Plasma free fatty acids (FFAs) are elevated in obesity and can induce insulin resistance via endoplasmic reticulum (ER) stress. However, it is unknown whether hepatic insulin resistance caused by the elevation of plasma FFAs is alleviated by chemical chaperones. Rats received one of the following i.v. treatments for 48 h: saline, intralipid plus heparin (IH), IH plus the chemical chaperone 4-phenylbutyric acid (PBA), or PBA alone and a hyperinsulinemic-euglycemic clamp was performed during the last 2 h. PBA co-infusion normalized IH-induced peripheral insulin resistance, similar to our previous findings with an antioxidant and an IκBα kinase β (IKKβ) inhibitor. Different from our previous results with the antioxidant and IKKβ inhibitor, PBA also improved IH-induced hepatic insulin resistance in parallel with activation of Akt. Unexpectedly, IH did not induce markers of ER stress in the liver, but PBA prevented IH-induced elevation of phosphorylated eukaryotic initiation factor-2α protein in adipose tissue. PBA tended to decrease circulating fetuin-A and significantly increased circulating fibroblast growth factor 21 (FGF21) without affecting markers of activation of hepatic protein kinase C-δ or p38 mitogen-activated protein kinase that we have previously involved in hepatic insulin resistance in this model. In conclusion: (i) PBA prevented hepatic insulin resistance caused by prolonged plasma FFA elevation without affecting hepatic ER stress markers; (ii) the PBA effect is likely due to increased FGF21 and/or decreased fetuin-A, which directly signal to upregulate Akt activation.
Sandra Pereira, Jessy Moore, Jia-Xu Li, Wen Qin Yu, Husam Ghanim, Filip Vlavcheski, Yemisi Deborah Joseph, Paresh Dandona, Allen Volchuk, Carolyn L Cummins, Evangelia Tsiani, and Adria Giacca
Jing Hong, Wen-Yue Liu, Xiang Hu, Fei-Fei Jiang, Ze-Ru Xu, Fang Li, Fei-Xia Shen, and Hong Zhu
A prolonged heart rate-corrected QT interval (QTc) has been associated with peripheral artery disease (PAD) in the general population. However, no study to date has identified a link between prolonged QTc and the severity of PAD in patients with diabetes mellitus and foot ulcers (DFUs). This study aimed to investigate this relationship.
This multicenter study enrolled 281 patients with DFUs. The severity of PAD was classified into no severe PAD group (without stenosis or occlusion) and severe PAD group (with stenosis or occlusion) based on duplex ultrasonography. The association of prolonged QTc with severe PAD was evaluated in a multivariable mixed-effect logistic regression model, with the hospital as a random effect. Directed acyclic graphs were used to drive the selection of variables to fit the regression model.
Patients with severe PAD had longer QTc than those without. Based on the multivariable mixed-effect logistic regression model, a prolonged QTc was positively associated with severe PAD (odds ratio (OR) = 2.61; 95% CI: 1.07–6.35) and severe DFUs (Wagner grade score ≥ 3) (OR = 2.87; 95% CI: 1.42–5.81).
A prolonged QTc was associated with severe PAD in patients with DFUs. Further research is required to ascertain whether the association is causal.
Yen Kheng Tan, Yu Heng Kwan, David Choon Liang Teo, Marieke Velema, Jaap Deinum, Pei Ting Tan, Meifen Zhang, Joan Joo Ching Khoo, Wann Jia Loh, Linsey Gani, Thomas F J King, Eberta Jun Hui Tan, Shui Boon Soh, Vanessa Shu Chuan Au, Tunn Lin Tay, Lily Mae Quevedo Dacay, Keng Sin Ng, Kang Min Wong, Andrew Siang Yih Wong, Foo Cheong Ng, Tar Choon Aw, Yvonne Hui Bin Chan, Khim Leng Tong, Sheldon Shao Guang Lee, Siang Chew Chai, and Troy Hai Kiat Puar
In addition to increased cardiovascular risk, patients with primary aldosteronism (PA) also suffer from impaired health-related quality of life (HRQoL) and psychological symptoms. We assessed for changes in HRQoL and depressive symptoms in a cohort of Asian patients with PA, after surgical and medical therapy.
Thirty-four patients with PA were prospectively recruited and completed questionnaires from 2017 to 2020. HRQoL was assessed using RAND-36 and EQ-5D-3L, and depressive symptoms were assessed using Beck Depression Inventory (BDI-II) at baseline, 6 months, and 1 year post-treatment.
At 1 year post-treatment, significant improvement was observed in both physical and mental summative scores of RAND-36, +3.65, P = 0.023, and +3.41, P = 0.033, respectively, as well as four subscale domains (physical functioning, bodily pain, role emotional, and mental health). Significant improvement was also seen in EQ-5D dimension of anxiety/depression at 1 year post-treatment. Patients treated with surgery (n = 21) had significant improvement in EQ-5D index score post-treatment and better EQ-5D outcomes compared to the medical group (n = 13) at 1 year post-treatment. 37.9, 41.6 and 58.6% of patients had symptoms in the cognitive, affective and somatic domains of BDI-II, respectively. There was a significant improvement in the affective domain of BDI-II at 1 year post-treatment.
