Coffin-Siris综合征(CSS)是一种罕见疾病,ARID1B基因突变可导致CSS.报道1例26岁女性患者因ARID1B基因突变导致CSS且伴DM的临床表现及诊断过程,并对相关文献进行复习.

To evaluate effects of PDCA cycle in improving residency diagnosis and treatment ability of endocrine and metabolic diseases, this paper selected the problems of insufficient diagnosis and treatment ability in the results of the 2016 endocrinology examination paper as the research breakthrough point, and investigated 62 residents receiving standardized residency training to analyze main reasons of the problems such as "busy clinical work", "special clinical thinking" and "difficult to remember knowledge of endocrinology". The online teaching, daily self-education, following the law of memory to remember and re-recognize knowledge, strengthening the construction of teachers, improving teaching methods were used and evaluated. It’s found that the application of PDCA cycle can improve the residents' ability of clinical diagnosis and treatment in endocrine and metabolic diseases.

Osteoporosis(OS)is a systemic skeletal disorder characterized by low bone mass and increased risk of fracture.Bone mineral density(BMD)is a gold standard in the diagnosis of OS,but is not sensitive enough for detecting the earlier bone loss.Bone metabolic markers have high sensitivity and specificity.Therefore,they are able to reflect the early changes of bone mass and can be used to monitor the efficacy of anti-OS agents.This article summarizes the research advance in both traditional and newly identified bone metabolic markers.

A 39-year-old female with central diabetes insipidus complained of polydipsia and polyuria and was found to be accompanied by lung lesions. The diagnosis of IgG4-related disease was confirmed by laboratory and pathological results. It should be alert to consider the possibility of IgG4-related disease in a patient with central diabetes insipidus coexisting with the signs of multisystem lesions such as lung disease.

Metformin or glucagon-like peptide-1 (GLP-1) analogue liraglutide has cardiovascular benefits. However, it is not clear whether their combined treatment have additive or synergistic effects on the vasculature. In this study, human umbilical vein endothelial cells (HUVECs), exposed to palmitic acid (PA) to induce endothelial dysfunction, were incubated with metformin, liraglutide or their combination. High fat diet (HFD)-fed ApoE-/- mice were randomized into control, metformin, liraglutide, and combination treatment groups. Results showed that in PA-treated HUVECs and HFD-fed ApoE-/- mice, combination of metformin and liraglutide at lower dose significantly improved endothelial dysfunction compared with the single treatment. Metformin upregulated GLP-1 receptor (GLP-1R) level and protein kinase A (PKA) phosphorylation. However, PKA inhibition but not GLP-1R blockade eliminated the protective effects of metformin on endothelial function. Furthermore, AMPK inhibitor compound C abolished the metformin-mediated upregulation of GLP-1R level and PKA phosphorylation. In conclusion, combination of metformin and liraglutide has synergistic protective effects on endothelial function. Moreover, metformin stimulates GLP-1R and PKA signalling via AMPK-dependent pathway, which may account for its synergistic protective effects with liraglutide. Our findings provide new insights on the interaction between metformin and GLP-1, and provide important information for designing new GLP-1-based therapy strategies in treating type 2 diabetes.

Microenvironment regulates cell fate and function. In this study, we investigated the effects of the infarcted cardiac microenvironment on cardiac differentiation of human embryonic stem cells (hESCs). hESCs were intramyocardially transplanted into infarcted or uninjured rat hearts. After 4 weeks, mesodermal and cardiac lineage markers were detected by immunofluorescence. Cardiac function was assessed by echocardiography. hESCs were differentiated in vitro under hypoxic (5% O2 ), low-nutrient (5% FBS), or control condition. The numbers of beating clusters, proportions of cardiac troponin T (cTnT)-positive cells, and relative levels of cardiac-specific markers were determined. Results showed that in both uninjured and infarcted hearts, hESCs survived, underwent development, and formed intracardiac grafts, with a higher proportion in the uninjured hearts. However, cells that were double positive for human fetal liver kinase 1 (Flk1), a marker of cardiac progenitors, and human β-tubulin, a marker for labeling human cells, were found in the uninjured hearts but not in the infarcted hearts. hESC transplantation did not restore the cardiac function of acutely infarcted rats. In vitro, low FBS treatment was associated with fewer beating clusters, a lower proportion of cTnT-positive cells and lower levels of cardiac troponin I (cTnI) and α-myosin heavy chain (α-MHC) expression than those in the control. Conversely, hypoxia treatment was associated with a higher proportion of cTnT-positive cells and higher levels of cTnI expression. In conclusion, transplanted hESCs differentiate toward Flk1-positive cardiac progenitors in the uninjured but not infarcted hearts. The infarcted cardiac microenvironment recapitulated is unsuitable for cardiac differentiation of hESCs, likely due to nutrient deprivation.

Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9-39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9-39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.

Objective To investigate the effects and mechanism of glucagon-like peptide-1 ( GLP-1 ) receptor agonist liraglutide on the proliferation and apoptosis of human pancreatic cancer cells. Methods The human pancreatic cancer cell line MIA PaCa-2 was incubated for 24 h with liraglutide at various concentrations (10-1 000 nmol/ L), or with 100 nmol/ L liraglutide for various durations (0-72 h). Cell proliferation was determined by Cell Counting Kit-8 (CCK-8) analysis. RT-PCR and Western blot were used to detect the mRNA and protein expression levels of related genes. Results GLP-1 receptor was expressed in the MIA PaCa-2 cells. Liraglutide suppressed cell proliferation, up-regulated the expression levels of pro-apoptotic protein Bax and down-regulated the expression levels of anti-apoptotic protein Bcl2 in human pancreatic cancer cells in a dose- and time-dependent manner. Meanwhile, liraglutide down-regulated the expression levels of insulin receptor (INSR) and insulin-like growth factor-1 receptor (IGF-1R), and the phosphorylation levels of their downstream signaling proteins Erk1 / 2 and Akt, in a dose- and time-dependent way. Conclusion Liraglutide inhibits proliferation and promotes apoptosis of human pancreatic cancer cells; the process may be mediated via suppressing the expression of INSR and IGF-1R and inhibiting activation of the downstream MEK/ Erk1 / 2 and PI3k/ Akt pathways.

Objective To investigate the effect and underlying mechanism of miR-375 on regulating differentiation of human embryonic stem (hES) cells into insulin producing cells (IPCs). Methods hES cells were induced into IPCs in vitro. The dynamic expression of miR-375 and hepatocyte nuclear factor 1β(HNF-1β) the predicted target gene, during the differentiation was analyzed. The stage 2-cells during the differentiation infected with miR-375-overexpression lentiviral vector were divided into 3 groups:control group, GFP control group and miR-375-overexpression group. The expressions of miR-375, HNF-1βand the specific markers related to pancreatic islet differentiation or function were determined by realtime PCR and/or Western blotting. Independent sample t test was used to analyze the difference between two group. ANOVA and Q test were used to analyze the difference among multiple groups. Results miR-375 expression in the stage 1-to 5-cells were 100%, (472.25 ± 33.53)%, (768.00 ± 25.65)%, (54.25 ± 5.74)% and (30.75±5.70)%, respectively (F=1137.57, P<0.001). The expression of HNF-1βincreased from stage 3 ((279.50 ± 21.30)%), and peaked at stage 4 ((645.00 ± 64.55)%,F=224.86, P<0.001). The dynamic level of HNF-1βwas similar as that of 1/miR-375. After the lentivirus infection, the mRNA level of HNF-1βin miR-375-overexpression group was not statistically different from that of both the GFP group and control group (F=1.467, P>0.28), whereas the protein level of HNF-1βdecreased to (38.75 ± 9.22)%of the GFP group in the miR-375-overexpression group (F=60.69,P<0.001). miR-375 overexpression upregulated the expression of pancreatic and duodenal homeobox 1 (Pdx-1) in stage 4-cells (F=412.15, P<0.001), and downregulated the expression of the pancreatic islet specific markers, e.g. Nkx6.1, paired box 4 (Pax-4) and insulin in the stage 5-cells (F=105.19-484.05,all P<0.001) when compared with the GFP group. Conclusion miR-375 plays a modulatory role in the IPC differentiation from hES cells. That may be mediated via regulating the expression of the transcription factor HNF-1β.

Glucagon-like peptide-1 (GLP-1) promotes pancreatic β-cell regeneration through GLP-1 receptor (GLP-1R) activation. However, whether it promotes exocrine pancreas growth and thereby increases the risk of pancreatic cancer has been a topic of debate in recent years. Clinical data and animal studies published so far have been controversial. In the present study, we report that GLP-1R activation with liraglutide inhibited growth and promoted apoptosis in human pancreatic cancer cell lines in vitro and attenuated pancreatic tumor growth in a mouse xenograft model in vivo. These effects of liraglutide were mediated through activation of cAMP production and consequent inhibition of Akt and ERK1/2 signaling pathways in a GLP-1R-dependent manner. Moreover, we examined GLP-1R expression in human pancreatic cancer tissues and found that 43.3% of tumor tissues were GLP-1R-null. In the GLP-1R-positive tumor tissues (56.7%), the level of GLP-1R was lower compared with that in tumor-adjacent normal pancreatic tissues. Furthermore, the GLP-1R-positive tumors were significantly smaller than the GLP-1R-null tumors. Our study shows for the first time that GLP-1R activation has a cytoreductive effect on human pancreatic cancer cells in vitro and in vivo, which may help address safety concerns of GLP-1-based therapies in the context of human pancreatic cancer.

