Sonic hedgehog-heat shock protein 90ß axis promotes the development of nonalcoholic steatohepatitis in mice.

Sonic hedgehog (SHH) and heat shock protein 90ß (HSP90ß) have been implicated in nonalcoholic steatohepatitis (NASH) but their molecular mechanisms of action remain elusive. We find that HSP90ß is a key SHH downstream molecule for promoting NASH process. In hepatocytes, SHH reduces HSP90ß ubiquitylation through deubiquitylase USP31, thus preventing HSP90ß degradation and promoting hepatic lipid synthesis. HSP90ß significantly increases in NASH mouse model, leading to secretion of exosomes enriched with miR-28-5p. miR-28-5p directly targetes and decreases Rap1b levels, which in turn promotes NF-κB transcriptional activity in macrophages and stimulates the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90ß axis, or delivery of miR-28-5p to macrophages in the male mice liver, impairs NASH symptomatic development. Importantly, there is a markedly higher abundance of miR-28-5p in NASH patient sera. Taken together, the SHH-HSP90ß-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a NASH diagnostic biomarker.

CHI3L1 signaling impairs hippocampal neurogenesis and cognitive function in autoimmune-mediated neuroinflammation.

Chitinase-3-like protein 1 (CHI3L1) is primarily secreted by activated astrocytes in the brain and is known as a reliable biomarker for inflammatory central nervous system (CNS) conditions such as neurodegeneration and autoimmune disorders like neuromyelitis optica (NMO). NMO is an astrocyte disease caused by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4) and leads to vision loss, motor deficits, and cognitive decline. In this study examining CHI3L1's biological function in neuroinflammation, we found that CHI3L1 expression correlates with cognitive impairment in our NMO patient cohort. Activated astrocytes secrete CHI3L1 in response to AQP4 autoantibodies, and this inhibits the proliferation and neuronal differentiation of neural stem cells. Mouse models showed decreased hippocampal neurogenesis and impaired learning behaviors, which could be rescued by depleting CHI3L1 in astrocytes. The molecular mechanism involves CHI3L1 engaging the CRTH2 receptor and dampening ß-catenin signaling for neurogenesis. Blocking this CHI3L1/CRTH2/ß-catenin cascade restores neurogenesis and improves cognitive deficits, suggesting the potential for therapeutic development in neuroinflammatory disorders.

Inhibition of complement C3 signaling ameliorates locomotor and visual dysfunction in autoimmune inflammatory diseases.

Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by transverse myelitis and optic neuritis. The pathogenic serum IgG antibody against the aquaporin-4 (AQP4) on astrocytes triggers the activation of the complement cascade, causing astrocyte injury, followed by oligodendrocyte injury, demyelination, and neuronal loss. Complement C3 is positioned as a central player that relays upstream initiation signals to activate downstream effectors, potentially stimulating and amplifying host immune and inflammatory responses. However, whether targeting the inhibition of C3 signaling could ameliorate tissue injury, locomotor defects, and visual impairments in NMO remains to be investigated. In this study, using the targeted C3 inhibitor CR2-Crry led to a significant decrease in complement deposition and demyelination in both slice cultures and focal intracerebral injection models. Moreover, the treatment downregulated the expression of inflammatory cytokines and improved motor dysfunction in a systemic NMO mouse model. Similarly, employing serotype 2/9 adeno-associated virus (AAV2/9) to induce permanent expression of CR2-Crry resulted in a reduction in visual dysfunction by attenuating NMO-like lesions. Our findings reveal the therapeutic value of inhibiting the complement C3 signaling pathway in NMO.

Remyelination in neuromyelitis optica spectrum disorder is promoted by edaravone through mTORC1 signaling activation.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disease of the central nervous system that is manifested as secondary myelin loss. Oligodendrocyte progenitor cells (OPCs) are the principal source of myelinating oligodendrocytes (OLs) and are abundant in demyelinated regions of NMOSD patients, thus possibly representing a cellular target for pharmacological intervention. To explore the therapeutic compounds that enhance myelination due to endogenous OPCs, we screened the candidate drugs in mouse neural progenitor cell (NPC)-derived OPCs. We identified drug edaravone, which is approved by the Food and Drug Administration (FDA), as a promoter of OPC differentiation into mature OLs. Edaravone enhanced remyelination in organotypic slice cultures and in mice, even when edaravone was administered following NMO-IgG-induced demyelination, and ameliorated motor impairment in a systemic mouse model of NMOSD. The results of mechanistic studies in NMO-IgG-treated mice and the biopsy samples of the brain tissues of NMOSD patients indicated that the mTORC1 signaling pathway was significantly inhibited, and edaravone promoted OPC maturation and remyelination by activating mTORC1 signaling. Furthermore, pharmacological activation of mTORC1 signaling significantly enhanced myelin regeneration in NMOSD. Thus, edaravone is a potential therapeutic agent that promotes lesion repair in NMOSD patients by enhancing OPC maturation.

