Characteristics of bone metabolism in postmenopausal women with newly diagnosed type 2 diabetes mellitus.

OBJECTIVE: The characteristics of bone metabolism in T2DM are still controversial. This study aims to recognize bone turnover features in patients with newly diagnosed T2DM who have never been treated with anti-diabetic drugs and further explore the possible factors contributing to their impaired bone turnover. MATERIALS AND METHODS: An analytic sample of 88 patients with newly diagnosed T2DM and 152 non-diabetic control individuals were studied. All the participants were postmenopausal women. Demographics variables and clinical history were recorded. We measured lipid profile, glucose metabolism, bone turnover markers indices as well as their related hormones, serum calcium and phosphorus. Bone mineral density was detected by dual-energy X-ray absorptiometry. We compared the differences in bone turnover markers and their regulating hormones between two groups and further analysed the factors related to bone turnover in T2DM. RESULTS: Compared with the control group, patients with T2DM had a higher level of bone alkaline phosphatase (BALP), lower levels of procollagen type I intact N-terminal (P1NP), osteocalcin (OC) and parathyroid hormone (PTH). Multiple linear regression analysis showed that in patients with T2DM, HbA1c was negatively correlated with P1NP and OC. For patients without diabetes, HbA1c was negatively related to BALP and OC. CONCLUSIONS: Patients with newly diagnosed T2DM may have impaired osteoblastic maturation and bone formation, which may be mainly attributed to hyperglycaemia.

Postnatal deletion of ß-catenin in osterix-expressing cells is necessary for bone growth and intermittent PTH-induced bone gain.

wnt/ß-catenin signaling has been shown to influence bone homeostasis and is important for parathyroid hormone (PTH)-induced bone gain. To further understand the role of ß-catenin in the early stages of osteoblastic lineage cells for postnatal bone homeostasis and the anabolic actions of PTH on bone, we examined mice with postnatal disruption of ß-catenin in osterix-expressing cells (ß-catenin KO mice) by mating floxed ß-catenin mice with transgenic mice expressing cre under the control of the osterix promoter suppressible by doxycycline. After withdrawal of doxycycline, ß-catenin KO mice developed progressive bone loss, ectopic cartilage formation, accumulation of mesenchymal stromal cells, and bone marrow adiposity. The ß-catenin-defective osteoblasts sorted by flow cytometry from ß-catenin KO mice exhibited decreased EdU incorporation, increased annexin V activity, and profound alterations in gene expression including wnt target genes, osteoclast regulators, and osteoblast markers. A dramatic increase in osteoclasts was observed in both neonatal and postnatal ß-catenin KO mice. Intermittent administration of PTH for 4 weeks significantly increased bone mass in control mice; however, this anabolic effect of PTH was substantially blunted in ß-catenin KO mice. Our data indicate that ß-catenin in osterix-expressing cells is required for postnatal osteoblast differentiation, osteoblast proliferation, and bone resorption, and is essential for the anabolic actions of PTH in bone.

Deletion of ß-Arrestin2 in Mice Limited Pancreatic ß-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway.

ß-Arrestin2 (ßarr2) is an adaptor protein that interacts with numerous signaling molecules and regulates insulin sensitivity. We reported previously that ßarr2 was abundantly expressed in mouse pancreatic ß-cells, and loss of ßarr2 leads to impairment of acute- and late-phase insulin secretion. In the present study, we examined the dynamic changes of ß-cell mass in ßarr2-deficient (ßarr2-/-) mice in vivo and explored the underlying mechanisms involved. ßarr2-/- mice with exclusively luciferase overexpression in ß-cells were generated and fed a high-fat diet (HFD). ß-Cell mass was determined by in vivo noninvasive bioluminescence imaging from 4 to 20 wks of age. Proliferation was measured by 5-bromo-2-deoxyuridine (BrdU) incorporation and fluorescence-activated cell sorter analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting were conducted for gene and protein expression. We found that ß-cell mass was reduced dramatically in ßarr2-/- mice at 12 wks old compared with that of their respective HFD-fed controls. The percentage of BrdU- and Ki67-positive cells reduced in islets from ßarr2-/- mice. Exposure of ßarr2-/- islets to high levels of glucose and free fatty acids (FFAs) exacerbated cell death, which was associated with upregulation of the JNK pathway in these islets. Conversely, overexpression of ßarr2 amplified ß-cell proliferation with a concomitant increase in cyclinD2 expression and a decrease in p21 expression and protected ß-cells from glucose- and FFA-induced cell death through JNK-activation inhibition. In conclusion, ßarr2 plays roles in regulation of pancreatic ß-cell mass through the modulation of cell cycle regulatory genes and the inhibition of JNK activation induced by glucolipotoxity, which implicates a role for ßarr2 in the development of type 2 diabetes.