糖尿病的患病率在我国呈现快速增高趋势。2型糖尿病（T2DM）的传统内科治疗包括饮食控制、运动锻炼、口服降糖药、胰岛素治疗等，但目前尚无任何一种方法能够有效地控制疾病进展和预防并发症。近年来的研究显示，减肥手术不仅可使肥胖患者的体重下降，还可使其T2DM的缓解率明显增加。因此，减肥手术作为治疗糖尿病的新方法受到了越来越广泛的关注。

Human embryonic stem cells (hESCs) are pluripotent and capable of undergoing multilineage differentiation into highly specialized cells including pancreatic islet cells. Thus, they represent a novel alternative source for targeted therapies and regenerative medicine for diabetes. Significant progress has been made in differentiating hESCs toward pancreatic lineages. One approach is based on the similarities of pancreatic β cell and neuroepithelial development. Nestin-positive cells are selected as pancreatic β cell precursors and further differentiated to secrete insulin. The other approach is based on our knowledge of developmental biology in which the differentiation protocol sequentially reproduces the individual steps that are known in normal β cell ontogenesis during fetal pancreatic development. In the present study, the hESC cell line PKU1.1 was induced to differentiate into insulin-producing cells (IPCs) using both protocols. The differentiation process was dynamically investigated and the similarities and differences between both strategies were explored. Our results show that IPCs can be successfully induced with both differentiation strategies. The resulting IPCs from both protocols shared many similar features with pancreatic islet cells, but not mature, functional β cells. However, these differently-derived IPC cell types displayed specific morphologies and different expression levels of pancreatic islet development-related markers. These data not only broaden our outlook on hESC differentiation into IPCs, but also extend the full potential of these processes for regenerative medicine in diabetes.

Human embryonic stem (hES) cells with the capacity of self-renewal and multilineage differentiation are promising sources for generation of pancreatic islet cells for cell replacement therapy in diabetes. Here we induced hES cells into insulin-producing cells (IPCs) in a stepwise process which recapitulated islet organogenesis by directing cells through the stages resembling definitive endoderm, gut-tube endoderm, pancreatic precursor and cells that expressed pancreatic endocrine hormones. The dynamic expression of microRNAs (miRNAs) during the differentiation was analyzed and was compared with that in the development of human pancreatic islets. We found that the dynamic expression patterns of miR-375 and miR-7 were similar to those seen in the development of human fetal pancreas, whereas the dynamic expression of miR-146a and miR-34a showed specific patterns during the differentiation. Furthermore, the expression of Hnf1β and Pax6, the predicted target genes of miR-375 and miR-7, was reciprocal to that of miR-375 and miR-7. Over-expression of miR-375 down-regulated the expression of gut-endoderm/pancreatic progenitor specific markers Hnf1β and Sox9. Therefore, the miRNAs may directly or indirectly regulate the expression of pancreatic islet organogenesis-specific transcription factors to control the differentiation and maturation of pancreatic islet cells.

Aim. To investigate whether pioglitazone had detrimental effects on biochemical markers of bone turnover in patients with type 2 diabetes (T2DM). Methods. Seventy patients with T2DM were included in this study. The patients remained on their previous antihyperglycemic therapies during the trial. Pioglitazone was then added on their regimen for 3 months. Results. After 3 months of treatment with pioglitazone, the levels of fasting blood glucose and HbA1c were significantly decreased (7.9 ± 1.5 mmol/L versus 9.1 ± 1.6 mmol/L and 7.1 ± 1.0% versus 8.2 ± 1.4%, resp., P < 0.01), compared with baseline in the overall patients. Serum concentrations of P1NP and BAP were significantly decreased from baseline (45.0 ± 20.0  μ g/L versus 40.6 ± 17.9  μ g/L and 13.23 ± 4.7  μ g/L versus 12.3 ± 5.0  μ g/L, resp., P < 0.01) in female group, but not in male group. The serum levels of OC and CTX were unchanged in both female and male subgroups. In addition, the levels of serum BAP and P1NP were significantly decreased after pioglitazone treatment in postmenopausal subgroup, comparing with baseline. Conclusion. Pioglitazone inhibits bone formation and does not seem to affect bone resorption. Postmenopausal female patients rather than premenopausal or male patients are particularly vulnerable to this side effect of pioglitazone.

