NCOA5, a molecular link between type 2 diabetes and liver cancer

It is reported that nuclear receptor co-activator 5 (NCOA5) is a possible susceptibility gene to both type 2 diabetes (T2D) and hepatocellular carcinoma (HCC). The link between these two diseases is an important area of study with the growing prevalence of T2D. Thus, discovery of a genetic link may have great impact on the field. The group used NCOA5^+/– mice to observe the effects of the gene’s haploinsufficiency on the symptoms of T2D and HCC and claimed NCOA5’s regulation of IL-6 in the pathogenesis of the diseases.     

Global Biochemical Profiling Identifies β-Hydroxypyruvate as a Potential Mediator of Type 2 Diabetes in Mice and Humans

Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are incretins secreted by respective K and L enteroendocrine cells after eating and amplify glucose-stimulated insulin secretion (GSIS). This amplification has been termed the “incretin response.” To determine the role(s) of K cells for the incretin response and type 2 diabetes mellitus (T2DM), diphtheria toxin–expressing (DT) mice that specifically lack GIP-producing cells were backcrossed five to eight times onto the diabetogenic NONcNZO10/Ltj background. As in humans with T2DM, DT mice lacked an incretin response, although GLP-1 release was maintained. With high-fat (HF) feeding, DT mice remained lean but developed T2DM, whereas wild-type mice developed obesity but not diabetes. Metabolomics identified biochemicals reflecting impaired glucose handling, insulin resistance, and diabetes complications in prediabetic DT/HF mice. β-Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting β-hydroxypyruvate production from d-serine. In vitro, β-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. β-Hydroxypyruvate–to–d-serine ratios were lower in humans with impaired glucose tolerance compared with normal glucose tolerance and T2DM. Earlier human studies unmasked a neural relay that amplifies GIP-mediated insulin secretion in a pattern reciprocal to β-hydroxypyruvate–to–d-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and β-cells by regulating β-hydroxypyruvate levels.     

Alterations of morphology and phosphorylated protein expression in the seminal vesicles of diabetic mice

Although many studies reported the detrimental effects of type 1 and 2 diabetes mellitus (T1DM and T2DM) on testis, reproductive parameter changes in DM seminal vesicles have never been documented. This study aimed to examine the morphology, biochemical levels and tyrosine phosphorylation in seminal vesicles of T1DM and T2DM mice. Fifty‐six male C57BL/6 mice were divided into four groups (n = 14/each): T1DM control, T1DM, T2DM control and T2DM. T1DM mice were daily injected of streptozotocin (STZ; 40 mg/kg BW) for 5 days. T2DM mice received high‐fat diet for 14 days prior to STZ injection at a single dose (85 mg/kg BW). At the end of experiments (days 36 and 72), magnesium (MG) and fructosamine (FRA) levels, and phosphorylated protein expression in seminal vesicle were examined. The results showed that seminal and prostate weights and MG and FRA levels of T1DM animals were significantly increased as compared to T2DM mice. Some seminal histopathologies and decreased epithelial height were observed in both DM groups. Significantly, a 72‐kDa phosphorylated protein expression was increased in DM seminal vesicle. We concluded that changes of biochemical components and phosphorylated proteins in seminal vesicle of T1DM and T2DM mice may be associated with low‐quality seminal plasma.     

SGLT2抑制剂对2型糖尿病患者骨骼的影响

钠葡萄糖共转运体2(sodium-glucose cotransporter 2,SGLT2)抑制剂是一种新型降糖药物,其作用机理是通过抑制肾小管对尿糖的重吸收,以增加尿糖排泄降低血糖。近期来自国外的多个临床药物试验发现SGLT2抑制剂可能对2型糖尿病患者的骨代谢、骨密度以及骨折率产生影响。本文将通过复习国内外相关研究,尝试综述SGLT2抑制剂对2型糖尿病患者骨骼的影响。     

Copper Transporter ATP7A Protects Against Endothelial Dysfunction in Type 1 Diabetic Mice by Regulating Extracellular Superoxide Dismutase