A new discriminant strategy combined with four TIRADS screening procedures increases ultrasound diagnostic accuracy-focusing on "wrong diagnostic" thyroid nodules.

OBJECTIVE: To utilize the discrepancies of different TIRADS, including ACR-TIRADS, Kwak-TIRADS, C-TIRADS, and EU-TIRADS, to explore methods for improving ultrasound diagnostic accuracy. METHODS: In total, 795 nodules with cytological or surgical pathology were included. All nodules were screened by the four TIRADS according to their diagnostic concordance (Screening procedures, SP). Discriminant strategy (DS) derived from predictor variables was combined with SP to construct the evaluation method (SP+DS). The diagnostic performance of the SP+DS method alone and its derivational methods and two-TIRADS combined tests was evaluated. RESULTS: A total of 86.8% (269/310) malignant nodules and 93.6% (365/390) benign cases diagnosed by the four TIRADS simultaneously were pathologically confirmed, while 12.0% (95/795) nodules could not be consistently diagnosed by them. The criteria of DS were that iso- or hyper-echogenicity nodules should be considered benign, while hypo- or marked hypo-echogenicity nodules malignant. For 95 inconsistently diagnosed nodules screened by at least two TIRADS, DS performed best with an accuracy of 79.0%, followed by Kwak-TIRADS (72.6%). In the overall sample, the sensitivity and AUC were highest for the SP+DS method compared to the four TIRADS (91.3%, 0.895). Combining ACR-TIRADS and Kwak-TIRADS via parallel test resulted in significant improvements in the sensitivity and AUC compared to ACR-TIRADS (89.2% vs. 81.4%, 0.889 vs. 0.863). Combining C-TIRADS and DS in serial resulted in the highest AUC (0.887), followed by Kwak-TIRADS (0.884), while EU-TIRADS was the lowest (0.879). CONCLUSIONS: For undetermined or suspected thyroid nodules, two-TIRADS combined tests can be used to improve diagnostic accuracy. Otherwise, considering the inconsistent diagnosis of two TIRADS may require attention to the echo characteristics to differentiate between benign and malignant nodules. KEY POINTS: • The discrepancies in the diagnostic performance of different TIRADS arise from their performance on inconsistently diagnosed nodules. • ACR-TIRADS improves sensitivity via combining with Kwak-TIRADS in parallel (from 81.4 to 89.2%), while C-TIRADS increases specificity via combining with EU-TIRADS in serial (from 80.9 to 85.7%). • If the diagnostic findings of two TIRADS are inconsistent, echo characteristics will be helpful for the differentiation of benign and malignant nodules with an accuracy of 79.0%.

The utility of serum anti-thyroglobulin antibody and thyroglobulin in the preoperative differential diagnosis of thyroid follicular neoplasms.

PURPOSE: Distinguishing follicular thyroid carcinoma (FTC) from follicular thyroid adenoma (FTA) before surgery is inherently challenging owing to the lack of malignant features on ultrasound, poor sensitivity of fine-needle biopsy, and the absence of definitive markers. We investigated whether thyroglobulin (Tg), anti-thyroglobulin antibody (TgAb), thyroid peroxidase antibodies (TPOAb), and thyroid stimulating hormone (TSH) can help differentiate FTC from FTA. METHODS: Data pertaining to 319 patients with follicular neoplasms were retrospectively analyzed. We compared the serum markers between patients with confirmed FTC and FTA. We also analyzed the prevalence of FTC in different subgroups of patients based on serum marker levels. RESULTS: TgAb was a risk factor for FTC. Compared to TgAb ≤11.68 IU/mL group, the odds ratio (OR) for FTC in TgAb 11.69-30.50 IU/mL group and TgAb >30.50 IU/mL group were 2.206 (1.114-4.369, P = 0.023) and 3.247 (1.684-6.260, P < 0.001), respectively. The prevalence of malignancy in TgAb >30.50 IU/mL group was significantly higher than in the TgAb ≤11.68 IU/mL group (32.9 vs. 13.1%, P = 0.001). In patients with TgAb (-) status, Tg was another risk factor for FTC. Compared to Tg ≤38.51 ng/mL group, OR of Tg >434.60 ng/mL group was 3.836 (1.625-9.058, P = 0.002); the prevalence of malignancy in the Tg >434.60 ng/mL group was 47.2% and higher than other groups. CONCLUSIONS: TgAb and Tg levels may be useful markers for preoperative differential diagnosis of follicular neoplasms. Higher TgAb and Tg levels were associated with greater malignant risk. Thus, we should be cautious of preoperative TgAb and Tg in follicular neoplasms.