Thiazolidinediones(TZDs),selective agonists of peroxisome proliferator-activated receptor gamma,are oral anti-diabetic drugs.Several large-scale clinical trials have reported that TZDs may contribute to decreased bone mineral density and increased risk of fracture.In this article,the effects and mechanisms of thiazolidinediones on bone metabolism in the patients with type 2diabetes are reviewed in details.

[Summary] A 19-year-old male patient with central diabetes insipidus complained of polydipsia and polyuria and was found to be accompanied by cervical vertebra lesions.The diagnosis of Langerhans cell histiocytosis was confirmed by laboratory and pathological results.Therefore,it should be alert to consider the possibility of Langerhans cell histiocytosis in a patient with central diabetes insipidus coexisting with the signs of multisystem lesions such as bone disease.

Recent studies showed that chronic inflammations played important roles in the pathogenesis of insulin resistance(IR).Interleukin 18(IL-18),as an important inflammatory cytokine,might be closely related to insulin resistance.In this article,we reviewed the effects and mechanisms of IL-18on insulin resistance.

Aim: Ghrelin is involved in regulating the differentiation of mesoderm-derived precursor cells. The aim of this study was to investigate whether ghrelin modulated the differentiation of human embryonic stem (hES) cells into cardiomyocytes and, if so, whether the effect was mediated by growth hormone secretagogue receptor 1α (GHS-R1α). Methods: Cardiomyocyte differentiation from hES cells was performed according to an embryoid body (EB)-based protocol. The cumulative percentage of beating EBs was calculated. The expression of cardiac-specific markers including cardiac troponin I (cTnI) and α-myosin heavy chain (α-MHC) was detected using RT-PCR, real-time PCR and Western blot. The dispersed beating EBs were examined using immunofluorescent staining. Results: The percentage of beating EBs and the expression of cTnI were significantly increased after ghrelin (0.1 and 1 nmol/L) added into the differentiation medium. From 6 to 18 d of differentiation, the increased expression of cTnI and α-MHC by ghrelin (1 nmol/L) was time-dependent, and in line with the alteration of the percentages of beating EBs. Furthermore, the dispersed beating EBs were double-positively immunostained with antibodies against cTnI and α-actinin. However, blockage of GHS-R1α with its specific antagonist D -[lys 3 ]-GHRP-6 (1 μmol/L) did not alter the effects of ghrelin on cardiomyocyte differentiation. Conclusion: Our data show that ghrelin enhances the generation of cardiomyocytes from hES cells, which is not mediated via GHS-R1α.

Objective To evaluate the structure and function of left ventricle in diabetes mellitus (DM) patients without complications by myocardial velocity gradient (MVG) measured by myocardial velocity profile (MVP). Methods Thirty type 2 DM patients without complications and 30 healthy volunteers as controls were enrolled. The heart structure, systolic function and diastolic function of left ventricle were measured by echocardiography and the left ventricular mass index (LVMI) was calculated. Mitral annular systolic movement (Sm) , early rapid filling phase movement ( Em) and atrial contraction movement(Am) were measured by tissue Doppler image and the left ventricular MVG at diastole and systole in subendocardium and subepicardium (MVGs,MVGd) were measured by MVP. Results The diameter of left atria and left ventricle, thickness of interventricular septum and LVMI were higher in DM group than those of control group ( P <0. 05 or P <0. 01) , MVGs, MVGd, and Em were lower in DM group than those of control group( P <0. 05 or P <0. 01). There were no significant differences on E/A, Em/Am and E/Em between two groups. In addition, there were also no significant differences on Sm,left ventricular ejection fraction and left ventricular fraction shortening between two groups. Conclusions Structure and function of left ventricle have changed in patients of DM without complications. MVG measured by MVP is an accurate and sensitive index to assess left ventricular systolic and diastolic function.

肥胖和2型糖尿病的患病率呈逐年增高的趋势.减肥手术作为减轻体质量的有效方法,近年来逐渐得到广泛的应用.其主要分为限制型手术、吸收不良型手术及联合型手术.减肥手术在减轻体质量的同时也使肥胖患者的糖尿病得到了缓解,但其缓解糖尿病的机制目前尚不完全清楚.除了体质量减轻、摄食减少外,关于肠促胰岛素在减肥手术中的作用也受到了越来越多的重视.本文对减肥手术的术式、疗效、安全性及治疗糖尿病的可能机制进行讨论.