Both surgical and medical therapy improve HRQoL and psychological symptoms in patients with PA, with surgery providing better outcomes. This highlights the importance of early diagnosis, accurate subtyping and appropriate treatment of PA.
Ivar Følling, Anna B Wennerstrøm, Tor J Eide, and Hilde Loge Nilsen
Phaeochromocytomas are tumours originating in the medulla of the adrenal gland. They produce catecholamines, and some tumours also produce ectopic hormones. Two types of glucose imbalances occur in phaeochromocytoma patients, hyperglycaemia and hypoglycaemic attacks. Therefore, we tested whether insulin transcript (INS), insulin, and a hybrid read-through transcript between exons from insulin and insulin-like growth factor 2 (INS-IGF2) were expressed in phaeochromocytomas.
We measured the expression of insulin using immunohistochemistry. The expression of INS-IGF2 was determined by qRT-PCR in formalin-fixed and paraffin-embedded tissue from 20 phaeochromocytomas. The expression of INS and INS-IGF2 transcriptswas also analysed in 182 phaeochromocytomas and paragangliomas using publicly available datasets in The Cancer Genome Atlas (TCGA) Database.
Of 20 phaeochromocytomas, 16 stained positive for insulin. The distribution of positive cells was mostly scattered, with some focal expression indicating clonal expansion. Nineteen tumours expressed high levels of INS and INS-IGF2 transcripts. The expression of the two transcripts corresponded closely. In the TCGA dataset, phaeochromocytoma expresses higher levels of INS and INS-IGF2 transcripts compared to the normal non-tumour adrenal glands. Thus, the expression of INS and INS-IGF2 seems to be a general phenomenon in phaeochromocytoma.
Most phaeochromocytomas contain cells that overexpress INS and INS-IGF2 transcripts. Most tumours also display heterogeneous expression of polypeptides immunoreactive to monoclonal anti-insulin antibodies. Clinically this may relate to both hyperglycaemia and hypoglycaemic attacks seen in patients with phaeochromocytoma as well as autocrine tumour growth.
Keiko Ohkuwa, Kiminori Sugino, Mitsuji Nagahama, Wataru Kitagawa, Kenichi Matsuzu, Akifumi Suzuki, Chisato Tomoda, Kiyomi Hames, Junko Akaishi, Chie Masaki, and Koichi Ito
Radioactive iodine (RAI) therapy is effective for differentiated thyroid cancer (DTC) patients with lung metastasis. However, some patients have a poor prognosis despite the RAI accumulation. The utility of inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), has been reported as a prognostic factor for many carcinomas. This study aimed to investigate the risk factors related to DTC patient survival with RAI-avid lung metastasis and to attempt risk stratification.
Design and methods
This retrospective study included 123 patients with RAI-accumulating lung metastatic DTC. The cause-specific survival (CSS) rate from the time of detection of lung metastasis was tested using the Kaplan–Meier log-rank test, and the multivariate analysis was calculated using the Cox proportional hazards model. NLR was retrospectively calculated using the blood sample collected before initial RAI treatment. The NLR cutoff value was 2.6 on the ROC curve.
Age ≥ 55 years at the time of operative treatment, follicular carcinoma, lung metastasis tumor ≥ 10 mm in diameter, age ≥ 55 years at the time of detection of lung metastasis, age ≥ 55 years at the time of RAI treatment, and NLR ≥ 2.6 at the initial RAI treatment were predictive of decreased CSS. Multivariate analysis identified that the independent prognostic factors were lung metastatic tumor ≥ 10 mm in diameter and NLR ≥ 2.6. Patients in the high-risk group with both factors had significantly lower CSS rates than those in the low- and intermediate-risk groups with one or none of these factors.
The high-risk group patients had significantly poorer survival, and these patients could be considered as future candidates for tyrosine kinase inhibitor therapy.
Erika Biegelmeyer, Iury Scanagata, Laura Alves, Murilo Reveilleau, Fernando Pereira Schwengber, and Simone Magagnin Wajner
Low T3 syndrome refers to a set of thyroid hormone metabolism alterations present in the disease state. A correlation between low T3 and poor clinical outcomes in the intensive care unit is more established. Nonetheless, studies on non-critically ill patients are few and controversial.
To evaluate the prevalence and predictive value of low T3 levels on 30-day and 6-month mortality in non-critically ill patients. Secondary outcomes evaluated the length of hospital stay, overall mortality, and hospital readmission.
Prospective cohort study.