An association analysis of lipid profile and diabetic cardiovascular autonomic neuropathy in a Chinese sample.

BACKGROUND: Recent studies have shown that triglyceride (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) are related to the prevalence of cardiovascular autonomic neuropathy (CAN). However, little is known about the association of lipid profile with diabetic cardiovascular autonomic neuropathy (DCAN), or its severity in the Chinese population. The purpose of this study is to explore the extent of this phenomenon using a Chinese sample. METHODS: A subgroup analysis on 455 diabetic patients with undiagnosed DCAN was performed to evaluate the relationships of lipids profile and DCAN. DCAN was diagnosed if there were at least two abnormal cardiovascular autonomic reflex test results, based on short-term heart rate variability tests. Multivariable logistic regression (MLR)was carried out to control potential confounders for determining the independent association of variables with DCAN in different models. RESULTS: MLR analysis indicated that TG was significantly and independently associated with DCAN when controlling for confounding factors (P < 0.1 for two models). Additionally, TG combined with TC (LRS-1) and LDL (LRS-2) was associated with this outcome (P < 0.1 for LRS-1 and LRS-2). CONCLUSION: Our findings indicate that TG and the severity of lipids profile is significantly and independently associated with DCAN, respectively. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02461472 , retrospectively registered 2 Jun, 2015.

Characteristics of bone metabolism in the male patients with diabetic neuropathy.

BACKGROUND: This study aimed to evaluate the characteristics of bone metabolism and fracture risk in the type 2 diabetes mellitus (T2DM) patients with distal symmetric polyneuropathy (DSPN). METHODS: A total of 198 T2DM individuals were recruited from January 2017 to December 2020. Patients with DSPN were evaluated by strict clinical and sensory thresholds. Biochemical parameters and bone mineral density (BMD) were measured. The BMD, bone turnover markers, and probability of fracture were compared between two groups, and the factors related to BMD and probability of hip fracture in 10 years were further explored. RESULTS: Compared with type 2 diabetes mellitus without distal symmetric polyneuropathy (T2DN-) patients, type 2 diabetes mellitus with distal symmetric polyneuropathy (T2DN+) patients had lower level of cross-linked C-telopeptide (CTX) (0.32 ± 0.19 vs 0.38 ± 0.21 ng/mL, p = 0.038) and higher level of bone-specific alkaline phosphatase (BALP) (15.28 ± 5.56 vs 12.58 ± 4.41 µg/mL, p = 0.003). T2DN+ patients had higher BMD of lumbar L1-L4 (1.05 ± 0.19 vs 0.95 ± 0.37, p = 0.027) and higher probability of hip fracture (0.98 ± 0.88 vs 0.68 ± 0.63, p = 0.009) as compared to T2DN- individuals. Univariate correlation analysis showed that BALP level (coefficient (coef) = -0.054, p = 0.038), CTX level (coef = -2.28, p = 0.001), and hip fracture risk (coef = -1.02, p < 0.001) were negatively related to the BMD of L1-L4. As for the risk of hip fracture evaluated by WHO Fracture Risk Assessment Tool (FRAX), age (coef = 0.035, p < 0.001), use of insulin (coef = 0.31, p =0.015), and levels of BALP (coef = 0.031, p = 0.017) and CTX (coef = 0.7, p = 0.047) were positively related to the risk of hip fracture. Multivariate regression analysis showed that CTX level (coef = -1.41, p = 0.043) was still negatively related to BMD at the lumbar spine. CONCLUSION: This study indicates that T2DM patients with DSPN have special bone metabolism represented by higher BALP level and lower CTX level which may increase BMD at the lumbar spine.