Performance of current ultrasound-based malignancy risk stratification systems for thyroid nodules in patients with follicular neoplasms.

OBJECTIVES: To investigate the ability of the currently used ultrasound-based malignancy risk stratification systems for thyroid neoplasms (ATA, AACE/ACE/AME, K-TIRADS, EU-TIRADS, ACR-TIRADS and C-TIRADS) in distinguishing follicular thyroid carcinoma (FTC) from follicular thyroid adenoma (FTA). Additionally, we evaluated the ability of these systems in correctly determining the indication for biopsy. METHODS: Three hundred twenty-nine follicular neoplasms with definitive postoperative histopathology were included. The nodules were categorized according to each of six stratification systems, based on ultrasound findings. We dichotomized nodules into the positive predictive group of FTC (high and intermediate risk) and negative group of FTC based on the classification results. Missed biopsy was defined as neoplasms that were diagnosed as FTCs but for which biopsy was not indicated based on lesion classification. Unnecessary biopsy was defined as neoplasms that were diagnosed as FTAs but for whom biopsy was considered indicated based on classification. The diagnostic performance and missed and unnecessary biopsy rates were evaluated for each stratification system. RESULTS: The area under the curve of each system for distinguishing follicular neoplasms was < 0.700 (range, 0.511-0.611). The missed biopsy rates were 9.0-22.4%. The missed biopsy rates for lesions ≤ 4 cm and lesions sized 2-4 cm were 16.2-35.1% and 0-20.0%, respectively. Unnecessary biopsy rates were 65.3-93.1%. In ≤ 4 cm group, the unnecessary biopsy rates were 62.2-89.7%. CONCLUSION: The malignancy risk stratification systems can select appropriate nodules for biopsy in follicular neoplasms, while they have limitations in distinguishing follicular neoplasms and reducing unnecessary biopsy. Specific stratification systems and recommendations should be established for follicular neoplasms. KEY POINTS: • Current ultrasound-based malignancy risk stratification systems of thyroid nodules had low efficiency in the characterization of follicular neoplasms. • The adopted stratification systems showed acceptable performance for selecting FTC for biopsy but unsatisfactory performance for reducing unnecessary biopsy.

Sensitivity to Thyroid Hormone Indices Are Closely Associated With NAFLD.

Background: Previous studies on the association between thyroid function and non-alcoholic fatty liver disease (NAFLD) have contradicted. Acquired resistance to thyroid hormone theory might provide a reasonable explanation for these contradictions. We aimed to analyze the association between sensitivity to thyroid hormone indices with NAFLD. Methods: A total of 4,610 individuals from the health medical center of the First Hospital of China Medical University were included in this study. The previously used thyroid feedback quantile-based index (TFQIFT4) was calculated. Also, we substituted free triiodothyronine (FT3) into the TFQI formulas to get the TFQIFT3 index. NAFLD was defined using abdominal ultrasound. Results: Study results showed that FT3/FT4 and TFQIFT3 were positively correlated with the triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels (P<0.05) and negatively correlated with high-density lipoprotein cholesterol (HDL-C) level (P<0.05). In contrast, TFQIFT4 was positively correlated with HDL-C level (P < 0.05). After adjustment for multiple confounders, FT3, FT3/FT4, and TFQIFT3 were positively associated with the risks of dyslipidemia and NAFLD (P < 0.05). TFQIFT3 and FT3/FT4 performed better than TFQIFT4 on ROC analyses for NAFLD prediction, although the diagnostic sensitivity and specificity at the optimal cut-points were low. However, no association was observed between TFQIFT4 with the risks of dyslipidemia and NAFLD. Conclusion: TFQIFT3 and FT3/FT4 can be used as new indicators for predicting dyslipidemia and NAFLD, although with low sensitivity and specificity at the optimal cut-points, while TFQIFT4 has insufficient evidence in predicting dyslipidemia and NAFLD.