Oxidative stress and endothelial dysfunction contribute to vascular complication in diabetes. Extracellular superoxide dismutase (SOD3) is one of the key antioxidant enzymes that obtains copper via copper transporter ATP7A. SOD3 is secreted from vascular smooth muscles cells (VSMCs) and anchors at the endothelial surface. The role of SOD3 and ATP7A in endothelial dysfunction in type 1 diabetes mellitus (T1DM) is entirely unknown. Here we show that the specific activity of SOD3, but not SOD1, is decreased, which is associated with increased O₂^•− production in aortas of streptozotocin-induced and genetically induced Ins2^Akita T1DM mice. Exogenous copper partially rescued SOD3 activity in isolated T1DM vessels. Functionally, acetylcholine-induced, endothelium-dependent relaxation is impaired in T1DM mesenteric arteries, which is rescued by SOD mimetic tempol or gene transfer of SOD3. Mechanistically, ATP7A expression in T1DM vessels is dramatically decreased whereas other copper transport proteins are not altered. T1DM-induced endothelial dysfunction and decrease of SOD3 activity are rescued in transgenic mice overexpressing ATP7A. Furthermore, SOD3-deficient T1DM mice or ATP7A mutant T1DM mice augment endothelial dysfunction and vascular O₂^•− production versus T1DM mice. These effects are in part due to hypoinsulinemia in T1DM mice, since insulin treatment, but not high glucose, increases ATP7A expression in VSMCs and restores SOD3 activity in the organoid culture of T1DM vessels. In summary, a decrease in ATP7A protein expression contributes to impaired SOD3 activity, resulting in O₂^•− overproduction and endothelial dysfunction in blood vessels of T1DM. Thus, restoring copper transporter function is an essential therapeutic approach for oxidant stress–dependent vascular and metabolic diseases.Endothelial dysfunction plays important roles in the development of vascular complications in type 1 diabetes mellitus (T1DM), which is the most common cause of morbidity and mortality and is characterized by insulin deficiency or impaired insulin signaling (1–3). Although the role of oxidative stress in vascular dysfunction in T1DM has been extensively studied (4), the function of antioxidant enzymes in these pathological diseases remains unknown. One of the major antioxidant defense systems in the vasculature are the superoxide dismutases (SODs), which consist of the cytoplasmic Cu/Zn SOD (SOD1), the mitochondrial MnSOD (SOD2), and the extracellular SOD (SOD3) (5,6). SOD3 is a major extracellular antioxidant enzyme highly expressed in the vasculature and synthesized by vascular smooth muscle cells (VSMCs) and fibroblasts. It is secreted and anchored to the extracellular matrix and endothelial cell surface through the heparin-binding domain (HBD). Because of its extracellular location, SOD3 plays a major role in protecting against inactivation of nitric oxide (NO) by superoxide (O₂^•−), thereby preventing endothelial dysfunction in oxidative stress–dependent cardiovascular diseases (7–10). Gene transfer of SOD3 decreases endothelial dysfunction and arterial pressure in hypertension (11) and aging (12) and restores erectile function in streptozotocin (STZ)-induced diabetes (13). Furthermore, diabetic patients showed elevated plasma SOD3 levels (14). Of note, the R213G polymorphism in the SOD3 gene, which reduces binding to the endothelial surface and increases serum SOD3 levels, has been linked to an increase in cardiovascular risk (15). Little is known about the activities of SOD3 as well as the role of endogenous SOD3 in endothelial dysfunction in T1DM.SOD3 is a secretory copper enzyme that requires copper as a catalytic cofactor for its full enzymatic activity in a fashion similar to SOD1 (5). Under physiological conditions, the intracellular level of free copper is extraordinarily restricted due to copper toxicity (16). Thus, soluble copper transport proteins are required to directly transfer copper to specific cellular target proteins. SOD1 obtains copper through interaction with the cytosolic copper chaperone CCS, whereas secretory copper enzyme SOD3 receives copper via the copper chaperone antioxidant-1 (Atox1)–copper transporter ATP7A (Menkes ATPase) pathway (5,17,18). Patients with Menkes disease show multiple abnormalities secondary to deficiencies in the activity of some secretory copper enzymes, such as dopamine β-mono-oxygenase, tyrosinase, and lysyl oxidase, leading to death in infancy (19). We previously reported that specific SOD3 activity is decreased in blood vessels of ATP7A dysfunctional mutant mice, which is rescued by copper addition (20). However, the role of copper transport proteins in vascular dysfunction in T1DM is entirely unknown.We performed the current study to determine the role of SOD3 and copper transport proteins in modulating O₂^•−-mediated endothelial dysfunction in T1DM animals. Here we show that specific activity of SOD3, but not SOD1, is decreased in diabetic vessels, thereby increasing O₂^•− production and impaired endothelium-dependent relaxation of resistant arteries, which is rescued by SOD mimetic tempol and gene transfer of SOD3. Mechanistically, copper transporter ATP7A protein expression is significantly reduced in blood vessels from T1DM mice in part due to the insulin deficiency but not high glucose. Transgenic mice overexpressing ATP7A restore T1DM-induced impaired SOD3 activity and endothelial function by reducing O₂^•− levels. The SOD3-deficient or ATP7A mutant T1DM mice further enhance endothelial dysfunction and vascular O₂^•− production versus T1DM mice. These findings provide new insights into the protective role of the endogenous ATP7A-SOD3 pathway in vascular dysfunction in oxidant stress–dependent metabolic and cardiovascular diseases.     