Fluorescent ligand-directed co-localization of the parathyroid hormone 1 receptor with the brush-border scaffold complex of the proximal tubule reveals hormone-dependent changes in ezrin immunoreactivity consistent with inactivation.

Through binding to parathyroid hormone (PTH), PTH1R interacts with kidney-specific scaffold proteins, including the sodium hydrogen exchanger regulatory factors 1 and 2 (NHERFs), and ezrin. To facilitate in vivo localization, tetramethylrhodamine-labeled PTH (PTH-TMR) was used as a fluorescent probe. In mice, PTH-TMR localizes to luminal surfaces of tubular S1 segments that overlap PTH1R immunostaining, but does not directly overlap with megalin-specific antibodies. PTH-TMR staining directly overlaps with Npt2a in nascent, endocytic vesicles, marking the location of transporter regulation. PKA substrate antibodies display marked staining increases in segments labeled with PTH-TMR, demonstrating a functional effect. In the presence of secondary hyperparathyroidism, PTH-TMR staining is markedly reduced and shifts to co-localizing with megalin. At 15min post-injection, PTH-TMR-labeled vesicles do not co-localize with either NHERF or ezrin, suggesting PTH1R dissociation from the scaffold complex. At the 5min time point, PTH-TMR stains the base of microvilli where it localizes with both NHERF2 and ezrin, and only partially with NHERF1. Strikingly, the bulk of ezrin protein becomes undetectable with the polyclonal, CS3145 antibody, revealing a PTH-induced conformational change in the scaffold. A second ezrin antibody (3C12) is capable of detecting the altered ezrin protein. The CS3145 antibody only binds to the active form of ezrin and fails to recognize the inactive form, while the 3C12 reagent can detect either active or inactive ezrin. Here we show that the PTH1R is part of the ezrin scaffold complex and that acute actions of PTH suggest a rapid inactivation of ezrin in a spatially defined manner.

Correlation of hemoglobin with osteoporosis in elderly Chinese population: A cross-sectional study.

Introduction: In the elder population, both low hemoglobin (Hb)/anemia and osteoporosis (OP) are highly prevalent. However, the relationship between Hb and OP is still poorly understood. This study was to evaluate the correlation between Hb and OP in Chinese elderly population. Methods: One thousand and sisty-eight individuals aged 55-85 years were enrolled into this cross-sectional study during June 2019-November 2019. Data on the demographics and clinical characteristics were recorded. Detections of complete blood count, liver/kidney function, glucose metabolism and lipid profile, and thoracolumbar X-ray were performed, and bone mineral density (BMD) at lumbar spine 1-4, femur neck, and total hip was measured by dual-energy X-ray absorptiometry (DXA). Univariate and multivariate linear regression analyses were employed to evaluate the correlation between Hb with BMD T-score. Logistic regression analysis was performed to access the correlation between different Hb levels and the odds ratio (OR) for OP. Results: Compared with non-OP group, OP patients had lower level of Hb. Univariate linear regression analysis indicated Hb level was positively related to the BMD of lumbar spine 1-4, femur neck and total hip, and this relationship remained after adjusting confounding variables [gender, age, body mass index (BMI), diabetes mellitus (DM) and morphological vertebral fracture]. Logistic regression analysis showed the ORs for OP decreased with the increase of Hb. Compared with the subjects with the lowest quartile of Hb, the OR for OP in the highest quartile group was 0.60 (0.41-0.89) after adjusting for gender, age and BMI, and the OR for OP was 0.62 (0.41-0.92) after further adjustment for gender, age, BMI, DM, and lipid indexes. Discussion: In conclusion, Lower Hb level is related to lower BMD in the elderly population. However, whether Hb level could be used to predict the risk of OP needs to be further determined in more longitudinal clinical studies.

Postnatal deletion of ß-catenin in preosteoblasts regulates global energy metabolism through increasing bone resorption and adipose tissue fibrosis.