Thyroid Feedback Quantile-based Index correlates strongly to renal function in euthyroid individuals.

BACKGROUND: Previous studies have reported a negative relationship between thyroid-stimulating hormone (TSH) and renal function in euthyroid individuals, but others have found that higher free thyroxine (FT4) was associated with an increased risk of chronic kidney disease. This study was designed to analyze the relationship between thyroid and renal function from a new perspective of sensitivity to thyroid hormone. METHODS: This retrospective study included 2831 euthyroid individuals who underwent a health examination at the First Hospital of China Medical University between January 2017 and December 2018. Parametric Thyroid Feedback Quantile-based Index (PTFQIFT4), TSH index (TSHI), thyrotroph T4 resistance index (TT4RI), free triiodothyronine to FT4 ratio (FT3/FT4), the secretory capacity of the thyroid gland (SPINA-GT) and the sum activity of peripheral deiodinases (SPINA-GD) were calculated. We also innovated the TT3RI and PTFQIFT3 indices based on FT3 and TSH. Renal function was assessed by estimated glomerular filtration rate (eGFR) CKD-EPI and creatinine-cystatin C-KDIGO equations. RESULTS: After adjustment of basic characteristics and comorbidities, linear regression showed that eGFR CKD-EPI was positively associated with FT3/FT4 (ß = 23.31), and inversely correlated to PTFQI FT4 (ß= -2.69) (both p < .001). When comparing the fourth versus the first quartile of PTFQI FT4, the odds ratio (OR) for a reduced renal function was 1.89 (95% CI 1.28-2.80), and the OR was 0.64 (95% CI 0.43-0.95) when comparing quartiles of FT3/FT4 (both pfor trend< .05). In addition, for every 1SD increase in PTFQI FT4, the OR for a reduced renal function was 1.27 (95%CI 1.10-1.47). TSHI, TT4RI and TT3RI also showed a negative correlation to renal function. Similar results were obtained in SPINA-GD as in FT3/FT4. CONCLUSIONS: In euthyroid individuals, decreased sensitivity to thyroid hormone is associated with reduced renal function. The composite PTFQIFT4 index correlates more strongly to renal function than TSH or T4 alone.KEY MESSAGESDecreased sensitivity to thyroid hormone is associated with reduced renal function in the euthyroid population.The recently developed composite index PTFQIFT4 seems to correlate more strongly to renal function than individual TSH or FT4 parameters.Innovative indices TT3RI and PTFQIFT3 based on the interaction between T3 and TSH may also reflect sensitivity to thyroid hormone.

Waist-to-height ratio, an optimal anthropometric indicator for metabolic dysfunction associated fatty liver disease in the Western Chinese male population.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has been entitled as metabolic-dysfunction associated fatty liver disease (MAFLD). Therefore anthropometric indicators of adiposity may provide a non-invasive predictive and diagnostic tool for this disease. This study intended to validate and compare the MAFLD predictive and diagnostic capability of eight anthropometric indicators. METHODS: The study involved a population-based retrospective cross-sectional design. The Fangchenggang area male health and examination survey (FAMHES) was used to collect data of eight anthropometric indicators, involving body mass index (BMI), waist-to-height ratio (WHtR), waist-hip ratio (WHR), body adiposity index (BAI), cardiometabolic index (CMI), lipid accumulation product (LAP), visceral adiposity index (VAI), and abdominal volume index (AVI). Receiver operating characteristics (ROC) curves and the respective areas under the curves (AUCs) were utilized to compare the diagnostic capacity of each indicator for MAFLD and to determine the optimal cutoff points. Binary logistic regression analysis was applied to identify the odds ratios (OR) with 95% confidence intervals (95% CI) for all anthropometric indicators and MAFLD. The Spearman rank correlation coefficients of anthropometric indicators, sex hormones, and MAFLD were also calculated. RESULTS: All selected anthropometric indicators were significantly associated with MAFLD (P < 0.001), with an AUC above 0.79. LAP had the highest AUC [0.868 (95% CI, 0.853-0.883)], followed by WHtR [0.863 (95% CI, 0.848-0.879)] and AVI [0.859 (95% CI, 0.843-0.874)]. The cutoff values for WHtR, LAP and AVI were 0.49, 24.29, and 13.61, respectively. WHtR [OR 22.181 (95% CI, 16.216-30.340)] had the strongest association with MAFLD, regardless of potential confounders. Among all the anthropometric indicators, the strongest association was seen between LAP and sex hormones. CONCLUSION: All anthropometric indicators were associated with MAFLD. WHtR was identified as the strongest predictor of MAFLD in young Chinese males, followed by LAP and AVI. The strongest association was found between LAP and sex hormones.

