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Open access

Ping Gu, Yuege Lin, Qi Wan, Dongming Su, and Qun Shu

Background

Increased insulin production and secretion by pancreatic β-cells are important for ensuring the high insulin demand during gestation. However, the underlying mechanism of β-cell adaptation during gestation or gestational diabetes mellitus (GDM) remains unclear. Oxytocin is an important physiological hormone in gestation and delivery, and it also contributes to the maintenance of β-cell function. The aim of this study was to investigate the role of oxytocin in β-cell adaptation during pregnancy.

Methods

The relationship between the blood oxytocin level and pancreatic β-cell function in patients with GDM and healthy pregnant women was investigated. Gestating and non-gestating mice were used to evaluate the in vivo effect of oxytocin signal on β-cells during pregnancy. In vitro experiments were performed on INS-1 insulinoma cells.

Results

The blood oxytocin levels were lower in patients with GDM than in healthy pregnant women and were associated with impaired pancreatic β-cell function. Acute administration of oxytocin increased insulin secretion in both gestating and non-gestating mice. A 3-week oxytocin treatment promoted the proliferation of pancreatic β-cells and increased the β-cell mass in gestating but not non-gestating mice. Antagonism of oxytocin receptors by atosiban impaired insulin secretion and induced GDM in gestating but not non-gestating mice. Oxytocin enhanced glucose-stimulated insulin secretion, activated the mitogen-activated protein kinase pathway, and promoted cell proliferation in INS-1 cells.

Conclusions

These findings provide strong evidence that oxytocin is needed for β-cell adaptation during pregnancy to maintain β-cell function, and the lack of oxytocin could be associated with the risk of GDM.

Open access

Hong Wang, Jie Cao, Jian-bin Su, Xue-qin Wang, Dong-mei Zhang, and Xiao-hua Wang

Background

Antithrombin 3 (AT3) is a physiological inhibitor of thrombin, and serum AT3 activity was found to decrease at the status of type 2 diabetes (T2D). T2D was presented with an increased risk of thrombotic complications at the background of impaired insulin sensitivity. The aim of this study was to investigate the relationship between insulin sensitivity indices and serum AT3 activity in patients with T2D.

Methods

We conducted a cross-sectional study in patients with T2D who consented to participate in the study at the Endocrinology Department of Affiliated 2 Hospital of Nantong University from January 2015 to June 2018. All patients received serum AT3 activity test and 75 g oral glucose tolerance test (OGTT). Basal and systemic insulin sensitivity were assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda index (ISIMatsuda), respectively, from the OGTT. And other relevant clinical data were also collected.

Results

Total of 1612 patients with T2D were enrolled in the study, with a mean age of 58.67 ± 13.09 years and a median diabetes duration of 6 years (interquartile range, 1–10 years). Across ascending quartiles of serum AT3 activity, HOMA-IR progressively decreased, while ISIMatsuda progressively increased (all P for trend < 0.001). Moreover, serum AT3 activity was negatively correlated with HOMA-IR (r = −0.189, P < 0.001) and positively correlated with ISIMatsuda (r = 0.221, P < 0.001). After adjusting for other metabolic risk factors, hemostatic parameters and glucose-lowering therapies by multivariate linear regression analysis, HOMA-IR (β = −0.185, t = −5.960, P < 0.001) and ISIMatsuda (β = 0.197, t = 6.632, P < 0.001) remained independently associated with the serum AT3 activity in patients with T2D, respectively.

Conclusions

Reduced basal and systemic insulin sensitivity are associated with decreased serum AT3 activity in patients with T2D.

Open access

Beibei Zhu, Yan Han, Fen Deng, Kun Huang, Shuangqin Yan, Jiahu Hao, Peng Zhu, and Fangbiao Tao

Objectives

Compared with other thyroid markers, fewer studies have explored the associations between triiodothyronine (T3), T3/free thyroxine (fT4) and glucose abnormality during pregnancy. Thus, we aimed to: (i) examine the associations of T3 and T3/fT4 with glucose metabolism indicators and (ii) evaluate, in the first trimester, the performance of the two markers as predictors of gestational diabetes mellitus (GDM) risk.

