Correction: Runx1 is a central regulator of osteogenesis for bone homeostasis by orchestrating BMP and WNT signaling pathways.

[This corrects the article DOI: 10.1371/journal.pgen.1009233.].

Runx1 is a central regulator of osteogenesis for bone homeostasis by orchestrating BMP and WNT signaling pathways.

Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1f/fTwist2-Cre) and osteoblast-specific (Runx1f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/ß-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast-adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/ß-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis.

Fat distribution measurements by chemical shift-encoded transition region extraction predict the risk of hyperglycaemia, dyslipidaemia and metabolic syndrome in mice.

Metabolically healthy or unhealthy obesity is closely related to metabolic syndrome (MetS). To validate a more accurate diagnostic method for obesity that reflects the risk of metabolic disorders in a pre-clinical mouse model, C57BL/6J mice were fed high-sucrose-high-fat and chow diets for 12 weeks to induce obesity. MRI was performed and analysed by chemical shift-encoded fat-water separation based on the transition region extraction method. Abdominal fat was divided into upper and lower abdominal regions at the horizontal lower border of the liver. Blood samples were collected, and the glucose level, lipid profile, liver function, HbA1c and insulin were tested. k-means clustering and stepwise logistic regression were applied to validate the diagnosis of hyperglycaemia, dyslipidaemia and MetS, and to ascertain the predictive effect of MRI-derived parameters to the metabolic disorders. Pearson or Spearman correlation was used to assess the relationship between MRI-derived parameters and metabolic traits. The receiver-operating characteristic curve was used to evaluate the diagnostic effect of each logistic regression model. A two-sided p value less than 0.05 was considered to indicate statistical significance for all tests. We made the precise diagnosis of obesity, dyslipidaemia, hyperglycaemia and MetS in mice. In all, 14 mice could be diagnosed as having MetS, and the levels of body weight, HbA1c, triglyceride, total cholesterol and low-density lipoprotein cholesterol were significantly higher than in the normal group. Upper abdominal fat better predicted dyslipidaemia (odds ratio, OR = 2.673; area under the receiver-operating characteristic curve, AUCROC = 0.9153) and hyperglycaemia (OR = 2.456; AUCROC = 0.9454), and the abdominal visceral adipose tissue (VAT) was better for predicting MetS risk (OR = 1.187; AUCROC = 0.9619). We identified the predictive effect of fat volume and distribution in dyslipidaemia, hyperglycaemia and MetS. The upper abdominal fat played a better predictive role for the risk of dyslipidaemia and hyperglycaemia, and the abdominal VAT played a better predictive role for the risk of MetS.

Notch1 is a marker for in situ resting osteocytes in a 3-dimensional gel culture model.

PURPOSE: Osteocytes in vivo exhibit different functional states, but no specific marker to distinguish these is currently available. MATERIALS AND METHODS: To simulate the differentiation process of pre-osteoblasts to osteocytes in vitro, MC3T3-E1 cells were cultured on type I collagen gel and a three-dimensional (3D) culture system was established. The Notch expression of osteocyte-like cells in 3D culture system was compared with that of in situ osteocytes in bone tissues. RESULTS: Immunohistochemistry demonstrated that Notch1 was not detected in "resting" in situ osteocytes, but was detected in normal cultured osteocyte-like cell line MLO-Y4. Osteocytes obtained from conventional osteogenic-induced osteoblasts and long-term cultured MLO-Y4 cells could not replicate the Notch1 expression pattern from in situ osteocytes. From day 14-35 of osteogenic induction, osteoblasts in 3D culture system gradually migrated into the gel to form canaliculus-like structures similar to bone canaliculus. On day 35, stellate-shaped osteocyte-like cells were observed, and expression of DMP1 and SOST, but not Runx2, was detected. Notch1 was not detected by immunohistochemistry, and Notch1 mRNA level was not significantly different from that of in situ osteocytes. In MC3T3-E1 cells, down-regulation of Notch2 increased Notch1, Notch downstream genes (ß-catenin and Nfatc1), and Dmp1. In MLO-Y4 cells, Notch2 decreased after Notch1 siRNA transfection. Downregulation of Notch1 or Notch2 decreased Nfatc1, ß-catenin, and Dmp1, and increased Sost. CONCLUSIONS: We established "resting state" osteocytes using an in vitro 3D model. Notch1 can be a useful marker to help differentiate the functional states of osteocytes (activated vs. resting state).

