diagnosed but one of them progressed to T1D-like insulin deficiency. In addition, we found a fourth case with previously undetected features of Wolfram syndrome.

Conclusions

Non-syndromic diabetes due to WFS1 mutation may be common among Chinese pediatric patients with diabetes. It is important to differentiate it from other maturity-onset diabetes in the young subtypes with similar phenotype by molecular diagnosis because of different prognosis and, potentially, therapy.

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Naoya Fujita, Yosuke Ono, Azusa Sano, Motohiro Kimata, Seigo Oyama, Kenichi Hashimoto, Ikuya Sato, Masahiko Kudo, Yoshimichi Miyashiro, Akira Fujikata, and Yuji Tanaka

Objective

Conventional diagnostic methods are limited in their ability to differentiate destructive thyroiditis from Graves’ disease. We hypothesised that serum diiodotyrosine (DIT) and monoiodotyrosine (MIT) levels could be biomarkers for differentiating destructive thyroiditis from Graves’ disease.

Design

Patients with destructive thyroiditis (n  = 13) and Graves’ disease (n  = 22) were enrolled in this cross-sectional study.

Methods

We assayed the serum DIT and MIT levels using liquid chromatography-tandem mass spectrometry. A receiver operating characteristic (ROC) curve analysis was used to determine the sensitivity and specificity of the serum DIT and MIT levels as biomarkers for differentiating destructive thyroiditis from Graves’ disease.

Results

The serum DIT and MIT levels were significantly higher in patients with destructive thyroiditis than in those with Graves’ disease. The ROC curve analysis showed that the serum DIT levels (≥359.9 pg/mL) differentiated destructive thyroiditis from Graves’ disease, significantly, with 100.0% sensitivity and 95.5% specificity (P < 0.001). The diagnostic accuracy of the serum MIT levels (≥119.4 pg/mL) was not as high as that of the serum DIT levels (sensitivity, 84.6%; specificity, 77.3%; P = 0.001).

Conclusions

The serum DIT levels may serve as a novel diagnostic biomarker for differentiating destructive thyroiditis from Graves’ disease.

Restricted access

Peter Wolf, Sylvie Salenave, Emmanuel Durand, Jacques Young, Peter Kamenicky, Philippe Chanson, and Luigi Maione

Background

Acromegaly is associated with changes in body composition. Long-term changes following acromegaly treatment and the impact of different treatments have been less investigated.

Methods

We performed a retrospective study in 201 patients with acromegaly. Body composition was assessed by dual-energy X-ray absorptiometry. To investigate the specific effects of treatment vs aging, changes in body composition were compared in one group of patients evaluated both at the time of active and controlled disease (active-to-controlled (A>C); n  = 31) and in another group of patients evaluated two times while the disease was controlled (controlled-to-controlled (C>C); n  = 32).

Results

In the whole cohort, insulin-like growth factor I (IGF-I) was correlated with fat (r = −0.369; P  < 0.001) and lean mass (r = 0.383; P  < 0.001). Patients from A>C and C>C groups were comparable for age, sex, BMI and follow-up duration (P = n.s.). Reduction in IGF-I levels was associated with an increase in fat mass and a decrease in lean mass in the A>C group, which was four and eight times more pronounced compared to the C>C group (fat mass: +39 ± 34% vs +10 ± 15%, P  < 0.001; lean mass: −8 ± 8% vs −0.2 ± 6%, P  < 0.001, respectively). Changes in fat mass were negatively associated with IGF-I (r = −0.450; P = 0.011) and independent of the individual therapy. The daily dose of pegvisomant correlated with fat mass (r = 0.421; P = 0.002) and insulin sensitivity index (r = −0.466; P  < 0.001).

Conclusions

Treatment of acromegaly strongly impacts body composition until biochemical disease remission, characterized by an increase in fat mass and a decrease in lean mass. These changes are closely associated with the normalization of IGF-I. Thereafter, body composition changes are similar to what is observed with aging.

Open access

Mikiko Okazaki-Hada, Eijun Nishihara, Mako Hisakado, Takumi Kudo, Mitsuru Ito, Shuji Fukata, Mitsushige Nishikawa, Takashi Akamizu, and Akira Miyauchi

Objective

Resistance to thyroid hormone beta (RTHβ) is an inherited syndrome caused by mutations in the thyroid hormone receptor β (THRB) gene. Patients with RTHβ typically have elevated thyroid hormone levels with non-suppressed serum thyroid-stimulating hormone (TSH). We aimed to elucidate the clinical, laboratory, and imaging findings of RTHβ patients and further to explore their association with THRB gene mutations.

Design and methods

We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHβ patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital.

Results

Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHβ patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (P  = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; 8 (42.1%) with AITD and 5 (20%) without AITD) temporarily showed thyroid function test results inconsistent with RTHβ. Two patients with the R383H mutation, which has little dominant-negative effect, temporarily showed normal thyroid hormone and TSH levels without AITD.

Conclusions

The frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives. More than 20% of RTHβ patients temporarily showed laboratory findings atypical of RTHβ during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Open access

Dilek Cicek, Nick Warr, Gozde Yesil, Hatice Kocak Eker, Firdevs Bas, Sukran Poyrazoglu, Feyza Darendeliler, Gul Direk, Nihal Hatipoglu, Mehmet Eltan, Zehra Yavas Abali, Busra Gurpinar Tosun, Sare Betul Kaygusuz, Tuba Seven Menevse, Didem Helvacioglu, Serap Turan, Abdullah Bereket, Richard Reeves, Michelle Simon, Matthew Mackenzie, Lydia Teboul, Andy Greenfield, and Tulay Guran

Context

Homozygous and heterozygous variants in PPP2R3C are associated with syndromic 46,XY complete gonadal dysgenesis (Myo-Ectodermo-Gonadal Dysgenesis (MEGD) syndrome), and impaired spermatogenesis, respectively. This study expands the role of PPP2R3C in the aetiology of gonadal dysgenesis (GD).

Method

We sequenced the PPP2R3C gene in four new patients from three unrelated families. The clinical, laboratory, and molecular characteristics were investigated. We have also determined the requirement for Ppp2r3c in mice (C57BL6/N) using CRISPR/Cas9 genome editing.

Results

A homozygous c.578T>C (p.L193S) PPP2R3C variant was identified in one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. The patients with complete GD had low gonadal and adrenal androgens, low anti-Müllerian hormone, and high follicle-stimulating hormone and luteinizing hormone concentrations. All patients manifested characteristic features of MEGD syndrome. Heterozygous Ppp2r3c knockout mice appeared overtly normal and fertile. Inspection of homozygous embryos at 14.5, 9.5, and 8.5 days post coitum(dpc) revealed evidence of dead embryos. We conclude that loss of function of Ppp2r3c is not compatible with viability in mice and results in embryonic death from 7.5 dpc or earlier.

Conclusion

Our data indicate the essential roles for PPP2R3C in mouse and human development. Germline homozygous variants in human PPP2R3C are associated with distinctive syndromic GD of varying severity in both 46,XY and 46,XX individuals.