Methods

Longitudinal data from 2723 individuals, consisting of three repeated measurements of T3 and fT4, from the Man’anshan birth cohort study (MABC), China, were analyzed using a time-specific generalized estimating equation (GEE). The receiver operating characteristic curve (ROC) – area under the curve (AUC) and Hosmer–Lemeshow goodness of fit test was used to assess the discrimination and calibration of prediction models.

Results

T3 and T3/fT4 presented stable associations with the level of fasting glucose, glucose at 1h/2 h during pregnancy. T3 and T3/fT4 in both the first and second trimesters were positively associated with the risk of GDM, with the larger magnitude of association observed in the second trimester (odds ratio (OR) = 2.50, 95% CI = 1.95, 3.21 for T3; OR = 1.09, 95% CI = 1.07, 1.12 for T3/fT4). T3 ((AUC) = 0.726, 95% CI = 0.698, 0.754) and T3/fT4 (AUC = 0.724, 95% CI = 0.696, 0.753) in the first trimester could improve the performance of the prediction model; however, the overall performance is not good.

Conclusion

Significant and stable associations of T3, T3/fT4 and glucose metabolism indicators were documented. Both T3 and T3/fT4 improve the performance of the GDM predictive model.

Open access

Yue-Yue Wang, Qian Wu, Lu Chen, Wen Chen, Tao Yang, Xiao-Quan Xu, Fei-Yun Wu, Hao Hu, and Huan-Huan Chen

Purpose

To evaluate the value of MRI-based texture analysis of extraocular muscle (EOM) and orbital fat (OF) in monitoring and predicting the response to glucocorticoid (GC) therapy in patients with thyroid-associated ophthalmopathy (TAO).

Methods

Thirty-seven active and moderate-to-severe TAO patients (responders, n = 23; unresponders, n = 14) were retrospectively enrolled. MRI-based texture parameters (entropy, uniformity, skewness and kurtosis) of EOM and OF were measured before and after GC therapy, and compared between groups. Correlations between the changes of clinical activity score (CAS) and imaging parameters before and after treatment were assessed. Receiver operating characteristic curves were used to evaluate the predictive value of identified variables.

Results

Responsive TAOs showed significantly decreased entropy and increased uniformity at EOM and OF after GC therapy (P < 0.01), while unresponders showed no significance. Changes of entropy and uniformity at EOM and OF were significantly correlated with changes of CAS before and after treatment (P < 0.05). Responders showed significantly lower entropy and higher uniformity at EOM than unresponders before treatment (P < 0.01). Entropy and uniformity of EOM and disease duration were identified as independent predictors for responsive TAOs. Combination of all three variables demonstrated optimal efficiency (area under curve, 0.802) and sensitivity (82.6%), and disease duration alone demonstrated optimal specificity (100%) for predicting responsive TAOs.

Conclusion

MRI-based texture analysis can reflect histopathological heterogeneity of orbital tissues. It could be useful for monitoring and predicting the response to GC in TAO patients.

Open access

Sarah Bakhamis, Faiqa Imtiaz, Khushnooda Ramzan, Edward De Vol, Osamah AlSagheir, Abdulrahman AlRajhi, Abdullah Alashwal, Bassam Bin Abbas, Nadia Sakati, and Afaf Al-Sagheir

Vitamin-D deficiency remains a major cause of rickets worldwide. Nutritional factors are the major cause and less commonly inheritance causes. Recently, CYP2R1 has been reported as a major factor for 25-hydroxylation contributing to the inherited forms of vitamin D deficiency. We conducted a prospective cohort study at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia to review cases with 25-hydroxylase deficiency and to describe their clinical, biochemical, and molecular genetic features. We analyzed 27 patients from 9 different families who presented with low 25-OH vitamin-D and not responding to usual treatment. Genetic testing identified two mutations: c.367+1G>A (12/27 patients) and c.768dupT (15/27 patients), where 18 patients were homozygous for their identified mutation and 9 patients were heterozygous. Both groups had similar clinical manifestations ranging in severity, but none of the patients with heterozygous mutation had hypocalcemic manifestations. 13/18 of homozygous patients and all the heterozygous patients responded to high doses of vitamin-D treatment, but they regressed after decreasing the dose, requiring lifelong therapy. 5/18 of homozygous patients required calcitriol to improve their biochemical data, whereas none of the heterozygous patients and patients who carried the c.367+1G>A mutation required calcitriol treatment. To date, this is the largest cohort series analyzeing CYP2R1-related 25-hydroxylase deficiency worldwide, supporting its major role in 25-hydroxylation of vitamin-D. It is suggested that a higher percentage of CYP2R1 mutations might be found in the Saudi population. We believe that our study will help in the diagnosis, treatment, and prevention of similar cases in the future.