Hyperglycemia and blood glucose deterioration are risk factors for severe COVID-19 with diabetes: A two-center cohort study.

We aimed to assess whether blood glucose control can be used as predictors for the severity of 2019 coronavirus disease (COVID-19) and to improve the management of diabetic patients with COVID-19. A two-center cohort with a total of 241 confirmed cases of COVID-19 with definite outcomes was studied. After the diagnosis of COVID-19, the clinical data and laboratory results were collected, the fasting blood glucose levels were followed up at initial, middle stage of admission and discharge, the severity of the COVID-19 was assessed at any time from admission to discharge. Hyperglycemia patients with COVID-19 were divided into three groups: good blood glucose control, fair blood glucose control, and blood glucose deterioration. The relationship of blood glucose levels, blood glucose control status, and severe COVID-19 were analyzed by univariate and multivariable regression analysis. In our cohort, 21.16% were severe cases and 78.84% were nonsevere cases. Admission hyperglycemia (adjusted odds ratio [aOR], 1.938; 95% confidence interval [95% CI], 1.387-2.707), mid-term hyperglycemia (aOR, 1.758; 95% CI, 1.325-2.332), and blood glucose deterioration (aOR, 22.783; 95% CI, 2.661-195.071) were identified as the risk factors of severe COVID-19. Receiver operating characteristic (ROC) curve analysis, reaching an area under ROC curve of 0.806, and a sensitivity and specificity of 80.40% and 68.40%, respectively, revealed that hyperglycemia on admission and blood glucose deterioration of diabetic patients are potential predictive factors for severe COVID-19. Our results indicated that admission hyperglycemia and blood glucose deterioration were positively correlated with the risk factor for severe COVID-19, and deterioration of blood glucose may be more likely to the occurrence of severe illness in COVID-19.

Runt-related transcription factor 1 is required for murine osteoblast differentiation and bone formation.

Despite years of research investigating osteoblast differentiation, the mechanisms by which transcription factors regulate osteoblast maturation, bone formation, and bone homeostasis is still unclear. It has been reported that runt-related transcription factor 1 (Runx1) is expressed in osteoblast progenitors, pre-osteoblasts, and mature osteoblasts; yet, surprisingly, the exact function of RUNX1 in osteoblast maturation and bone formation remains unknown. Here, we generated and characterized a pre-osteoblast and differentiating chondrocyte-specific Runx1 conditional knockout mouse model to study RUNX1's function in bone formation. Runx1 ablation in osteoblast precursors and differentiating chondrocytes via osterix-Cre (Osx-Cre) resulted in an osteoporotic phenotype and decreased bone density in the long bones and skulls of Runx1f/fOsx-Cre mice compared with Runx1f/f and Osx-Cre mice. RUNX1 deficiency reduced the expression of SRY-box transcription factor 9 (SOX9), Indian hedgehog signaling molecule (IHH), Patched (PTC), and cyclin D1 in the growth plate, and also reduced the expression of osteocalcin (OCN), OSX, activating transcription factor 4 (ATF4), and RUNX2 in osteoblasts. ChIP assays and promoter activity mapping revealed that RUNX1 directly associates with the Runx2 gene promoter and up-regulates Runx2 expression. Furthermore, the ChIP data also showed that RUNX1 associates with the Ocn promoter. In conclusion, RUNX1 up-regulates the expression of Runx2 and multiple bone-specific genes, and plays an indispensable role in bone formation and homeostasis in both trabecular and cortical bone. We propose that stimulating Runx1 activity may be useful in therapeutic approaches for managing some bone diseases such as osteoporosis.