Familial Dysalbuminemic Hyperthyroxinemia (FDH), Albumin Gene Variant (R218S), and Risk of Miscarriages in Offspring.

BACKGROUND: Familial dysalbuminemic hyperthyroxinemia (FDH) is a rare autosomal dominant disorder whose clinical characteristics remain incompletely understood, we investigated the role of albumin gene mutation in relation to miscarriage rate in a large pedigree of FDH followed up for 4 years. PATIENTS AND METHODS: The proband and extended family with unexplained miscarriage and hyperthyroxinemia were identified and genotypes in candidate genes and thyroid function tests (TFTs), including changes in TFTs during pregnancy were comprehensively assessed. We also evaluated the development and growth of children in this large FDH pedigree during four years follow-up. RESULT: The R218S variant in the albumin gene was identified in the proband and her relatives with hyperthyroxinemia who were diagnosed as FDH. Among the family members who underwent TFTs, 11 of 17 (65%) had similar changes in levels of thyroid hormone, with an estimated FDH heritability of 86%. Moreover, 32% (95% CI 16-54%) of FDH women experienced miscarriages at a rate that was substantially higher than the spontaneous abortion rate reported in the general population in China (7-14%). During the follow-up, results revealed that free triiodothyronine (fT3) and thyroid stimulating hormone (TSH) levels were normal during the entire gestational period; comparing to their age-adjusted peers, both FDH affected and FDH unaffected children in this pedigree appeared to have lower body weight and height. CONCLUSIONS: Albumin gene variant (R218S) not only causes FDH but also may be associated with a higher risk of miscarriages, although the growth of their children appears not to be affected by the age of 2 years.

[Accuracy of two thyroid imaging, reporting and data systems for differential diagnosis of benign and malignant thyroid nodules].

OBJECTIVE: To compare the accuracy of two widely used thyroid imaging, reporting and data systems (TI-RADS), namely ACR TI-RADS and Kwak TI-RADS, in the differential diagnosis of benign and malignant thyroid nodules. METHODS: We reviewed the data of 350 thyroid nodules with definite diagnoses by surgical histopathology (n=144, 41.14%) or fine needle aspiration (FNA) cytopathology (n=206, 58.86%). The nodules were graded using ACR TI-RADS and Kwak TI-RADS based on the ultrasound images, and the diagnostic accuracy of these two systems was evaluated by the area under the receiveroperating characteristic curve (AUC). RESULTS: The AUCs of ACR TI-RADS and Kwak TI-RADS were both 0.879. For a differential diagnosis of the thyroid nodules, ACR TI-RADS had a diagnostic sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, Youden's index and accuracy of 77.3%, 89.1%, 83.0%, 85.1%, 7.101, 0.255, 27.848, 0.664 and 0.843, respectively, with an optimal threshold of TR5, as compared with 84.8%, 84.0%, 78.3%, 89.0%, 5.283, 0.181, 29.265, 0.688 and 0.843, respectively, of Kwak TI-RADS, which had an optimal threshold of 4c. CONCLUSIONS: Both ACR TI-RADS and Kwak TI-RADS have good performance for differential diagnosis of thyroid nodules, but ACR TI-RADS has a higher specificity and a lower sensitivity compared with Kwak TI-RADS.

Dietary Manganese, Plasma Markers of Inflammation, and the Development of Type 2 Diabetes in Postmenopausal Women: Findings From the Women's Health Initiative.

OBJECTIVE: To examine the association between manganese intake and the risk of type 2 diabetes in postmenopausal women and determine whether this association is mediated by circulating markers of inflammation. RESEARCH DESIGN AND METHODS: We included 84,285 postmenopausal women without a history of diabetes from the national Women's Health Initiative Observational Study (WHI-OS). Replication analysis was then conducted among 62,338 women who participated in the WHI-Clinical Trial (WHI-CT). Additionally, data from a case-control study of 3,749 women nested in the WHI-OS with information on biomarkers of inflammation and endothelial dysfunction were examined using mediation analysis to determine the relative contributions of these known biomarkers by which manganese affects type 2 diabetes risk. RESULTS: Compared with the lowest quintile of energy-adjusted dietary manganese, WHI-OS participants in the highest quintile had a 30% lower risk of type 2 diabetes (hazard ratio [HR] 0.70 [95% CI 0.65, 0.76]). A consistent association was also confirmed in the WHI-CT (HR 0.79 [95% CI 0.73, 0.85]). In the nested case-control study, higher energy-adjusted dietary manganese was associated with lower circulating levels of inflammatory biomarkers that significantly mediated the association between dietary manganese and type 2 diabetes risk. Specifically, 19% and 12% of type 2 diabetes risk due to manganese were mediated through interleukin 6 and hs-CRP, respectively. CONCLUSIONS: Higher intake of manganese was directly associated with a lower type 2 diabetes risk independent of known risk factors. This association may be partially mediated by inflammatory biomarkers.