Fatty liver disease in diabetes mellitus

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus (T2DM), likely reflecting the frequent occurrence of obesity and insulin resistance in T2DM. NAFLD also can occur in type 1 DM (T1DM), but must be distinguished from the more common glycogen hepatopathy as a cause of hepatomegaly and liver function abnormalities in T1DM. Weight reduction achieved by diet and exercise is effective in preventing and treating NAFLD in obese diabetic subjects. Bariatric surgery also has been shown to reverse NAFLD in T2DM, and recently approved weight loss medications should be evaluated for their impact on the development and progression of NAFLD. There is limited evidence suggesting that specific drugs used for blood glucose control in T2DM [thiazolidinediones (TZDs), glucagon-like peptide-1 (GLP-1) analogs, and dipeptidyl peptidase-4 (DPP-4) inhibitors] and also statins may have a role in preventing or treating NAFLD in patients with diabetes.     

IRAK-M Deficiency Promotes the Development of Type 1 Diabetes in NOD Mice

Type 1 diabetes mellitus (T1DM) is an organ-specific autoimmune disease characterized by progressive destruction of insulin-secreting pancreatic β-cells. Both T-cell–mediated adaptive responses as well as innate immune processes are involved in pathogenesis. Interleukin-1 receptor–associated kinase M (IRAK-M) can effectively inhibit the MyD88 downstream signals in Toll-like receptor pathways, while lack of IRAK-M is known to be associated with autoimmunity. Our study showed that IRAK-M–deficient (IRAK-M^−/−) nonobese diabetic (NOD) mice displayed early onset and rapid progression of T1DM with impaired glucose tolerance, more severe insulitis, and increased serum anti-insulin autoantibodies. Mechanistic studies showed that the enhanced activation and antigen-presenting function of IRAK-M^−/− antigen-presenting cells from IRAK-M^−/− mice were responsible for the rapid progression of disease. Moreover, IRAK-M^−/− dendritic cells induced enhanced activation of diabetogenic T cells in vitro and the rapid onset of T1DM in vivo in immunodeficient NOD mice when cotransferred with diabetogenic T cells. This study illustrates how the modulation of innate immune pathways through IRAK-M influences the development of autoimmune diabetes.     