Many studies revealed bone can regulate global energy metabolism and our previous study also showed that Wnt/ß-catenin pathway is involved in this process. To better understand the participation of canonical Wnt pathway in energy metabolism, we examined the ß-catenin knock-out (ß-cat KO) mice by crossing the osterix-cre transgenic mice with ß-cateninflox/flox mice. First, we identified that postnatal deletion of ß-catenin in preosteoblasts led to decreased fat mass and increased energy expenditure in mice. Osteoprotegerin administration largely rescued the decreased fat mass and partly normalized the energy expenditure accompanied by the inhibition of bone resorption. Anti-resorption with alendronate or RANKL-antibody could also partly rescued the decreased bone mass, decreased fat mass and increased energy expenditure in ß-cat KO mice. We further found that the adipose cells in the inguinal fat tissue were smaller and the extracellular matrix components around adipocytes accumulated more in ß-cat KO mice than their controls by histomorphology. Gene analysis by RT-PCR showed that the expression of collagen VI is 4.8 folds in adipose tissue of the ß-cat KO mice compared with the control mice. We further detected the expression of cytokines which were related to fibrosis and the data showed that the level of TGF-beta1 was elevated in both of bone marrow serum and adipose tissue derived from the ß-cat KO mice. After administration of TGF-beta1 neutralizing antibody, the impaired energy metabolism was partly rescued in ß-cat KO mice. Besides, anti-resorption treatment and TGF-beta1 antibody could partly suppress the increased expression of genes related to fat tissue fibrosis. These results indicate that the abnormal global energy metabolism in ß-cat KO mice may be attributed to increasing bone resorption and adipose tissue fibrosis.

Correlation of Osteoporosis in Patients With Newly Diagnosed Type 2 Diabetes: A Retrospective Study in Chinese Population.

This study aimed to explore the risk factors attributed to osteoporosis in newly type 2 diabetes mellitus (T2DM) patients. This study aimed to recruit 244 T2DM patients and 218 non-diabetic controls. We collected demographic characteristics, medical history, bone mineral density and biomarkers including bone specific alkaline phosphatase (BALP), osteocalcin, N-terminal peptide of type I procollagen (P1NP), tartrate-resistant acid phosphatase 5b (TRCAP-5b), ß-Cross Laps of type I collagen-containing cross-linked C-telopeptide (ß-CTX), 25-hydroxyvitamin D, parathyroid hormone were recorded or detected. Bone mineral density (BMD) was our primary outcome. Based on the result of BMD, we divided both the control group and T2DM group into three subgroups: normal bone mass, osteopenia and osteoporosis. In control group, we found age, sex, menopausal status, BMI, P1NP, BALP, TRACP-5b, osteocalcin, and corrected serum calcium are differential among three subgroups. In T2DM group, we found age, sex, menopausal status, drinking status, BMI, HbA1c, TRACP-5b and OC were differential among three subgroups. In T2DM and control groups, age, female, postmenopausal status, BALP, TRACP-5b and osteocalcin were positively correlated while BMI was negatively correlated with osteoporosis. In control group, ß-CTX was positively correlated with osteoporosis. In T2DM group, HbA1c and corrected serum calcium concentration were positively correlated with osteoporosis. After further adjustment of age, BMI in male, TRACP-5b was positively correlated with the risk of osteoporosis in newly diagnosed T2DM. After adjusted of age, BMI and menopausal status in female, OC was positively correlated with the risk of osteoporosis in newly diagnosed T2DM and controls. In female T2DM, BALP and P1NP were positively correlated with the risk of osteoporosis. In conclusion, age, BMI and menopausal status are common risk factors for osteoporosis in diabetic and non-diabetic patients, however TRACP-5b, BALP and osteocalcin are special risk factors for osteoporosis in newly diagnosed T2DM patients but not non-diabetic patients, which may be applied to identify osteoporosis risk in T2DM patients, but this result needs to be proven with fracture data.

Anti-diabetic Role of Adropin in Streptozotocin Induced Diabetic Rats via Alteration of PI3K/Akt and Insulin Signaling Pathway.