Insulin receptor substrate-1 inhibits high-fat diet-induced obesity by browning of white adipose tissue through miR-503.

Genetic variation of insulin receptor substrate 1 (IRS-1) was found to modulate the insulin resistance of adipose tissues, but the underlying mechanism was not clear. To investigate how the IRS-1 was involved in the browning of white adipose tissue through miRNA, we identified a mutated Irs-1 (Irs-1-/- ) mice model and found that this mice had a reduced subcutaneous WAT (sWAT) and increased brown adipose tissue (BAT) in the interscapular region. So we isolated the bone marrow stromal cells and analyzed differentially expressed miRNAs and adipogenesis-related genes with miRNA arrays and PCR arrays. Irs-1-/- mice showed decreased miR-503 expression, but increased expression of its target, bone morphogenetic protein receptor type 1a (BMPR1a). Overexpression of miR-503 in preadipocytes downregulated BMPR1a and impaired adipogenic activity through the phosphotidylinositol 3-kinase (PI3K/Akt) pathway, while the inhibitor had the opposite effect. In both Irs-1-/- and cold-induced models, sWAT exhibited BAT features, and showed tissue-specific increased BMPR1a expression, PI3K expression, and Akt phosphorylation. Thus, our results showed that IRS-1 regulated brown preadipocyte differentiation and induced browning in sWAT through the miR-503-BMPR1a pathway, which played important roles in high-fat diet-induced obesity.

Runx1 up-regulates chondrocyte to osteoblast lineage commitment and promotes bone formation by enhancing both chondrogenesis and osteogenesis.

One of the fundamental questions in bone biology is where osteoblasts originate and how osteoblast differentiation is regulated. The mechanism underlying which factors regulate chondrocyte to osteoblast lineage commitment remains unknown. Our data showed that Runt-related transcription factor 1 (Runx1) is expressed at different stages of both chondrocyte and osteoblast differentiation. Runx1 chondrocyte-specific knockout (Runx1f/fCol2α1-cre) mice exhibited impaired cartilage formation, decreased bone density, and an osteoporotic phenotype. The expressions of chondrocyte differentiation regulation genes, including Sox9, Ihh, CyclinD1, PTH1R, and hypertrophic chondrocyte marker genes including Col2α1, Runx2, MMP13, Col10α1 in the growth plate were significantly decreased in Runx1f/fCol2α1-cre mice chondrocytes. Importantly, the expression of osteoblast differentiation regulation genes including Osx, Runx2, ATF4, and osteoblast marker genes including osteocalcin (OCN) and osteopontin (OPN) were significantly decreased in the osteoblasts of Runx1f/fCol2α1-cre mice. Notably, our data showed that osteoblast differentiation regulation genes and marker genes are also expressed in chondrocytes and the expressions of these marker genes were significantly decreased in the chondrocytes of Runx1f/fCol2α1-cre mice. Our data showed that chromatin immunoprecipitation (ChIP) and promoter mapping analysis revealed that Runx1 directly binds to the Indian hedgehog homolog (Ihh) promoter to regulate its expression, indicating that Runx1 directly regulates the transcriptional expression of chondrocyte genes. Collectively, we revealed that Runx1 signals chondrocyte to osteoblast lineage commitment and promotes endochondral bone formation through enhancing both chondrogenesis and osteogenesis genes expressions, indicating Runx1 may be a therapeutic target to enhance endochondral bone formation and prevent osteoporosis fractures.

Higher Serum Neuropeptide Y Levels Are Associated with Metabolically Unhealthy Obesity in Obese Chinese Adults: A Cross-Sectional Study.