男性2型糖尿病伴代谢综合征患者血清维生素D水平的研究

目的观察男性2型糖尿病(T2DM)患者血清25-羟维生素D[25(OH) D]水平与代谢综合征(MS)及其组分的关系。方法收集2018年3月至2019年6月在遵义医科大学附属医院内分泌科住院的男性T2DM患者203例及同期健康男性对照组(NC组) 42例,糖尿病患者中根据有无MS分为T2DM+MS组(122例)、T2DM+非MS组(81例),另根据符合MS诊断标准数目分为T2DM组(单纯糖尿病组)、T2DM+1组(除血糖异常外另加一个组分)、T2DM+2组(除血糖异常外另加两个组分)、T2DM+3组(除血糖异常外另加三个组分)、T2DM+4组(具备MS的所有组分),分析WC、BMI、SBP、DBP、FBG、Hb Alc、HOMAIR、TG、TC、LDL-C、HDL-C和25(OH) D水平。结果 T2DM+MS组及T2DM+非MS组血清25(OH) D水平均较NC组显著降低(P0.05),T2DM+MS组血清25(OH) D水平较T2DM+非MS组显著降低(P0.05)。NC组、T2DM组、T2DM+1组、T2DM+2组、T2DM+3组、T2DM+4组血清25(OH) D水平逐渐降低,差异有统计学意义(P 0.05)。Pearson相关分析显示血清25(OH) D水平与WC、BMI、SBP、DBP、HOMA-IR、FBG、TG、TC、LDL-C呈负相关(P0.05),与HDL-C呈正相关(P0.05)。多元线性回归提示HOMA-IR是血清25(OH) D水平的独立影响因素(P0.05)。二元Logistic回归分析显示血清25(OH) D是T2DM伴MS患者的独立保护因素(P0.05)。结论血清维生素D水平在男性T2DM患者代谢综合征的发生发展中可能起着一定作用。低水平维生素D与MS组分数目增加存在一定相关性。     

新诊断男性2型糖尿病患者骨密度临床分析

目的研究新诊断男性2型糖尿病患者(T2DM)骨密度改变情况及危险因素。方法应用双能X射线吸收法测定了200例新诊断男性T2DM和200例男性对照组的L2-4、Wards区、股骨颈、大转子骨密度。并记录年龄、体重指数、血糖、胰岛素及糖化血红蛋白(HbAlc)等临床指标进行比较。结果男性T2DM的血糖、糖化血红蛋白显著高于对照组(P<0.001),而BMD较对照组显著降低(P<0.05)。T2DM的骨质疏松检出率明显高于对照者(P<0.05)。线性回归分析显示HbA1c为BMD独立危险因素(P=0.003,OR=2.15,95%可信区间:2.89～3.52)。结论 T2DM的骨密度降低明显,骨质疏松发生率高,加强控制糖尿病。     

High HbA1c is a risk factor for complications after hepatectomy and influences for hepatocellular carcinoma without HBV and HCV infection

BackgroundCurrently, the population with type 2 diabetes mellitus (DM) is increasing worldwide. However, the influence of DM or hyperglycemia on the outcome of resected hepatocellular carcinoma (HCC) is unclear.MethodsWe analyzed 756 patients with HCC who underwent hepatectomy. These patients were assigned to an HbA1c ≥7.0% (H-A1c; n=100) or HbA1c <7.0% (L-A1c; n=656) group depending on their HbA1c level at admission. We investigated prognoses, clinicopathological characteristics and surgical outcomes including morbidities of HCC patients with high HbA1c, prognoses according to the treatment for DM were also investigated.ResultsAmong all patients and those with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, overall survival (OS) and relapse-free survival (RFS) did not differ significantly between the H-A1c and L-A1c groups. In contrast, the 5-year OS rate of the H-A1c group was 55% and that of the L-A1c group 71% among patients without HBV and HCV (NBNC patients) (P=0.03). Among NBNC patients, the median RFS of the H-A1c group was 13 months, and that of the L-A1c group was 26 months (P=0.02). In addition, metformin use was an independent favorable factor for both OS and RFS. The H-A1c group had significantly higher rates of hyperbilirubinemia, wound infection, and pneumonia.ConclusionsHCC patients with high HbA1c might have poor prognoses for both survival and recurrence in NBNC-HCC. High HbA1c may also be a risk factor for morbidities after hepatectomy. Metformin use may constitute a good option for NBNC patients with HCC.     

