An imbalance in sex hormones has an important impact on type 2 diabetes (T2DM) mainly through the involvement of visceral adipose tissue. Androgens have an interesting sex-dimorphic association with T2DM, since hyperandrogenism in females and hypogonadism in males are risk factors for T2DM. Thus, treatments aimed at correcting hyperandrogenism in females and hypogonadism in males may prevent the development of T2DM or help in its treatment.
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Alessandra Gambineri and Carla Pelusi
Zi-Di Xu, Wei Zhang, Min Liu, Huan-Min Wang, Pei-Pei Hui, Xue-Jun Liang, Jie Yan, Yu-Jun Wu, Yan-Mei Sang, Cheng Zhu and Gui-Chen Ni
This study aims to summarize and analyze the clinical manifestations, genetic characteristics, treatment modalities and long-term prognosis of congenital hyperinsulinemia (CHI) in Chinese children. Sixty children with CHI, who were treated at Beijing Children’s Hospital from January 2014 to August 2017, and their families, were selected as subjects. The CHI-related causative genes in children were sequenced and analyzed using second-generation sequencing technology. Furthermore, the genetic pathogenesis and clinical characteristics of Chinese children with CHI were explored. Among the 60 CHI children, 27 children (27/60, 45%) carried known CHI-related gene mutations: 16 children (26.7%) carried ABCC8 gene mutations, seven children (11.7%) carried GLUD1 gene mutations, one child carried GCK gene mutations, two children carried HNF4α gene mutations and one child carried HADH gene mutations. In these 60 patients, eight patients underwent 18F-L-DOPA PET scan for the pancreas, and five children were found to be focal type. The treatment of diazoxide was ineffective in these five patients, and hypoglycemia could be controlled after receiving partial pancreatectomy. In conclusion, ABCC8 gene mutation is the most common cause of CHI in Chinese children. The early genetic analysis of children’s families has an important guiding significance for treatment planning and prognosis assessment.
Sandra R Dahl, Ingrid Nermoen, Ingeborg Brønstad, Eystein S Husebye, Kristian Løvås and Per M Thorsby
Immunoassays of steroid hormones are still used in the diagnosis and monitoring of patients with congenital adrenal hyperplasia. However, cross-reactivity between steroids can give rise to falsely elevated steroid levels. Here, we compare the use of immunoassays and liquid chromatography–tandem mass spectrometry (LC–MS/MS) in the monitoring of patients with classic 21-hydroxylase deficiency (21OHD). Steroid profiles in different mutation groups (genotypes) were also compared. Fifty-five patients with classic 21OHD (38 women) were studied. Blood samples were collected in the morning after an overnight medication fast. LC–MS/MS and immunoassays were employed to assay 17-hydroxyprogesterone (17OHP), testosterone and androstenedione. In addition, 21-deoxycortisol (21DF), 11-deoxycortisol (11DF), corticosterone, deoxycorticosterone, cortisone and cortisol were analyzed by LC–MS/MS. Testosterone, androstenedione and 17OHP levels were consistently lower (by about 30–50%) when measured by LC–MS/MS compared with immunoassays, with exception of testosterone in men. There was a significant correlation between 21DF and 17OHP (r = 0.87, P < 0.001), but three patients had undetectable 21DF. Subjects with no enzyme activity had significantly lower mean 11DF concentrations than subjects with residual activity. The use of LC–MS/MS gives a more specific view of adrenal steroid levels in 21OHD compared with immunoassays, which seem to considerably overestimate the levels of 17OHP and androstenedione. Falsely elevated levels of 17OHP and androstenedione could lead to overtreatment with glucocorticoids.
Kristin Ottarsdottir, Anna G Nilsson, Margareta Hellgren, Ulf Lindblad and Bledar Daka
The objective of this study was to investigate whether there is a bidirectional association between testosterone concentrations and insulin resistance, in a prospective population study. A random population sample of 1400 men, aged 30–74, was examined in 2002–2005 in southwestern Sweden and followed up in 2012–2014 (N = 657). After excluding subjects without information on sex hormones and insulin resistance, 1282 men were included in the baseline study. Fasting measurements of plasma glucose, insulin and hormones were performed. Insulin resistance was defined using HOMA-Ir. Mean age at baseline was 47.3 ± 11.4 years. From the follow-up survey 546 men were included, mean age 57.7 ± 11.6 years. Low concentrations of total testosterone at baseline were significantly associated with high logHOMA-Ir at follow-up in a multivariable model including age, waist–hip ratio, physical activity, alcohol intake, smoking, LDL, CRP, hypertension, diabetes and logHOMA-Ir at baseline as covariates (β = −0.096, P = 0.006). Similar results were observed for bioavailable testosterone. Men within the lowest quartile of total testosterone at baseline had significantly higher logHOMA-Ir at follow-up than other quartiles (Q1 vs Q2 P = 0.008, Q1 vs Q3 P = 0.001, Q1 vs Q4 P = 0.052). Multivariable analysis of the impact of insulin resistance at baseline on testosterone levels at follow-up revealed no significant associations regarding testosterone concentrations (β = −0.003, P = 0.928) or bioavailable testosterone (β = −0.006, P = 0.873), when adjusting for baseline concentrations of total testosterone, age, waist–hip-ratio, LDL, CRP, physical activity, alcohol intake, smoking, hypertension and diabetes. Low testosterone concentrations at baseline predicted higher insulin resistance at follow-up, but high insulin resistance at baseline could not predict low testosterone at follow-up.