OBJECTIVE: Neuropeptide Y (NPY), an orexigenic peptide known to cause hyperphagia, has been involved in the occurrence and development of obesity. However, differences in the distribution of serum NPY levels in obese phenotypes (including metabolically unhealthy obesity (MUO) phenotype and metabolically healthy obesity (MHO) phenotype) and the association of NPY with MUO phenotype have not been unequivocally established. We therefore determined associations of serum NPY levels with MUO phenotype in obese Chinese adults. METHODS: A cross-sectional study was conducted from 400 obese adults in Hunan province, who underwent a health examination in the Second Xiangya Hospital, and 164 participants were finally enrolled in the study and divided into MHO and MUO groups. Serum NPY levels were examined; univariate and multivariate analyses as well as smooth curve fitting analyses were conducted to measure the association of NPY serum levels with the MUO phenotype. RESULTS: Serum NPY levels were significantly elevated in the MUO group compared with the MHO group ((667.69 ± 292.90) pg/mL vs. (478.89 ± 145.53) pg/mL, p < 0.001). A threshold and nonlinear association between serum NPY levels and MUO was found (p = 0.001). When serum NPY levels exceeded the turning point (471.5 pg/mL), each 10 pg/mL increment in the NPY serum level was significantly associated with an 18% increased odds ratio of MUO phenotype (OR: 1.18, 95% CI: 1.07-1.29, p = 0.0007) after adjusted for confounders. CONCLUSIONS: Higher NPY serum levels were positively correlated with MUO phenotype in obese Chinese adults.

Flavonoid genistein protects bone marrow sinusoidal blood vessels from damage by methotrexate therapy in rats.

Cancer chemotherapy can cause significant damage to the bone marrow (BM) microvascular (sinusoidal) system. Investigations must now address whether and how BM sinusoidal endothelial cells (SECs) can be protected during chemotherapy. Herein we examined the potential protective effects of genistein, a soy-derived flavonoid, against BM sinusoidal damage caused by treatment with methotrexate (MTX). The groups of young adult rats were gavaged daily with genistein (20 mg/kg) or placebo. After 1 week, rats also received daily injections of MTX (0.75 mg/kg) or saline for 5 days and were killed after a further 4 days. Histological analyses showed that BM sinusoids were markedly dilated ( p < 0.001) in the MTX-alone group but were unaffected or less dilated in the genistein+MTX group. In control rats, genistein significantly enhanced expression of vascular endothelial growth factor (VEGF; p < 0.01), particularly in osteoblasts, and angiogenesis marker CD31 ( p < 0.001) in bone. In MTX-treated rats, genistein suppressed MTX-induced apoptosis of BM SECs ( p < 0.001 vs MTX alone group) and tended to increase expression of CD31 and VEGF ( p < 0.05). Our in vitro studies showed that genistein in certain concentrations protected cultured SECs from MTX cytotoxic effects. Genistein enhanced tube formation of cultured SECs, which is associated with its ability to induce expression of endothelial nitric oxide synthase and production of nitric oxide. These data suggest that genistein can protect BM sinusoids during MTX therapy, which is associated, at least partially, with its indirect effect of promoting VEGF expression in osteoblasts and its direct effect of enhancing nitric oxide production in SECs.

C/ebpα controls osteoclast terminal differentiation, activation, function, and postnatal bone homeostasis through direct regulation of Nfatc1.

Osteoclast lineage commitment and differentiation have been studied extensively, although the mechanism by which transcription factor(s) control osteoclast terminal differentiation, activation, and function remains unclear. CCAAT/enhancer-binding protein α (C/ebpα) has been reported to be a key regulator of osteoclast cell lineage commitment, yet C/ebpα's roles in osteoclast terminal differentiation, activation and function, and bone homeostasis, under physiological or pathological conditions, have not been studied because newborn C/ebpα-null mice die within several hours after birth. Furthermore, the function of C/ebpα in osteoclast terminal differentiation, activation, and function is largely unknown. Herein, we generated and analyzed an osteoclast-specific C/ebpα conditional knockout (CKO) mouse model via Ctsk-Cre mice and found that C/ebpα-deficient mice exhibited a severe osteopetrosis phenotype due to impaired osteoclast terminal differentiation, activation, and function, including mildly reduced osteoclast number, impaired osteoclast polarization, actin formation, and bone resorption, which demonstrated the novel function of C/ebpα in cell function and terminal differentiation. Interestingly, C/ebpα deficiency did not affect bone formation or monocyte/macrophage development. Our results further demonstrated that C/ebpα deficiency suppressed the expression of osteoclast functional genes, e.g. encoding cathepsin K (Ctsk), Atp6i (Tcirg1), and osteoclast regulator genes, e.g. encoding c-fos (Fos), and nuclear factor of activated T-cells 1 (Nfatc1), while having no effect on Pu.1 (Spi1) expression. Promoter activity mapping and ChIP assay defined the critical cis-regulatory element (CCRE) in the promoter region of Nfatc1, and also showed that the CCREs were directly associated with C/ebpα, which enhanced the promoter's activity. The deficiency of C/ebpα in osteoclasts completely blocked ovariectomy-induced bone loss, indicating that C/ebpα is a promising new target for the treatment of osteolytic diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Body mass index and C-peptide are important for the promptly differential diagnosis of maturity-onset diabetes from familial type 2 diabetes in outpatient clinic.