Mutation profile and its correlation with clinicopathology in Chinese hepatocellular carcinoma patients

BackgroundHepatocellular carcinoma (HCC) is one of the most common causes of cancer worldwide. Although many studies have focused on oncogene characteristics, the genomic landscape of Chinese HCC patients has not been fully clarified.MethodsA total of 165 HCC patients, including 146 males and 19 females, were enrolled. The median age was 55 years (range, 27–78 years). Corresponding clinical and pathological information was collected for further analysis. A total of 168 tumor tissues from these patients were selected for next-generation sequencing (NGS)-based 450 panel gene sequencing. Genomic alterations including single nucleotide variations (SNV), short and long insertions and deletions (InDels), copy number variations, and gene rearrangements were analyzed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. The top quartile of HCC was classified as TMB high.ResultsA total of 1,004 genomic alterations were detected from 258 genes in 168 HCC tissues. TMB values were identified in 160 HCC specimens, with a median TMB of 5.4 Muts/Mb (range, 0–28.4 Muts/Mb) and a 75% TMB of 7.7 Muts/Mb. The most commonly mutated genes were TP53, TERT, CTNNB1, AXIN1, RB1, TSC2, CCND1, ARID1A, and FGF19. SNV was the most common mutation type and C:G>T:A and guanine transformation were the most common SNVs. Compared to wild-type patients, the proportion of Edmondson grade III–IV and microvascular invasion was significantly higher in TP53 mutated patients (P<0.05). The proportion of tumors invading the hepatic capsule was significantly higher in TERT mutated patients (P<0.05). The proportion of Edmondson grade I-II, alpha fetoprotein (AFP) <25 µmg/L, and those without a history of hepatitis B was significantly higher in CTNNB1 mutated patients (P<0.05). CTNNB1 mutations were associated with TMB high in HCC patients (P<0.05). Based on correlation analysis, the mutation of TP53 was independently correlated with microvascular invasion (P=0.002, OR =3.096) and Edmondson grade III–IV (P=0.008, OR =2.613). The mutation of TERT was independently correlated with tumor invasion of the liver capsule (P=0.001, OR =3.030), and the mutation of CTNNB1 was independently correlated with AFP (<25 µmg/L) (P=0.009, OR =3.414).ConclusionsThe most frequently mutated genes of HCC patients in China were TP53, TERT, and CTNNB1, which mainly lead to the occurrence and development of HCC by regulating the P53 pathway, Wnt pathway, and telomere repair pathway. There were more patients with microvascular invasion and Edmondson III–IV grade in TP53 mutated patients and more patients with hepatic capsule invasion in TERT mutated patients, while in CTNNB1 mutated patients, there were more patients with Edmondson I–II grade, AFP <25 µmg/L, and a non-hepatitis B background. Also, the TMB values were significantly higher in CTNNB1 mutated patients than in wild type patients.     

男性2型糖尿病患者骨密度检测75例分析

目的 分析2型糖尿病（Type 2 diabetes mellitus,T2DM）患者骨密度（Bone mineral density,BMD）与患者年龄、空腹及餐后血糖、糖化血红蛋白、血钙、血磷、甘油三脂及总胆固醇之间的关系,并分析其临床指导价值.方法选择2011年5月至2013年5月间,在本院初次诊断T2DM并以注射胰岛素作为血糖控制方案的男性患者.采用双能X线骨密度仪（Dual energy X-ray absorption,DEXA）检测腰椎前后位（L1～4）BMD值（g/cm2）,记录患者身高和体重以计算身体质量指数（Body mass index,BMI）,检测患者空腹血糖、餐后2小时血糖、糖化血红蛋白A1C（Hemoglobin A1C,HbA1c）、血钙、血磷、甘油三脂及总胆固醇浓度.结果 T2DM患者腰椎前后位（L1-4）平均BMD为（1.08±0.17）g/cm2,与年龄、血钙、血磷、甘油三酯、总胆固醇、身高、体重和BMI间均无相关性.T2DM患者BMD与其空腹血糖、餐后血糖和糖化血红蛋白呈负相关,差异均具有统计学意义（r=-0.666,P＜0.001;r=-0.74,P＜0.001;r=-0.693,P＜0.001）.结论中年男性T2DM患者血糖水平越高,平均持续时间越长患者BMD越低,对于糖化血红蛋白水平高者应积极开展BMD检查以早期发现低骨量和OP患者.     