Diabetes mellitus (DM) is a hyperglycemia-related multifactorial condition with an elevated risk of microvascular and microvascular complications associated with this disease. The current experimental study was to examine the antidiabetic activity of streptozotocin (STZ)-induced adropin against diabetic rats by altering the PI3K/Akt and insulin signaling pathways. STZ (60 mg/kg) was used for the induction of DM and rats were divided into different groups and received the adropin (20, 40 and 80 mg/kg) and glibenclamide (10 mg/kg) till 28 days. Body weight, plasma insulin, blood glucose and food intake were estimated, respectively. Biochemical enzymes, carbohydrate enzymes, lipid parameters, AMPK and insulin signalling pathway parameters were estimated. GLUT4 and PPARγ expression were also estimated. Oral administration of adropin significantly (p < 0.001) increased the glycogen, glucose-6-phosphatase dehydrogenase, insulin, hexokinase and belittled the blood glucose level, fructose 1-6-biphosphatase, glucose-6-phosphatase at dose dependent manner. Adropin significantly (p < 0.001) reduced the level of triglyceride, cholesterol, low density lipoprotein, very low density lipoprotein and increased the level of high density lipoprotein at dose dependent manner. Adropin significantly (p < 0.001) activated the Akt, IRS-2, IRS-1, IR, p-AKT and PI3k, which are the key modulator molecules of PI3K/Akt, AMPK and insulin signalling pathway in DM rats. The current experimental study confirms the anti-diabetic effect of adropin on DM rats induced by AMPK and insulin signalling pathway against STZ.

[A randomized, multicenter, active-controlled trial to compare the efficacy of recombinant human parathyroid hormone (1-34) with that of elcatonin in postmenopausal women with osteoporosis in China].

OBJECTIVE: To compare the clinical efficacy and safety between recombinant human parathyroid hormone (rhPTH) (1-34) and elcatonin in the treatment of postmenopausal women with osteoporosis in China. METHODS: This 6 month, multicenter, randomized and controlled study enrolled 205 postmenopausal women with osteoporosis. They were randomized to receive either rhPTH (1-34) 20 µg (200 U) daily or elcatonin 20 U weekly. Lumbar spine (L1-4) and femoral neck bone mineral density (BMD) and biochemical markers of bone turnover were measured. In the meantime adverse events were recorded. RESULTS: The results showed that both rhPTH (1-34) and elcatonin increased L1-4 BMD significantly at the endpoint of the study, but femoral neck BMD did not change significantly. From baseline to endpoint, BMD of L1-4 and femoral neck in the rhPTH (1-34) group increased by 5.51% (P<0.01) and 0.65% (P>0.05), but BMD of L1-4 and femoral neck in elcatonin group increased by 1.55% (P<0.05) and 0.11% (P>0.05). Moreover, the rhPTH (1-34) group had better improvement in L1-4 BMD than the elcatonin group at 3, 6 months, but there was no difference of BMD in these two groups with regard to femoral neck. There were greater mean increases of the bone markers in the rhPTH (1-34) group than those in the elcatonin group at 3, 6 months [serum bone-specific alkaline phosphatase (BSAP) 36.79% vs 0.31%; 92.42% vs -0.17%; the ratio of urine N-telopeptide of type I collagen and creatinine (NTX/Cr) 48.91% vs -5.32%; 68.82% vs -10.86%]. Both kinds of treatment were well tolerated and there were no differences between the two groups in the rates of adverse events and serious adverse events. CONCLUSION: It is concluded that rhPTH (1-34) has more positive effects on bone formation than elcatonin as shown by the greater increments of L1-4 BMD and bone formation markers and the less occurrence of adverse events as well as no significant change in hepatic, renal or hemopoietic function.

Prevalence of vitamin D deficiency in the pregnant women: an observational study in Shanghai, China.