G protein-coupled receptor kinase-2: A potential biomarker for early diabetic cardiomyopathy.

BACKGROUND: G protein-coupled receptor kinase-2 (GRK2) has been shown as a key regulator of cardiac function, and the myocardial GRK2 levels are mirrored by the levels in peripheral blood mononuclear cells (PBMCs). In this study, we evaluated the myocardial and PBMCs GRK2 levels in early diabetic cardiomyopathy (DCM). METHODS: C57BL/KS-db/db male diabetic mice at 12 weeks of age, as the type 2 diabetes (T2DM) animal model of early DCM were evaluated. Forty-four T2DM patients with left ventricular diastolic dysfunction (LVDD), without evidence of hypertension, coronary artery diseases, congestive heart failure, and diabetic complications and without evidence of ischemia in a maximal treadmill exercise test, were recruited as the DM + LVDD group; 30 age-matched T2DM patients without LVDD were recruited as the DM control group. Left ventricular diastolic function was evaluated by cardiac tissue Doppler. The pseudonormal pattern of ventricular filling and E'/A' < 1 were regarded as LVDD. RESULTS: Compared to 8-week-old diabetic mice and 12-week-old control mice, GRK2-mRNA level and expression in myocardial tissues of 12-week-old diabetic mice were significantly increased, as well as the left ventricular wall thickness and systolic function. And the collagen volume fraction (CVF), collagen-3 expression, P53 expression, and cell apoptotic rate in the myocardium of 12-week-old diabetic mice elevated as well. The GRK2-mRNA level in PBMCs of DM with LVDD was significantly higher than in DM control without LVDD. CONCLUSIONS: GRK2 expression increased in the myocardial tissue and the PBMCs at the early stage of DCM. These data support further research on the role of GRK2 as the clinical biomarker for early DCM.

Dysregulation of PP2A-Akt interaction contributes to Sucrose non-fermenting related kinase (SNRK) deficiency induced insulin resistance in adipose tissue.

OBJECTIVE: We previously identified Sucrose non-fermenting related kinase (SNRK) as a regulator of adipose inflammation and energy homeostasis. In this study, we aimed to investigate the role of SNRK in insulin signaling in white (WAT) and brown adipose tissue (BAT). METHODS: Adipose tissue specific (SNRK deficiency in both WAT and BAT) and BAT specific knockout mouse models were employed. Phosphoproteomic studies were conducted to identify the novel SNRK pathway regulating insulin signaling in adipose tissue. RESULTS: SNRK ablation is sufficient to inhibit insulin-stimulated AKT phosphorylation and glucose uptake in both WAT and BAT. Phosphoproteomic study using SNRK deficient versus wild type BAT samples revealed 99% reduction of phosphorylation on Serine 80 of PPP2R5D, the regulatory subunit of Protein phosphatase 2A (PP2A). Drastic (142.5-fold) induction of phosphorylation on Serine 80 of PPP2R5D was observed in SNRK-deficient primary brown adipocytes overexpressing SNRK compared to control protein. In vitro phosphorylation reaction followed by targeted phosphoproteomic detection further confirms that human recombinant SNRK is able to phosphorylate human recombinant PPP2R5D. Dephosphorylated PPP2R5D promotes constitutive assembly of PP2A-AKT complex, therefore inhibits insulin-induced AKT phosphorylation and subsequent glucose uptake in both BAT and WAT. Knockdown of PPP2R5D in adipocytes can improve insulin sensitivity in adipocytes without SNRK expression. CONCLUSIONS: Our findings demonstrate that SNRK regulates insulin signaling through controlling PPP2R5D phosphorylation, which subsequently impacts PP2A activity and then AKT phosphorylation in both WAT and BAT. SNRK may represent a promising potential target for treating insulin resistance-related metabolic disorders.