Satoshi Inoue, Taichi Mizushima, Hiroki Ide, Guiyang Jiang, Takuro Goto, Yujiro Nagata, George J Netto and Hiroshi Miyamoto
We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.
Linfei Yang, Xiao Yu and Yongchao Yang
Although the upregulation of autotaxin (ATX) is associated with many solid tumours, its role in pancreatic neuroendocrine neoplasms (pNEN) has not been well elucidated. The expression of ATX in pNEN tissues and pNEN cell line BON1 was analysed by Western blot, PCR and immunocytochemistry upon exposure to interleukin-6 (IL-6). Additionally, pNEN cell line BON1 was transfected with siRNAs against ATX or signal transducer and activator of transcription 3 (STAT3) and assessed by in vitro invasion assays. The following results were obtained. The expression of ATX in pNEN tissues was significantly increased compared with that in normal pancreatic tissues. High ATX expression was strongly correlated with tumour grade, lymph node metastasis and tumour-node-metastasis stage. Furthermore, ATX downregulation notably inhibited the metastatic capacity of pNEN cells, whereas STAT3 knockdown was found to downregulate the expression of ATX. ATX expression was upregulated in BON1 cells upon stimulation with IL-6, and this was accompanied by activation/phosphorylation of STAT3. Western blot analysis of human pNEN tissue extracts confirmed increased ATX expression and STAT3 phosphorylation with elevated expression levels of IL-6. In conclusion, ATX is upregulated in pNEN and is correlated with the metastatic capacity of pNEN cells, potentially via interaction with STAT3 activation.
Søs Dragsbæk Larsen, Christine Dalgård, Mathilde Egelund Christensen, Sine Lykkedegn, Louise Bjørkholt Andersen, Marianne Andersen, Dorte Glintborg and Henrik Thybo Christesen
Low foetal vitamin D status may be associated with higher blood pressure (BP) in later life.
To examine whether serum 25-hydroxyvitamin D2+3 (s-25OHD) in cord and pregnancy associates with systolic and diastolic BP (SBP; DBP) in children up to 3 years of age.
Prospective, population-based cohort study.
We included 1594 singletons from the Odense Child Cohort with available cord s-25OHD and BP data at median age 3.7 months (48% girls), 18.9 months (44% girls) or 3 years (48% girls). Maternal s-25OHD was also assessed at gestational ages 12 and 29 weeks. Multiple regression models were stratified by sex a priori and adjusted for maternal educational level, season of birth and child height, weight and age.
In 3-year-old girls, SBP decreased with −0.7 mmHg (95% CI −1.1; −0.3, P = 0.001) and DBP with −0.4 mmHg (95% CI −0.7; −0.1, P = 0.016) for every 10 nmol/L increase in cord s-25OHD in adjusted analyses. Moreover, the adjusted odds of having SBP >90th percentile were reduced by 30% for every 10 nmol/L increase in cord s-25OHD (P = 0.004) and by 64% for cord s-25OHD above the median 45.1 nmol/L (P = 0.02). Similar findings were observed between pregnancy s-25OHD and 3-year SBP, cord s-25OHD and SBP at 18.9 months, and cord s-25OHD and DBP at 3 years. No consistent associations were observed between s-25OHD and BP in boys.
Cord s-25OHD was inversely associated with SBP and DBP in young girls, but not in boys. Higher vitamin D status in foetal life may modulate BP in young girls. The sex difference remains unexplained.