Type 2 diabetic patients are becoming younger and having a tendency to family aggregation, they are easily suspected as maturity-onset diabetes of young (MODY) in the outpatient clinic and send to genetic testing. 9 diabetic families were compared in our outpatient clinic who met the primary diagnosis criteria of MODY. Detailed clinical features and laboratory data including gene sequence were collected and analyzed. The patients met the primary clinical diagnostic criteria of MODY for genetic testing at the first look. However, members of families A1 to A3 had normal Body mass index (BMI) and a lower C-peptide level which indicated impaired pancreatic islet function. In contrast, the members with diabetes of families B1 to B6 had normal or increased C-peptide level which indicated insulin resistance and were overweight with BMI. Genetic testing showed that the mutations in HNF1A, INS, KCNJ11 and so on in families A were consistent with the diagnosis of MODY. No pathogenic mutation was found in the members of families B which were diagnosed with familial T2D. Before the clinical laboratory testing and the further gene test, BMI and the concentration of C-peptide are important for the promptly differential diagnosis of MODY from familial type 2 diabetes and medication instruction in the outpatient clinic which could help to alleviate the burden of genetic testing for them.

Insulin-like growth factor-1 promotes osteogenic differentiation and collagen I alpha 2 synthesis via induction of mRNA-binding protein LARP6 expression.

This study explored the mechanism underlying the stimulation of collagen synthesis and osteoblastic differentiation by insulin-like growth factor 1 (IGF1) in primary mouse osteoblasts. Primary mouse calvarial osteoblasts were cultured and treated with various doses of IGF1 before transfection with siRNA targeting the collagen type I alpha 2 (Col1a2) or La ribonucleoprotein domain family member 6 (Larp6) genes. Alkaline phosphatase (ALP) activity, osteocalcin staining, alizarin red quantification and the expression level of runt-related transcription factor 2 (RUNX2) were performed to assess the differentiation of pre-osteoblasts. Based on Western blot analysis, IGF1 up-regulated COL1A2 protein expression in the primary osteoblasts in a dose- and time-dependent manner. In addition, Col1a2 interference inhibited the differentiation and mineralization of osteoblasts. IGF1 also stimulated the differentiation of mouse primary osteoblasts and increased LARP6 expression during osteogenic differentiation. RNA-Immunoprecipitation (IP) indicated that LARP6 could bind to Col1a2 mRNA after IGF1 stimulation. However, transfection of Larp6-specific siRNA significantly reduced collagen and ALP secretion, mineralization and inhibited the expression of osteocalcin and RUNX2, indicating that Larp6 interference inhibited the differentiation ability of primary mouse calvarial osteoblasts, and these effects could not be reversed by IGF1. Thus, IGF1 could promote COL1A2 expression and osteoblast differentiation in primary mouse calvarial pre-osteoblasts by increasing LARP6 expression via a posttranscriptional mechanism.

Insulin receptor substrate-1 time-dependently regulates bone formation by controlling collagen Iα2 expression via miR-342.