Sugar-sweetened beverage intake and serum testosterone levels in adult males 20-39 years old in the United States.

BACKGROUND: This population-based study was designed to investigate whether consumption of sugar-sweetened beverages (SSB) is associated with lower serum total testosterone concentration in men 20-39 years old. METHODS: All data for this study were retrieved from the National Health and Nutrition Examination Survey (NHANES) 2011-2012. The primary outcome was serum testosterone concentration, and main independent variable was SSB intake. Other variables included age, race/ethnicity, poverty/income ratio, body mass index (BMI), serum cotinine, heavy drinking, and physical activity. RESULTS: Among all subjects (N = 545), 486 (90.4%) had normal testosterone levels (defined as ≥231 ng/dL) and 59 (9.6%) had low testosterone levels (defined as < 231 ng/dL). Multivariate logistic regression revealed the odds of low testosterone was significantly greater with increasing SSB consumption (Q4 [≥442 kcal/day] vs. Q1 [≤137 kcal/day]), adjusted odds ratio [aOR] = 2.29, p = 0.041]. After adjusting for possible confounding variables, BMI was an independent risk factor for low testosterone level; subjects with BMI ≥ 25 kg/m2 had a higher risk of having a low testosterone level than those with BMI < 25 kg/m2 (aOR = 3.68, p = 0.044). CONCLUSION: SSB consumption is significantly associated with low serum testosterone in men 20-39 years old in the United States.

[Correlation between ectopic fat accumulation and insulin sensitivity in obese individuals with different glucose tolerance levels].

OBJECTIVE: To investigate the correlation between liver and skeletal muscle fat contents and insulin resistance in obese individuals with different levels of glucose tolerance. METHODS: RESULTS: Ten non-obese individuals with normal glucose tolerance (NGT), 9 obese individuals with NGT, and 7 obese individuals with impaired glucose tolerance (IGT) were enrolled in this study. All the participants were examined for insulin sensitivity by hyperinsulinemic-euglycemic clamp and for liver and skeletal muscle fat accumulation quantified by proton magnetic resonance spectroscopy (1H MRS). The data were collected from the subjects including somatometric measurements, fasting plasma glucose, 2-h plasma glucose (2hPG), fasting insulin, and blood biochemistry. Linear correlation analysis and multiple linear stepwise regression analysis were used to analyze the relationship between ectopic fat accumulation and insulin resistance. RESULTS: The glucose infusion rates (GIR, presented as the M value) differed significantly among IGT-obese (3.95∓1.66 mg·kg-1·min-1), NGT-obese (6.14∓1.90 mg·kg-1·min-1) and NGT-non-obese (8.78∓2.46 mg·kg-1·min-1) groups (P<0.05). The 3 groups also showed significant differences in liver fat contents [(15.23∓3.09)%, (6.25∓0.38)%, and (1.89∓0.90)%, respectively, P<0.05] and intramyocellular lipids in the tibialis anterior (2.69∓0.95, 2.61∓1.45, and 1.54∓0.66 mmol/kg, respectively, P<0.05). Linear analysis revealed that liver fat content, but not skeletal muscle fat content, was significantly correlated with the M value. Multiple linear stepwise regression analysis using M value as the dependent variable (Y) revealed that liver fat content (X) was an independent factor inversely correlated with the M value (regression equation: Y=-30.562X+9.007, R2=0.717, P<0.01). CONCLUSIONS: Liver fat accumulation, but not skeletal muscle fat accumulation, is correlated with insulin resistance and impaired glucose metabolism.

Predictors of cardiorespiratory fitness in female and male adults with different body mass index: National Health and Nutrition Examination Survey 1999-2004 dataset.

BACKGROUND: The aim of this study was to explore factors affecting cardiorespiratory fitness in males and females with different body mass index (BMI). METHODS: The National Health and Nutrition Examination Survey 1999-2004 data were used for this retrospective study. Estimated maximal oxygen uptake (VO2max) is surrogate for cardiorespiratory fitness (CRF). Univariate and multivariate linear regression analyses were performed to explore whether study variables were associated with estimated VO2max stratified by gender and BMI categories. RESULTS: A total of 3292 subjects 20-49 years of age were included in the analysis. CRF significantly decreased as BMI increased in both females and males. Ethnic difference was found in normal BMI in both genders and obese females; homocysteine was significantly negatively associated with estimated VO2max, as was total cholesterol. Obese male subjects with diabetes had a lower estimated VO2max than those without diabetes, and C-reactive protein (CRP) level and vitamin B12 level were significantly negatively associated with CRF. Female subjects with diabetes had higher estimated VO2max than those without diabetes. Folate was significantly positively correlated with estimated VO2max, whereas CRP was negatively correlated in obese female. CONCLUSIONS: There are different predictors of CRF in males and females, and in individuals with different BMI. Key messages Different BMI classes are associated with different predictors of cardiorespiratory fitness. Indicators of cardiorespiratory fitness differ between sexes.