Yuan Fang, Xuehong Zhang, Huilin Xu, Stephanie A Smith-Warner, Dongli Xu, Hong Fang and Wang Hong Xu
The excess risk of cancer observed in patients with type 2 diabetes (T2DM) may have been influenced by detection bias. The aim of this study was to examine the real association by evaluating time-varying site-specific cancer risks in newly diagnosed T2DM patients. A total of 51,324 registered cancer-free individuals newly diagnosed with T2DM between 2004 and 2014 were linked with the Shanghai Cancer Registry and the Vital Statistics through September 2015. A total of 2920 primary, invasive cancer cases were identified during 325,354 person-years period. Within 1 year following diabetes onset, participants with T2DM had higher risks of total, lung and rectal cancer in men and total, liver, pancreas, thyroid, breast and uteri cancer in women. Thereafter the incidence for overall cancer decreased and then increased along with follow-up time, with the upward trend varying by cancer, suggesting potential detection bias. After the initial 1-year period, standardized incidence ratios (SIR) and 95% CIs for overall cancer were 0.80 (95% CI 0.76–0.85) in men and 0.93 (95% CI 0.88–0.99) in women, but a higher risk of breast and thyroid cancers were observed in women, with SIR and 95% CI being 1.13 (1.01, 1.28) and 1.37 (1.11, 1.63), respectively. Our results suggest that T2DM patients are at higher risk of certain cancers; this risk particularly increases shortly after diabetes diagnosis, which is likely to be due to detection bias caused by increased ascertainment. Prevention of female breast and thyroid cancers should be paid attention in Chinese individuals with T2DM.
Zhen-yu Song, Qiuming Yao, Zhiyuan Zhuo, Zhe Ma and Gang Chen
Previous studies investigating the association of circulating 25-hydroxyvitamin D level with prognosis of prostate cancer yielded controversial results. We conducted a dose–response meta-analysis to elucidate the relationship. PubMed and EMBASE were searched for eligible studies up to July 15, 2018. We performed a dose–response meta-analysis using random-effect model to calculate the summary hazard ratio (HR) and 95% CI of mortality in patients with prostate cancer. Seven eligible cohort studies with 7808 participants were included. The results indicated that higher vitamin D level could reduce the risk of death among prostate cancer patients. The summary HR of prostate cancer-specific mortality correlated with an increment of every 20 nmol/L in circulating vitamin D level was 0.91, with 95% CI 0.87–0.97, P = 0.002. The HR for all-cause mortality with the increase of 20 nmol/L vitamin D was 0.91 (95% CI: 0.84–0.98, P = 0.01). Sensitivity analysis suggested the pooled HRs were stable and not obviously changed by any single study. No evidence of publications bias was observed. This meta-analysis suggested that higher 25-hydroxyvitamin D level was associated with a reduction of mortality in prostate cancer patients and vitamin D is an important protective factor in the progression and prognosis of prostate cancer.
Laura van Iersel, Sarah C Clement, Antoinette Y N Schouten-van Meeteren, Annemieke M Boot, Hedi L Claahsen-van der Grinten, Bernd Granzen, K Sen Han, Geert O Janssens, Erna M Michiels, A S Paul van Trotsenburg, W Peter Vandertop, Dannis G van Vuurden, Hubert N Caron, Leontien C M Kremer and Hanneke M van Santen
The incidence of cranial radiotherapy (cRT)–induced central hypothyroidism (TSHD) in childhood brain tumor survivors (CBTS) is reported to be low. However, TSHD may be more frequent than currently suspected, as its diagnosis is challenging due to broad reference ranges for free thyroxine (FT4) concentrations. TSHD is more likely to be present when FT4 levels progressively decline over time. Therefore, we determined the incidence and latency time of TSHD and changes of FT4 levels over time in irradiated CBTS.
Nationwide, 10-year retrospective study of irradiated CBTS.
TSHD was defined as ‘diagnosed’ when FT4 concentrations were below the reference range with low, normal or mildly elevated thyrotropin levels, and as ‘presumed’ when FT4 declined ≥ 20% within the reference range. Longitudinal FT4 concentrations over time were determined in growth hormone deficient (GHD) CBTS with and without diagnosed TSHD from cRT to last follow-up (paired t-test).
Of 207 included CBTS, the 5-year cumulative incidence of diagnosed TSHD was 20.3%, which occurred in 50% (25/50) of CBTS with GHD by 3.4 years (range, 0.9–9.7) after cRT. Presumed TSHD was present in 20 additional CBTS. The median FT4 decline in GH-deficient CBTS was 41.3% (P < 0.01) to diagnosis of TSHD and 12.4% (P = 0.02) in GH-deficient CBTS without diagnosed TSHD.
FT4 concentrations in CBTS significantly decline over time after cRT, also in those not diagnosed with TSHD, suggesting that TSHD occurs more frequently and earlier than currently reported. The clinical relevance of cRT-induced FT4 decline over time should be investigated in future studies.