Insulin promotes bone formation via a well-studied canonical signaling pathway. An adapter in this pathway, insulin-receptor substrate (IRS)-1, has been implicated in the diabetic osteopathy provoked by impaired insulin signaling. To further investigate IRS-1's role in the bone metabolism, we generated Irs-1-deficient Irs-1smla/smla mice. These null mice developed a spontaneous mutation that led to an increase in trabecular thickness (Tb.Th) in 12-mo-old, but not in 2-mo-old mice. Analyses of the bone marrow stromal cells (BMSCs) from these mice revealed their differential expression of osteogenesis-related genes and miRNAs. The expression of miR-342, predicted and then proven to target the gene encoding collagen type Iα2 (COL1A2), was reduced in BMSCs derived from Irs-1-null mice. COL1A2 expression was then shown to be age dependent in osteoblasts and BMSCs derived from Irs-1smla/smla mice. After the induction of osteogenesis in BMSCs, miR-342 expression correlated inversely with that of Col1a2 Further, Col1a2-specific small interfering RNA (siRNA) reduced alkaline phosphatase (ALP) activity and inhibited BMSC differentiation into osteocyte-like cells, both in wild-type (WT) and Irs-1smla/smla mice. Conversely, in Irs-1smla/smla osteocytes overexpressing COL1A2, ALP-positive staining was stronger than in WT osteocytes. In summary, we uncovered a temporal regulation of BMSC differentiation/bone formation, controlled via Irs-1/miR-342 mediated regulation of Col1a2 expression.-Guo, Y., Tang, C.-Y., Man, X.-F., Tang, H.-N., Tang, J., Wang, F., Zhou, C.-L., Tan, S.-W., Feng, Y.-Z., Zhou, H.-D. Insulin receptor substrate-1 time-dependently regulates bone formation by controlling collagen Iα2 expression via miR-342.

Dose-dependent effects of neuropeptide Y on the regulation of preadipocyte proliferation and adipocyte lipid synthesis via the PPARγ pathways.

The objective of this study was to investigate the impact of neuropeptide Y (NPY) on preadipocyte proliferation and differentiation. Preadipocytes were incubated with a range of concentrations of NPY (10(-15)M - 10(-7)M). After NPY-induced differentiation, the extent of preadipocyte adipogenesis was evaluated. The expressions levels of related adipocyte markers such as PPARγ, C/EBPα and DLK-1 were examined by real-time PCR (RT-PCR) or western blot analysis. Furthermore, the mitogen-activated protein kinase (MAPK) signaling pathway proteins were also analyzed by western blot. Our results showed that low doses of NPY stimulated preadipocyte viability and proliferation, while high NPY doses inhibited cell viability. At high concentrations of NPY significantly promoted lipid accumulation and increased the size of lipid droplets. DLK-1 mRNA expression was inhibited, but the expression levels of PPARγ and C/EBPα were increased during differentiation with the presence of high concentration of NPY. High-dose NPY also suppressed the phosphorylation of the extracellular signal-regulated kinase (ERK) 1/2 protein. We conclude that NPY has a biphasic effect on preadipocyte proliferation. A high dose inhibits the proliferation of 3T3-L1 cell while promotes adipocyte differentiation, increasing lipid accumulation especially enlarged lipid droplets' size. NPY may lead to a better understanding for drug development to prevent hyperplastic obesity and hypertrophic obesity.

Risk of incident chronic kidney disease in metabolically healthy obesity and metabolically unhealthy normal weight: A systematic review and meta-analysis.