Open access

Guang-Ran Yang, Dongmei Li, and Zidian Xie

Objective: There is a lack of consensus on whether a high body mass index (BMI) increases the risk of diabetic retinopathy (DR). We aimed to investigate the association between BMI, overweight, obesity, and DR using the data of diabetes respondents in the 2015 US Behavioral Risk Factor Surveillance System survey.

Methods: Diabetes respondents aged over 18-year-old with complete information as well as undergone fundus examination in the past two years or had been diagnosed with DR were included. Weighted logistic regression analyses were used to identify the association of BMI with DR.

Results: Among the 21,647 diabetes respondents, 4588 respondents had DR with a weighted prevalence of 22.5%. The mean BMI of all diabetes respondents was 31.50±6.95 kg/m2 with18,498 (86.5%) overweight and 11,353 (54.6%) obese. The mean BMI of the DR group (31.83±7.41kg/m2) was significantly higher than that of the non-DR group (31.41±6.81kg/m2, p<0.05). The proportion of obese respondents in the DR group was higher than the non-DR group (54.3%, p<0.001).The weighted prevalence of DR was 0.8%, 13.8%, 29.7%, and 55.7% for the emaciation group, the normal weight group, the overweight group, and the obesity group, respectively (p<0.001). Weighted logistic regression analysis showed that both BMI (adjusted OR=1.004, 95%CI 1.003-1.004) and obesity (adjusted OR=1.051, 95%CI 1.048-1.055) were associated with DR after adjusting for the confounding variables. However, overweight was not significantly associated with DR.

Conclusion: The prevalence of DR in the normal weight, overweight, and obesity groups increased gradually. Obesity, rather than overweight, was significantly associated with increased DR prevalence.

Open access

Melinda Kertész, Szilárd Kun, Eszter Sélley, Zsuzsanna Nagy, Tamás Kőszegi, and István Wittmann

Background: Type 2 diabetes is characterized, beyond the insulin resistance, by polyhormonal resistance. Thyroid hormonal resistance has not yet been described in this population of patients. Metformin is used to decrease insulin resistance, and at present it is assumed to influence the effect of triiodothyronine, as well.

Methods: In this open label, pilot, hypothesis generating, follow-up study 21 patients were included, all of them euthyroid with drug naïve, newly diagnosed type 2 diabetes. Before and after four weeks of metformin therapy fructosamine, homeostasis model assessment for insulin resistance (HOMA-IR), thyroid hormones, T3/T4 ratio, and TSH, as well as blood pressure and heart rate using ambulatory blood pressure monitor were measured. We also conducted an in vitro study to investigate the possible mechanisms of T3 resistance, assessing T3 induced Akt phosphorylation among normal (5 mM) and high (25 mM) glucose levels with or without metformin treatment in a human embryonal kidney cell line.

Results: Metformin decreased the level of T3 (p<0.001), the ratio of T3/T4 (p=0.038), fructosamine (p=0.008) and HOMA-IR (p=0.022). All these changes were accompanied by an unchanged TSH, T4, triglyceride, plasma glucose, bodyweight, blood pressure and heart rate. In our in vitro study, T3 induced Akt phosphorylation decreased in cells grown in 25 mM glucose medium compared to those in 5 mM. Metformin could not reverse this effect.

Conclusion: Metformin seems to improve T3 sensitivity in the cardiovascular system in euthyroid, type 2 diabetic patients, the mechanism of which may be supracellular.

Open access

Elena V Varlamov, Dan Alexandru Niculescu, Swechya Banskota, Simona Andreea Galoiu, Catalina Poiana, and Maria Fleseriu

Purpose: The number of international acromegaly-related registries is increasing; however, heterogeneity of acromegaly symptoms and signs across countries is not well described. We compared clinical disease manifestations at diagnosis between two large University referral centers from two continents.