A total of 345 consecutive patients from the Internal Medicine ward of a tertiary hospital in southern Brazil were included and followed from October 2018 to April 2019 (6 months). Levels of total serum T3 were measured weekly, from admission to discharge, and correlated with 30-day and 6-month mortality.
Prevalence of low T3 was 36.6%. Low T3 levels were associated with higher 30-day hospital mortality (15.1% vs 4.1%, P < 0.001) and higher 6-month overall mortality (31.7% vs 13.2%, P < 0.001). Total serum T3 at admission was an independent predictor of 30-day hospital mortality.
Low T3 levels are a prevalent condition among non-critically ill patients, and this condition is associated with poor clinical outcomes in this population. Total serum T3 levels, alone or in association with other predictive scores, were demonstrated to be an easy and valuable tool for risk stratification and should be further employed in this setting.
Sarah Bakhamis, Faiqa Imtiaz, Khushnooda Ramzan, Edward De Vol, Osamah Al-Sagheir, Abdulrahman Al-Rajhi, 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 describe their clinical, biochemical, and molecular genetic features. We analyzed 27 patients from nine 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 the heterozygous mutation had hypocalcemic manifestations. Thirteen out of 18 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. Five out of 18 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 analyzing 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.
Li Yuanyuan, Li Dongmei, and Cheng Xingbo
Objective: Gestational diabetes mellitus (GDM) is common worldwide and seriously threatens maternal and infant health. The expression of non-coding RNA is tissue-specific and highly stable in eukaryotic cells and the circulatory system, which can act as an early molecular marker of GDM.
Methods: The differential expression of lncRNA and mRNA in the peripheral blood of patients with GDM (experimental group) and healthy pregnant women (control group) was analysed via lncRNA gene chip. Employing biological function clustering and KEGG signal pathway analysis, we selected the mRNAs and lncRNAs closely related to the insulin signal pathway of GDM to analys the possible regulatory mechanism in the pathogenesis of GDM. The sequencing results were further verified via quantitative polymerase chain reaction (Q-PCR).
Results: lncRNA microarray analysis revealed 7498 genes (3592 upregulated, 3906 downregulated) differentially expressed in the GDM group and healthy pregnant women control group, including 1098 differentially expressed lncRNAs (609 upregulated, 489 downregulated). According to the regulatory pathway of lncRNA mRNA network,six lncRNAs and four mRNAs were found to play a significant role in insulin resistance.
Conclusions: The lncRNAs ERMP1,TSPAN32 and MRPL38 form a co-expression network with TPH1, which is mainly involved in the tryptophan metabolism pathway and in the development of GDM, Moreover, lncRNA RPL13P5 forms a co-expression network with the TSC2 gene via the pi3k-akt and insulin signalling pathways, which are involved in the process of insulin resistance in GDM.
Reshma Aziz Merchant, Michael Wai Kit Wong, Jia Yi Lim, and John E Morley
Objective: To investigate the association of normal body mass index (BMI) with central obesity (CO), high BMI with CO, high BMI without CO, and normal BMI without CO, with function and cognition in older adults.
Methods: Cross-sectional study involving 754 participants ≥ 65 years. Data collected include demographics, cognition and physical measurements.
Results: Females had higher prevalence of high BMI with CO and lower prevalence of high BMI without CO than males (61.0% vs. 44.6% and 4.6% vs. 15.0% respectively). Within gender, CO groups, regardless of BMI, had lower mini-mental state examination (MMSE), handgrip strength (HGS) and Timed-Up-and-Go (TUG) scores. Overall, the high BMI without CO group had highest MMSE scores, HGS, and shortest TUG. Amongst males, HGS was significantly lower in the normal BMI with CO group (B -3.28, 95% CI -6.32 - -0.23, p=0.04). CO, regardless of normal/high BMI, had significantly longer TUG time (B 2.65, 95% CI 0.45 - 4.84, p = 0.02; B 1.07, 95% CI 0.25 - 1.88, p=0.01 respectively) than normal BMI without CO group. CO was associated with lower MMSE scores in both genders but significant only in males with normal BMI and CO (B -1.60, 95% CI -3.15 - -0.06, p=0.04).
Conclusion: CO may be a better predictor of obesity and adverse outcomes in older adults. High BMI without CO was associated with better outcomes especially in males but require further validation. Prospective longitudinal studies are needed to ascertain the impact of BMI and/or CO on function, cognition, mortality and gender differences.
Guang-Ran Yang, Dongmei Li, and Zidian Xie
There is a lack of consensus on whether a high 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.
Diabetes respondents aged over 18-year-old with complete information as well as undergone fundus examination in the past 2 years or had been diagnosed with DR were included. Weighted logistic regression analyses were used to identify the association of BMI with DR.
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 with 18,498 (86.5%) overweight and 11,353 (54.6%) obese. The mean BMI of the DR group (31.83 ± 7.41 kg/m2) was significantly higher than that of the non-DR group (31.41 ± 6.81 kg/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.
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.