Studies have reported inconsistent results about the risk of incident chronic kidney disease (CKD) in people with metabolically healthy obesity (MHO). We designed this systematic review and meta-analysis to evaluate the risk of developing CKD in people with MHO and metabolically unhealthy normal weight (MUNW). We used a predefined search strategy to retrieve eligible studies from multiple databases up to June 20, 2022. Random-effects model meta-analyses were implied to estimate the overall hazard ratio (HR) of incident CKD in obesity phenotypes. Eight prospective cohort studies, including approximately 5 million participants with a median follow-up ranging between 3 and 14 years, were included in this meta-analysis. Compared to the metabolically healthy normal weight (MHNW), the mean differences in cardiometabolic and renal risk factors in MHO, MUNW, and metabolically unhealthy obesity (MUO) were evaluated with overall HR of 1.42, 1.49, and 1.84, respectively. Compared to MHNW, the mean estimated glomerular filtration rate (eGFR) and high-density lipoprotein (HDL) were significantly lower, and low-density lipoprotein (LDL), blood pressure, blood glucose, and triglycerides were higher in MHO and MUNW. In conclusion, MHO and MUNW are not benign conditions and pose a higher risk for incident CKD. Obesity, whether in the presence or absence of metabolic health, is a risk factor for CKD.

Safety and efficacy of sequential treatments for postmenopausal osteoporosis: a network meta-analysis of randomised controlled trials.

Background: The sequential anti-osteoporotic treatment for women with postmenopausal osteoporosis (PMO) is important, but the order in which different types of drugs are used is confusing and controversial. Therefore, we performed a network meta-analysis to compare the efficacy and safety of available sequential treatments to explore the most efficacious strategy for long-term management of osteoporosis. Methods: In this network meta-analysis, we searched the PubMed, EMBASE, Web of Science, the Cochrane Library, and ClinicalTrials.gov from inception to September 19, 2023 to identify randomised controlled trials comparing sequential treatments for women with PMO. The identified trials were screened by reading the title and abstract, and only randomised clinical trials involving sequential anti-osteoporotic treatments and reported relevant outcomes for PMO were included. The main outcomes included vertebral fracture risk, the percentage change in bone mineral density (BMD) in different body parts, and all safety indicators in the stage after switching treatment. A frequentist network meta-analysis was performed using the multivariate random effects method and evaluated using the surface under the cumulative ranking curve (SUCRA). Certainty of evidence was assessed using the Confidence in the Network Meta-Analysis (CINeMA) framework. This study is registered with PROSPERO: CRD42022360236. Findings: A total of 19 trials comprising 18,416 participants were included in the study. Five different sequential treatments were investigated as the main interventions and compared to the corresponding control groups. The intervention groups in this study comprised the following treatment switch protocols: switching from an anabolic agent (AB) to an anti-resorptive agent (AR) (ABtAR), transitioning from one AR to another AR (ARtAAR), shifting from an AR to an AB (ARtAB), switching from an AB to a combined treatment of AB and AR (ABtC), and transitioning from an AR to a combined treatment (ARtC). A significant reduction in the incidence of vertebral fractures was observed in ARtC, ABtAR and ARtAB in the second stage, and ARtC had the lowest incidence with 81.5% SUCRA. ARtAAR and ABtAR were two effective strategies for preventing fractures and improving BMD in other body parts. Especially, ARtAAR could improve total hip BMD with the highest 96.1% SUCRA, and ABtAR could decrease the risk of total fractures with the highest 94.3% SUCRA. Almost no difference was observed in safety outcomes in other comparisons. Interpretation: Our findings suggested that the ARtAAR and ABtAR strategy are the effective and safe sequential treatment for preventing fracture and improving BMD for PMO. ARtC is more effective in preventing vertebral fractures. Funding: The National Natural Science Foundation of China (82170900, 81970762), the Hunan Administration of Traditional Chinese Medicine, and the Hunan Province High-level Health Talents "225" Project.

Exploring the role of lipoprotein(a) in cardiovascular diseases and diabetes in Chinese population.