BACKGROUND: Maternal vitamin D deficiency has been a worldwide concern in recent years. However the epidemiological data of vitamin D deficiency among large group of Chinese pregnant women is limited. This study is to evaluate the prevalence of vitamin D deficiency among pregnant women in Shanghai, China and to analyze the association of vitamin D status with some pregnancy outcomes (gestational diabetes and low birth weight). METHODS: A total of 34,417 pregnant women in Shanghai were included in this study from January 2014 to December 2017, and the serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured at 16th week of gestation by electrochemiluminescence assay. Seventy five grams of glucose was used to conduct oral glucose tolerance test during 24-28th week of gestational in all enrolled persons and the birth weight of newborns was recorded. RESULTS: The median serum 25(OH) D concentration in the pregnant women during 4 years was 42.87 nmol/L (32.88-51.90 nmol/L). 9.9% of the population were severe vitamin D deficient [25(OH)D < 25 nmol/L], 60.1% were deficient [25 nmol/L ≤ 25(OH)D < 50 nmol/L], 28.4% were insufficient [50 nmol/L ≤ 25(OH)D < 75 nmol/L] and only 1.6% of the enrolled population reached the level of adequate [25(OH)D ≥ 75 nmol/L]. Serum 25(OH) D concentrations showed significant difference among seasons with the highest level in winter and the lowest level in summer. Women with advanced maternal age were more likely to have better vitamin D status compared with younger women. The 25(OH) D levels were significantly different among 2014-2017. The year of 2017 had the highest 25(OH) D level with the median serum concentration reaching 47.80 nmol/L (41.00-55.00 nmol/L), while the lowest appeared in 2016 which has median 25(OH) D concentration at 38.87 nmol/L (28.76-49.97 nmol/L). No relations were found between the 25(OH) D status and the rate of gestational diabetes or low birth weight of newborns. CONCLUSION: Pregnant women in Shanghai were generally deficient in vitamin D status and the level of vitamin D was related to season and age. No evidence showed vitamin D deficiency in pregnant women contributes to the rate of gestational diabetes or low birth weight of newborns in this study. These results suggest that most of the pregnant women may need vitamin D supplementation to achieve adequate vitamin D level.

Differential expression of genes associated with hypoxia pathway on bone marrow stem cells in osteoporosis patients with different bone mass index.

BACKGROUND: This study aimed to assess gene expression changes associated with hypoxia pathway on bone marrow stem cells (BMSCs) and explore effects of bone mass index (BMI) on hypoxia pathway of osteoporosis (OP) patients. METHODS: Human BMSCs were isolated from bone marrow. Subjects were divided into healthy control group and OP group which was further divided into BMI <25 OP subgroup and BMI ≥25 OP subgroup. RESULTS: The genes downregulated in OP patients were involved in hypoxia pathway. Furthermore, those genes were even downregulated in OP patients BMI ≥25 subgroup than OP patients BMI <25 subgroup. The genes were expressed in response to decreased oxygen levels, and their functions are related to photoperiodism, positive regulation of myoblast differentiation, and entrainment of circadian clock by gene ontology (GO) analysis. CONCLUSIONS: The expression of genes associated with hypoxia pathway on BMSCs in OP patients are lower than healthy subjects, and the expression of genes related to carbohydrate metabolism are lower in overweight OP patients than in normal weight OP patients. These results need further research.

Fine mapping of thyroglobulin gene identifies two independent risk loci for Graves' disease in Chinese Han population.

BACKGROUND: This study aimed to determine independent risk loci of Graves' disease (GD) in the thyroglobulin (TG) region. METHODS: In this two-staged association study, a total of 9,757 patients with GD and 10,626 sex-matched controls were recruited from Chinese Han population. Illumina Human660-Quad BeadChips in the discovery stage and TaqMan SNP Genotyping Assays in the replication stage were used for genotyping. Trend test and logistic regression analysis were performed in this association study. RESULTS: In the discovery stage, rs2294025 and rs7005834 were the most highly associated susceptibility loci with GD in TG. In the replication phase, 7 SNPs, including rs2294025 and rs7005834, were selected for fine-mapping. Finally, we confirmed that rs2294025 and rs7005834 were the independent risk loci of GD in the combined populations. At the same time, there was no significant difference between the risk allele frequencies of rs2294025 and rs7005834 in different clinical phenotypes of GD. CONCLUSIONS: The fine mapping study of thyroglobulin identified two independent SNPs (rs2294025 and rs7005834) for GD susceptibility. However, no significant differences for rs2294025 and rs7005834 were observed, between the different clinical phenotypes of GD, including gender, Graves' ophthalmopathy (GO), and serum levels of thyrotropin receptor antibody, thyroid peroxidase antibody, and thyroglobulin antibody. These results provide a deeper understanding of the association mechanism of thyroglobulin and GD risk.

Prevalence of Vitamin D Deficiency during Second Trimester of Pregnancy in Shanghai China, Risk Factors and Effects on Pregnancy Outcomes.