Dolichandrone serrulata flower extract ameliorates male reproductive damages in type 2 diabetic rats

Dolichandrone serrulata flower (DSF) has been believed to reduce blood glucose in hyperglycaemic persons with sub-fertility but its effect on improvement of male reproductive impairment has never been elucidated scientifically. This study attempted to investigate the hypoglycaemic effects of DSF on male reproductive damages in type 2 diabetes mellitus (T2DM) rats. Adult Sprague Dawley rats were divided into four groups (control, T2DM, DSF200 + T2DM and DSF600 + T2DM; n = 10/each). Control rats received low-fat diet for 14 days before saline injection while streptozocin (50 mg/kg BW) induced T2DM groups received high-fat diet and were orally administered with DSF (200 and 600 mg/kg BW) for 28 days. At the end, fasted blood glucose (FBG), malondialdehyde (MDA), testosterone, sperm quality, histology and protein expressions were examined. The result showed that DSF decreased high FBG and testicular MDA and increased testosterone levels of T2DM-treated rats. Low-sperm quality and histological malfunction were ameliorated in DSF-treated group. There was significant decrease in the expression of androgen receptor, heat-shock 70 and steroidogenic acute regulatory proteins of T2DM-treated rats. Our study demonstrated changes of six bands (116, 51, 45, 39, 35 and 29 kDas) of tyrosine-phosphorylated proteins. In conclusion, DSF could reduce the FBGand ameliorate the reproductive damages in male T2DM rats.     

miR-139-5p对人肝癌细胞增殖和侵袭的影响

目的 探讨微小RNA(miRNA)-139-5p在肝癌组织中的表达及其对人肝癌细胞增殖、侵袭的影响和潜在的分子机制。方法 采用生物信息学方法,从GEO数据库中下载GSE36915数据集,进行差异miRNA分析,结合TCGA-LICH数据集中的生存数据,筛选与预后显著相关的miRNA。采用实时荧光定量PCR(qRT-PCR)检测miR-139-5p在肝癌及其癌旁组织中的表达。利用CCK-8实验、Transwell实验观察miR-139-5p对人肝癌细胞SK-Hep-1和SMMC-7721的表型变化。采用高通量测序检测过表达miR-139-5p的SK-Hep-1细胞中基因表达的变化,确定miR-139-5p调控的潜在的信号通路和靶基因,并采用免疫印迹实验和报告基因实验进行验证。结果 通过对GSE36915数据集进行分析,共鉴定到50个显著差异表达的miRNA。结合TCGA-LICH数据集中的生存数据,发现在差异最显著的20个miRNA中,miR-15b-3p、miR-1180-3p、miR-139-5p、miR-139-3p与预后显著相关,最终确定miR-139-5p为进一步研究对象。mi...     

Duodenal-Jejunal Bypass Surgery Ameliorates Glucose Homeostasis and Reduces Endoplasmic Reticulum Stress in the Liver Tissue in a Diabetic Rat Model

Background

Duodenal-jejunal bypass (DJB) has been shown to be an effective surgical treatment for type 2 diabetes mellitus (T2DM). However, the underlying mechanisms are poorly understood. Recently, accumulating evidences suggest that endoplasmic reticulum (ER) stress plays an important role in the development of insulin resistance in T2DM. The present study was designed to investigate the effect of DJB on glucose homeostasis, the ER stress state in the liver tissue, and the involving signaling independently of weight loss.