Continuous positive airway pressure and diabetes risk in sleep apnea patients: A systemic review and meta-analysis.

BACKGROUND: The study assessed the effect of continuous positive airway pressure (CPAP) therapy on the risk of developing type 2 diabetes by evaluating change in the homeostasis model assessment of insulin resistance (HOMA-IR) fasting blood glucose (FBG) and fasting insulin following CPAP treatment in non-diabetic patients and pre-diabetic with obstructive sleep apnea (OSA). METHODS: Medline, PubMed, Cochrane, and EMBASE databases were searched until August 24, 2015. The analysis included randomized controlled trials (RCTs), two arm prospective studies, cohort studies, and retrospective studies. The primary outcome measure was change of HOMA-IR in pre-diabetic patients receiving CPAP treatment. RESULTS: Twenty-three studies were included with 965 patients who had OSA. Nineteen studies were prospective studies and four were RCTs. CPAP therapy resulted in a significant reduction in the pooled standard difference in means of HOMA-IR (-0.442, P=0.001) from baseline levels compared with the control group. Change in FBG and fasting insulin from baseline levels was similar for the CPAP and control groups. For RCT studies (n=4), there was no difference in change in HOMA-IR or FBG levels from baseline between CPAP and control groups. The combined effect of RCTs showed that CPAP was associated with a significant reduction in change from baseline in fasting insulin than the control group (standardized diff. in means between groups=-0.479, P value=0.003). CONCLUSION: These findings support the use of CPAP in non-diabetic and pre-diabetic patients with OSA to reduce change of HOMA-IR and possibly reduce the risk of developing type 2 diabetes in this patient population.

[Efficacy of ultrasound-guided lauromacrogol sclerotherapy for benign thyroid cysts and factors affecting the therapeutic effect].

OBJECTIVE: To evaluate the clinical efficacy of ultrasound-guided lauromacrogol sclerotherapy for benign thyroid cysts and analyze the factors affecting the efficacy. METHODS: Ultrasound-guided lauromacrogol sclerotherapy was performed in 97 patients with a total of 99 benign thyroid cysts. The changes in cystic volume and other thyroid parameters were evaluated at 1, 3, 6, and 12 months after sclerotherapy. According to changes in the cystic volume, the efficacy of sclerotherapy was defined as therapeutic failure (with a volume reduction <50%), treatment success (volume reduction ≥50%) and cure (volume reduction ≥90%). The factors of affecting the efficacy of sclerotherapy was analyzed using COX regression. RESULTS: The mean cystic volume at 1, 3, 6 and 12 months after sclerotherapy were reduced from the baseline volume of 12.08∓11.56 cm3 to 5.63∓8.51 cm3, 5.96∓8.42 cm3, 3.80∓5.50 cm3 and 2.85∓3.98 cm3, respectively, with an average cystic volume reduction rate of (70.02∓33.72)%. Therapeutic success was achieved 82 of the 99 cysts (82.83%) and cure was achieved 63cysts (63.64%) at 12 months after the procedure. A second sclerotherapy was performed for 13 cysts which did not show a volume reduction at 1-3 months after the initial procedure. A disease course of over 12 months was an independent risk factor for a second sclerotherapy (23.7% [9/38] vs 6.6% [4/61], OR=4.473 [1.238-16.169], P=0.022). The efficacy of sclerotherapy was related to cystic cavity separation, cystic fluid viscosity, cystic/solid ratio and cystic wall thickness. COX regression analysis revealed that cystic cavity separation (HR=2.25, 95%CI: 1.19-4.25) and cystic fluid viscosity (HR=2.02, 95%CI: 1.19-3.43) were the major factors affecting the treatment efficacy. CONCLUSION: Ultrasound-guided lauromacrogol sclerotherapy is effective and safe for treatment of benign thyroid cysts, and the maximal treatment effect can be achieved at 6 months after sclerotherapy and in cases of uncomplicated cysts with non-viscous cystic fluid, no solid cystic cavity separation and a disease course of less than 12 months.