BACKGROUND: Vitamin D plays important roles in various physiological processes. Vitamin D deficiency is common among pregnant women in some regions, such as China. Our study aimed to determine the prevalence of Vitamin D deficiency during second trimester of pregnancy in Shanghai China, and explore its risk factors and effects on pregnant outcomes. METHODS: Overall, 23100 pregnant women (2013 to 2017, Shanghai, China) were included and vitamin D concentrations were measured at 16 weeks of gestation. Correlations between vitamin D concentrations and participants' general data and maternal and infant outcomes were analyzed by chi square test. Non-conditional multivariate logistic regression analysis was used to screen the independent risk factors for vitamin D deficiency. RESULTS: Vitamin D deficiency was significantly correlated with aging, education level, smoking, dirking, BMI before pregnancy, body weight gain during pregnancy (P<0.01), the use of vitamin D supplement and milk consumption, and older than 30 years, drinking, smoking, BMI before pregnancy> 36, body weight gain during pregnancy< 40g per day, no daily milk consumption, no vitamin D supplement, and education lever below college were independent risk factors for vitamin D deficiency in second trimester of pregnancy. In addition, vitamin D deficiency in second trimester of pregnancy was closely correlated with the occurrence of a serious of adverse maternal and infant outcomes. CONCLUSION: Vitamin D deficiency was still common among women in second trimester of pregnancy in Shanghai China. Vitamin D deficiency was closely correlated with the occurrence of a serious of adverse maternal and infant outcomes.

Wnt/ß-catenin signaling in osteoblasts regulates global energy metabolism.

Obesity, diabetes and osteoporosis have become a major public heath burden, and understanding the underlying mechanisms of these pathophysiological process will benefit their treatment. Osteoblast lineage cells in charge of the bone formation have been showed to participate in the whole-body energy metabolism. In this study, we identify that wnt/ß-catenin signaling in osteoblasts could regulate global energy metabolism, including glucose homeostasis, fat accumulation and energy expenditure. Mice lacking ß-catenin specifically in osteoblasts postnatally exhibit decreased bone mass, increased glucose level, decreased insulin production, decreased fat accumulation and increased energy expenditure. Osteocalcin supplement can rescue the impaired glucose balance by improving insulin production but cannot influence the abnormal fat accumulation and energy expenditure. Osteoprotegerin (OPG) overexpression exclusively in osteoblasts in ß-catenin deletion mice can normalize not only the decreased bone mass but also the decreased fat accumulation and increased energy expenditure. The effect of ß-catenin deletion and OPG overexpression in osteoblasts on global energy metabolism had no relation with inguinal fat browning. These results suggest that the regulation of bone on energy metabolism and fat accumulation is not mediated exclusively by osteocalcin. Our findings may provide a new insight into the regulation of bone on fat accumulation and energy metabolism.

[Effects of alendronate on bone mineral density, cytokines and indices of bone metabolism in postmenopausal osteoporotic patients].

OBJECTIVE: To observe the effects of alendronate on bone mineral density (BMD), cytokines and indices of bone metabolism in postmenopausal osteoporotic (PMO) patients. METHODS: 185 PMO patients, aged from 55 to 60 years, were randomized into three groups. All of them received a kind of calcium preparation, 1.0 g/d. Group A, 69 patients, received alendronate, 10 mg/d; group B, 66 patients, received tibolone 1.25 mg/d. The remaining patients, group C, received calcium preparation only. 20 women of 55 - 60 (57.4 +/- 3.5) years old were taken as normal controls. Dual-energy X-ray absorptiometry and measurement of a series of biochemical indices were carried out before and after medication at 24th and 48th week. RESULTS: After medication, BMD increased in alendronate and tibolone group. The increment in spine BMD was 2.53% and 3.65% (P < 0.05) and that in nondominant proximal femur BMD was 7.17% and 3.01% (P < 0.001). In the tibolone group, the levels of estradiol (E(2)) increased rapidly (P < 0.01), but those of IL-6, TNFalpha and type I collagen cross-linked N-telopeptides (NTX) decreased (P < 0.01). In the alendronate group, no change of levels of E(2) happened, while levels of alkaline phosphatase (ALP) and osteocalcin (BGP) increased (P < 0.05) and levels of NTX decreased (P < 0.05). There was no change of the levels of other parameters. In the calcium preparation group and control group, the levels of BMD, E(2), ALP, BGP and insulin-like growth factor I decreased (P < 0.05), while those of IL-6, TNFalpha and NTX increased (P < 0.05). CONCLUSION: Alendronate can significantly improve BMD as tibolone do. Thus it plays an important role in the treatment of osteoporosis. However calcium tablet can not prevent the loss of bone.