Methods

Thirty adult male T2DM Sprague-Dawley (SD) rats induced by high-fat diet and low dose of streptozotocin (STZ) were randomly divided into DJB and sham groups. Ten age-matched male SD rats were assigned as the control group. The parameters of body weight and calorie intake were measured at indicated time points. The glucose tolerance and insulin resistance were detected to evaluate the glucose homeostasis. Serum insulin was determined by enzyme-linked immunosorbent assay (ELISA). The markers of ER stress, the activity of c-Jun N-terminal kinase (JNK) and serine phosphorylation of insulin receptor substrate 1 (IRS-1) in the liver tissue, were determined by Western blotting.

Results

DJB induced significant improvements in glucose homeostasis and insulin sensitivity, but without weight loss. DJB improved the ER stress state indicated by decreased protein kinase RNA (PKR)-like ER protein kinase (PERK) and inositol-requiring enzyme 1 (IRE-1) phosphorylation in the liver tissue. The JNK activity and serine phosphorylation of IRS-1 in the liver tissue were significantly reduced after DJB.

Conclusions

DJB ameliorates glucose homeostasis. Meanwhile, our study helps to reveal that the reduced hepatic ER stress and the decreased JNK activity may contribute to the improved glucose homeostasis after DJB.

     

影响初发2型糖尿病患者IIEF-5评分的相关因素分析

目的:探讨影响初发2型糖尿病(T2DM)患者国际勃起功能指数-5(IIEF-5)评分的相关因素。方法:调查149例初发T2DM患者的IIEF-5评分与年龄、体重指数(BM I)、空腹血糖(FPG)、口服葡萄糖耐量实验(OGTT)中2 h血糖(2hPG)、空腹血胰岛素(INS)、空腹C肽、糖化血红蛋白(GHbA1c)、血清睾酮(T)、雌二醇(E2)、T/E2、血清一氧化氮(NO)、红细胞醛糖还原酶(AR)、吸烟、酗酒、伴发疾病(包括高血压、高脂血症、高尿酸血症、心脏疾病、肝脏疾病等)、其他慢性并发症(糖尿病神经病变、糖尿病视网膜病变、糖尿病肾病等)、药物使用(包括β受体阻滞剂、钙通道阻滞剂、血管紧张素转换酶抑制剂及利尿剂等可影响阴茎勃起功能的药物)的关系。结果:吸烟组、患有并发症组、伴发疾病组、应用药物治疗组IIEF-5评分明显低于对照组(P<0.05),饮酒组与不饮酒组的IIEF-5评分比较差异无显著性(P>0.05)。年龄、BM I、FPG、2hFPG、INS、GHBA1C、AR与IIEF-5评分具有显著性负相关关系(P<0.05);NO与IIEF-5评分具有显著性正相关关系(P<0.05),T、E2、T/E2与IIEF-5评分无相关关系(P>0.05)。结论:多种因素影响初发T2DM患者的IIEF-5评分。     

Stereotactic body radiation therapy versus radiofrequency ablation in patients with small hepatocellular carcinoma: a systematic review and meta-analysis

BackgroundThis study aimed to compare the clinical outcomes and toxicity between small hepatocellular carcinoma (HCC) patients treated with stereotactic body radiation therapy (SBRT) and those treated with radiofrequency ablation (RFA).MethodsWe searched databases for relevant clinical studies. The primary outcomes of interest were overall survival (OS) at 1 and 2 years, freedom from local progression (FFLP) rate at 2 years, and complications.ResultsFive cohorts from 5 retrospective studies and 4,814 patients with HCC were included. Pooled OS at 2 years was significantly lower for SBRT than for RFA [odds ratio (OR): 0.63; 95% confidence interval (CI): 0.51–0.79; P<0.0001], but the pooled FFLP rate at 2 years was higher for SBRT than for RFA (OR: 1.66; 95% CI: 1.05–2.61; P=0.03). In addition, there was no significant difference in the local and liver toxicities of the two treatments. The contradictory conclusion between the OS and FFLP outcome may be attributed to the difference in radiological dose and location, but there were no uniform criteria to illustrate the radiological dose and location in the included studies.ConclusionsSBRT had a higher local control ratio but poorer prognosis than RFA in patients with small HCC. The local toxicity was comparable in both treatments. Further trials should be designed with uniform standards for SBRT and RFA treatments.     

Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes

Apoptosis is the major cause of death of insulin-producing β-cells in type 1 diabetes mellitus (T1DM). Klotho is a recently discovered antiaging gene. We found that the Klotho gene is expressed in pancreatic β-cells. Interestingly, halplodeficiency of Klotho (KL^+/−) exacerbated streptozotocin (STZ)-induced diabetes (a model of T1DM), including hyperglycemia, glucose intolerance, diminished islet insulin storage, and increased apoptotic β-cells. Conversely, in vivo β-cell–specific expression of mouse Klotho gene (mKL) attenuated β-cell apoptosis and prevented STZ-induced diabetes. mKL promoted cell adhesion to collagen IV, increased FAK and Akt phosphorylation, and inhibited caspase 3 cleavage in cultured MIN6 β-cells. mKL abolished STZ- and TNFα-induced inhibition of FAK and Akt phosphorylation, caspase 3 cleavage, and β-cell apoptosis. These promoting effects of Klotho can be abolished by blocking integrin β1. Therefore, these cell-based studies indicated that Klotho protected β-cells by inhibiting β-cell apoptosis through activation of the integrin β1-FAK/Akt pathway, leading to inhibition of caspase 3 cleavage. In an autoimmune T1DM model (NOD), we showed that in vivo β-cell–specific expression of mKL improved glucose tolerance, attenuated β-cell apoptosis, enhanced insulin storage in β-cells, and increased plasma insulin levels. The beneficial effect of Klotho gene delivery is likely due to attenuation of T-cell infiltration in pancreatic islets in NOD mice. Overall, our results demonstrate for the first time that Klotho protected β-cells in T1DM via attenuating apoptosis.     

Effects of Obesity Surgery on Type 2 Diabetes Mellitus Asian Patients

Background  Obesity is a major risk factor for the development of type 2 diabetes mellitus (T2DM). Surgery is the most effective treatment for morbid obesity, and it has been shown to lead to dramatic improvement in type T2DM. However, data concerning obese Asian patients have not been reported, and the mechanism of improving T2DM after bariatric surgery in this population remains speculative. Methods  From April 1997 to March 2006, 1,375 patients undergoing obesity surgery were recruited for our study of the effects of weight loss surgery on type 2 diabetes mellitus (T2DM). Laparoscopic vertical banded gastric partition (LVBG) was performed in 552 patients (40.1%), laparoscopic gastric bypass in 660 patients (48.0%), and laparoscopic adjustable gastric banding (LAGB) in 140 patients (10.2%). Another 23 patients (1.7%) received open or revision surgery. We evaluated the clinical data and effect of obesity surgery on T2DM, impaired fasting glucose (IFG) and compared the changes with those with normal fasting glucose. Results  Among all the patients, 166 (12.1%) had impaired fasting glucose (IFG) and 247 (18.0%) had T2DM. Patients with IFG or DM were significantly older, more central obese, and they had higher insulin resistance and a higher HbA1C level than those with normal fasting glucose. The mean total weight loss for the population was 28.6%, 29.1%, 28.5%, 23.8%, and 24.4% (at 1, 2, 3, 5, and 7 years after surgery). There was no increase of surgical risk in T2DM or IFG patients. One year after operation, fasting plasma glucose returned to normal in 78.5% of T2DM patients and 94.7% of IFG patients. The HbA1C level returned to under 7.0 in 81.5% of T2DM and in 100% of IFG patients. Laparoscopic gastric bypass patients had a greater weight loss and a higher rate of glucose normalization (93.1%) than the LVBG patients (85.3%) and LAGB patients (73.9%), but no difference in HbA1C normalization. Conclusions  Obesity surgery resulted in significant and sustained weight loss with a cure rate of T2DM up to 80% in morbidly obese Asian patients. Gastric bypass surgery had a better result in T2DM cure rate than LVBG and LAGB because of better weight reduction.