A high level of lipoprotein (a) in the plasma has been associated with a variety of cardiovascular diseases and is considered to be an independent predictor of some other diseases. Based on recent studies, the concentration levels of Lp(a) in the Chinese population exhibit a distinctive variation from other populations. In the Chinese population, a high level of Lp(a) indicates a higher incidence of revascularization, platelet aggregation, and thrombogenicity following PCI. Increased risk of atherosclerotic cardiovascular disease (ASCVD) in Chinese population has been linked to higher levels of Lp(a), according to studies. More specifically, it has been found that in Chinese populations, higher levels of Lp(a) were linked to an increased risk of coronary heart disease, severe aortic valve stenosis, deep vein thrombosis in patients with spinal cord injuries, central vein thrombosis in patients receiving hemodialysis, and stroke. Furthermore, new and consistent data retrieved from several clinical trials also suggest that Lp (a) might also play an essential role in some other conditions, including metabolic syndrome, type 2 diabetes and cancers. This review explores the clinical and epidemiological relationships among Lp(a), cardiovascular diseases and diabetes in the Chinese population as well as potential Lp(a) underlying mechanisms in these diseases. However, further research is needed to better understand the role of Lp(a) in cardiovascular diseases and especially diabetes in the Chinese population.

Cardio-cerebrovascular Outcomes in MODY, Type 1 Diabetes, and Type 2 Diabetes: A Prospective Cohort Study.

CONTEXT: Cardio-cerebrovascular events are severe complications of diabetes. OBJECTIVE: We aim to compare the incident risk of cardio-cerebrovascular events in maturity onset diabetes of the young (MODY), type 1 diabetes, and type 2 diabetes. METHODS: Type 1 diabetes, type 2 diabetes, and MODY were diagnosed by whole exome sequencing. The primary endpoint was the occurrence of the first major adverse cardiovascular event (MACE), including acute myocardial infarction, heart failure, stroke, unstable angina pectoris, and cardio-cerebrovascular-related mortality. Cox proportional hazards models were applied and adjusted to calculate hazard ratios (HRs) and 95% CIs for the incident risk of MACE in type 1 diabetes, type 2 diabetes, MODY, and MODY subgroups compared with people without diabetes (control group). RESULTS: Type 1 diabetes, type 2 diabetes, and MODY accounted for 2.7%, 68.1%, and 11.4% of 26 198 participants with diabetes from UK Biobank. During a median follow-up of 13 years, 1028 MACEs occurred in the control group, contrasting with 70 events in patients with type 1 diabetes (HR 2.15, 95% CI 1.69-2.74, P < .05), 5020 events in patients with type 2 diabetes (HR 7.02, 95% CI 6.56-7.51, P < .05), and 717 events in MODY (HR 5.79, 95% CI 5.26-6.37, P < .05). The hazard of MACE in HNF1B-MODY was highest among MODY subgroups (HR 11.00, 95% CI 5.47-22.00, P = 1.5 × 10-11). CONCLUSION: MODY diagnosed by genetic analysis represents higher prevalence than the clinical diagnosis in UK Biobank. The risk of incident cardio-cerebrovascular events in MODY ranks between type 1 diabetes and type 2 diabetes.

Standardization of dual-energy x-ray visceral adipose tissue measures for comparison across clinical imaging systems.

OBJECTIVE: Excess visceral adipose tissue (VAT) is a major risk factor for metabolic syndrome (MetS) and clinical guidelines have been proposed to define VAT levels associated with increased risk. The aim was to standardize VAT measures between two dual-energy x-ray absorptiometry (DXA) manufacturers who provide different VAT estimates to support standardization of measures across imaging modalities. METHODS: Scans from 114 individuals (ages 18-81 years) on GE HealthCare (GEHC) and Hologic DXA systems were compared via Deming regression to standardize VAT between the two systems, validated in a separate sample (n = 15), with κ statistics to assess agreement of VAT measurements for classifying patients into risk categories. RESULTS: The GEHC and Hologic VAT measures were highly correlated and validated in the separate data set (r2 = 0.97). VAT area measures substantially agreed for metabolic risk classification (weighted κ = 0.76) with no significant differences in the population mean values. CONCLUSIONS: VAT measures can be estimated from GEHC and Hologic scans that classify individuals in a substantially similar way into metabolic risk categories, and systematic bias between the measures can be removed using simple regression equations. These findings allow for DXA VAT measures to be used in complement to other imaging modalities, regardless of whether scans used GEHC or Hologic systems.