Delayed insulin secretion response during an OGTT is associated with an increased risk for incidence of diabetes in NGT subjects.

AIMS: This study aimed to assess whether insulin secretion patterns during oral glucose tolerance tests (OGTTs) could predict future type 2 diabetes (T2D) in Chinese normal glucose tolerance (NGT) subjects. METHODS: A total of 558 NGT, 419 newly diagnosed impaired glucose tolerance, and 694 newly diagnosed T2D patients were assessed. NGT subjects were grouped based on the time of peak insulin secretion during a 3h- OGTT; at 30min (InsP30), 60min (InsP60), 120min (InsP120), or 180min (InsP180), respectively. NGT subjects were followed up for an average duration of 5.58±1.08years. Beta-cell function was estimated by Stumvoll insulin secretion. RESULTS: The InsP120 and InsP180 groups had lower Stumvoll first-phase insulin secretion levels compared with InsP30. At 5.58±1.08years, 25 (5.39%) NGT subjects had developed T2D. The cumulative incidence rate of diabetes was higher in the InsP120 and InsP180 groups (8.94%), compared with InsP30 (1.48%) (P<0.05). The adjusted relative risk for incident diabetes was 7.30 (95% CI: 1.53-34.72) times higher in the InsP120 and InsP180 groups. CONCLUSIONS: NGT subjects with late insulin responses had defective early insulin secretion and were at higher risk of developing diabetes. Insulin secretion patterns could be a useful T2D predictor in the Chinese population.

Implantation of placenta-derived mesenchymal stem cells accelerates murine dermal wound closure through immunomodulation.

BACKGROUND: Diabetic foot ulcer (DFU) is a major complication of diabetes mellitus. Although previous studies have established that inflammation, ischemia and neuropathy contribute to the development of DFU, it is still an unmet medical need due to lack knowledge of cellular and molecular mechanisms associated with DFU. In the present study, we tested our hypothesis that subcutaneous application of human placental mesenchymal stem cells (PMSCs) can accelerate diabetic dermal wound healing by modulating immunoresponse. METHODS AND RESULTS: By using an in vivo excisional wound healing model in Goto-Kakizaki (GK) rats, we found that injection of PMSCs accelerates wound closure. Further studies revealed that application of PMSCs can regulate inflammation associated with wound healing by controlling secretion of pro- and anti-inflammatory factors, the beneficial effects can be partially blocked by application of antibodies against interleukin-10 (IL-10). Furthermore, in vitro experiments suggested that co-culture of PMSCs with human dermal fibroblasts can significantly inhibit activation of NF-ĸB induced by lipopolysaccharides (LPS), indicating the molecular mechanism of PMSCs mediated immunomodulation. CONCLUSION: Taken together, our study suggested that the immunomodulation of PMSCs play an important role on diabetic dermal wound healing process, thus PMSCs might represent an attractive choice for treatment of diabetes dermal wound and DFU.

ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease of heterotopic endochondral ossification (HEO), and currently no effective therapies are available for this disease. A recurrent causative heterozygous mutation (c.617 G>A; R206H) for FOP was identified in activin receptor type IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor. This mutation aberrantly activates the BMP-Smad1/5/8 signaling pathway and leads to HEO in FOP patients. Here we report development of a soluble recombinant ACVR1-Fc fusion protein by combining the extracellular domain of human wild type ACVR1 and the Fc portion of human immunoglobulin gamma 1 (IgG1). The ACVR1-Fc fusion protein significantly down-regulated the dysregulated BMP signaling caused by the FOP ACVR1 mutation and effectively suppressed chondro-osseous differentiation in a previously described cellular FOP model, human umbilical vein endothelial cells (HUVECs) that were infected with adenovirus-ACVR1R206H (HUVECR206H). This ACVR1-Fc fusion protein holds great promise for prevention and treatment of HEO in FOP and related diseases.