Methods: Retrospective, comparative epidemiological study of acromegaly patients at two centers; 1) C. I. Parhon National Institute of Endocrinology, “Carol Davila” University of Medicine and Pharmacy Bucharest, Romania (Parhon), and 2) Pituitary Center, Oregon Health & Science University, Portland, Oregon, United States (OHSU) from approved registries was undertaken. Data were extracted from medical charts and questionnaires. Binary logistic regression analysis was undertaken for the most frequently noted symptoms and clinical signs.

Results: Study included 216 patients (87 Parhon, 129 OHSU). Age, sex and median delay in diagnosis were similar between centers. IGF-1 index was higher in patients at Parhon (3.3 vs 2.1, p < 0.001). The top five symptoms at both centers were; enlarged hands/feet, headache, arthralgia, fatigue, and irregular menses in women. A significant difference was noted for multiple signs and symptoms frequency, often >20 percentage points between centers. Center was a predictor of many signs and symptoms, independent of acromegaly biochemical severity or disease duration.

Conclusion: We show in the first comparative study that differences in medical practice, documentation, and likely cultural differences can influence patients’ symptom(s) reporting and screening patterns in geographically different populations. Pooling data into large multicenter international registries databases may lead to loss of regional characteristics and thus a mixed overall picture of combined cohorts.

Open access

Daisuke Watanabe, Satoshi Morimoto, Noriko Morishima, and Atsuhiro Ichihara

Objective

Primary aldosteronism (PA) is divided into two major subtypes, aldosterone-producing adenoma (APA) and bilateral idiopathic hyperplasia (IHA) and is associated with a higher risk of cardiovascular events. However, the nature of vascular function in PA patients remains to be determined. The aim of this study was to determine the vascular function and investigate the implications of vascular function assessments in the patients.

Methods

Flow-mediated dilation (FMD), as an index of endothelial function, and cardio-ankle vascular index (CAVI), as an index of arterial stiffness, were retrospectively compared between 42 patients with APA, 37 patients with IHA, and 42 patients with essential hypertension (EH). These values were also compared with background factors, KCNJ5 mutation and clinical outcome in terms of blood pressure reduction after adrenalectomy in the APA group.

Results

FMD was significantly lower in the APA group (4.8 ± 2.1%) and IHA group (4.1 ± 1.9%) than in the EH group (5.7 ± 2.1%). CAVI did not differ significantly among groups. Although no significant correlations were seen between FMD and background factors in the IHA group, FMD correlated negatively with BMI and plasma aldosterone concentration in the APA group (rs = −0.313, rs = −0.342, respectively). KCNJ5 mutational status was not associated with FMD value. High FMD was associated with blood pressure normalization after adrenalectomy in the APA group.

Conclusions

Patients with PA displayed impaired endothelial function. Complete clinical success after adrenalectomy was associated with preserved endothelial function. This study provides a better understanding of FMD assessment in patients with PA.

Open access

Xiaoli Liu, Lanxiang Liu, Rui Wang, Xiaojiao Jia, Binbin Liu, Ning Ma, and Qiang Lu

Background

We aimed to investigate early arteriosclerosis and its risk factors in populations with prediabetes and new-onset diabetes.

Materials and methods

A total of 148 participants who did not have diabetes mellitus were assigned to three groups through an oral glucose tolerance test: the normal glucose tolerance (NGT) group; the impaired glucose regulation, also known as prediabetes group and the new-onset type 2 diabetes mellitus group. The insulin resistance index was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR). An ELISA was used to determine the level of fibroblast growth factor 21 (FGF21). An arteriosclerosis detector was used to measure the brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI). The baPWV, ABI, and FGF21 were used to assess early arteriosclerosis.

Results

Significant differences in age, systolic blood pressure (SBP), fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), 2-h insulin (2hINS), and HOMA-IR were found between the NGT group and the prediabetes and new-onset diabetes groups. All of the above, except 2hINS, showed an increasing trend. Moreover, the FGF21 was higher in the new-onset diabetes group than in the NGT group. The baPWV was higher in the new-onset diabetes group than in the other two groups, but no significant difference was noted in the ABI. Age, SBP, diastolic blood pressure, FPG, 2hPG, and FGF21 were positively correlated with the baPWV. In addition, FPG, SBP, FGF21, and HOMA-IR were independent risk factors for the baPWV.

Conclusions

Patients with prediabetes and new-onset diabetes may have more significant early arteriosclerosis. The blood glucose level and insulin resistance index may be independent risk factors for early arteriosclerosis.