In recent years, evidence-based medicine has developed rapidly, and its ideas and methods have been increasingly used in medical education. We have promoted the model, theory and practical methods of evidence-based medicine in the teaching of endocrinology standardized residency training, which has improved students' learning enthusiasm and initiative, and also enhanced students' mastery of professional knowledge and cultivation and innovation of clinical thinking. In view of the existing problems, this essay puts forward some solutions to help residents to meet the requirements of rapid developments in endocrinology and generally promote the standardization of residents' medical practice behavior.

Background The benefits of fenofibrate (FB), a peroxisome proliferator-activated receptor-a agonist, against hyperlipidemia have been established. We investigated the effect of fenofibrate on insulin resistance of lipoprotein lipase knockout heterozygous (LPL+/-) mice, which represent inherited hypertriglyceridemia and impaired glucose tolerance. Methods Male LPL+/- mice were treated with FB (50 mg/kg, once daily) via gavage for 8 weeks. Plasma lipid, glucose tolerance test, systemic insulin sensitivity, insulin signaling of tissues, genes and proteins related to endoplasmic reticulum (ER) stress and oxidative stress were analyzed. Results Body weight of 40-week LPL+/- with FB were reduced by 30.3% (P<0.05), while the differences of 16- and 28-week LPL+/- with FB were not significant (P>0.05). FB improved the lipid profile of both 28 and 40-week LPL+/- (P<0.001 for both), while that of 16-week LPL+/- mice with FB was unaltered (P>0.05). Glucose tolerance of 40-week LPL+/- were improved by FB (P<0.05), while that of 16- and 28-week LPL+/- with FB kept unaltered (P>0.05). Fasting insulin of 40-week LPL +/- were improved by FB (P<0.05), thus HOMA-IR of 40-week LPL+/- was declined (P<0.05). HOMA-IR of 16- and 28-week LPL+/- with FB had no change. Insulin-stimulated phosphorylated Akt (Ser473) in liver and skeletal muscle of 28-week LPL+/- was enhanced by FB (P < 0.001 and P<0.05 respectively). ER stress biomarkers were detected decreased in liver of 16- to 40-week LPL+/- with FB whereas that in muscle of LPL+/- with FB unchanged. Reduced reactive oxygen species (ROS) levels and augmented mRNA expression of superoxide dismutase (SOD) and catalase (CAT) in skeletal muscle of 28- and 40-week LPL+/- mice with FB were observed. There was no significance on ROS levels and mRNA of SOD and CAT in liver between LPL+/- mice with and without FB. Conclusions Fenofibrate improved lipid profile, glucose tolerance, systemic and tissue-specific insulin resistance of LPL knockout heterozygous mice. This may be associated with alleviated endoplasmic reticulum stress in liver and reduced oxidative stress in muscle.

Objective To investigate the effect of fenofibrate on glucolipid metabolism and insulin sensitivity in lipoprotein lipase heterozygous knockout ( LPL+/-) mice, and to explore its mechanism. Methods LPL+/- mice and wild type ( WT) C57 mice were selected and divided into 3 groups ( n=6 each group):LPL+/-( FB) group, LPL+/-(W)group,andWTgroup.MiceinLPL+/-(FB)groupweregavagedwithfenofibrate(50mg·kg-1·d-1)for8 weeks. Mice in LPL+/-( W) and WT groups were orally fed with the same volume water as that in LPL+/-( FB) group for 8 weeks. Body weight was observed. Plasma triglyceride ( TG ) and free fatty acid ( FFA ) were measured. Intraperitoneal glucose tolerance test in 3 groups of mice were performed. The glucose area under the curve ( AUCG) and homeostasis model assessment for insulin resistance index ( HOMA-IR) were calculated. Insulin-stimulated Ser473 Akt phosphorylation in liver and skeletal muscle was measured by Western blot. Reactive oxygen species ( ROS) levels in liver and skeletal muscle were determined by dihydroethidium staining method and superoxide dismutase ( SOD) and catalase ( CAT) mRNA expression levels were detected by real-time PCR. Results Compared with LPL+/-( W) mice, body weight of LPL+/-( FB) mice was lowered, plasma TG and FFA levels were decreased by about 46.0％and 76.5％respectively, and fasting insulin level and HOMA-IR were decreased while there were no significant differences in fasting glucose level and AUCG between two groups. Insulin-stimulated Ser473 Akt phosphorylation levels in liver and skeletal muscle of LPL+/-mice were enhanced by fenofibrate. ROS level in skeletal muscle of LPL+/-( FB) mice was lower than that in LPL+/-( W) mice while there was no significant difference in ROS of liver between two groups. Fenofibrate significantly increased SOD and CAT mRNA expressions in skeletal muscle of LPL+/-mice, but not in liver. Conclusion Fenofibrate reduces body weight, ameliorates lipid metabolism, and improves insulin sensitivity in LPL+/- mice, with reduced oxidative stress.

Body mass index (BMI), waist circumference (WC), visceral adiposity index (VAI), triglyceride glucose index (TyG), TyG-BMI, and TyG-WC have been reported as markers of insulin resistance or type 2 diabetes mellitus (T2DM). However, little is known about the associations between the aforementioned markers and the risk of prediabetes and diabetes in first-degree relatives (FDRs) of T2DM patients.

Objectives To explore the association between the triglyceride to HDL-C ratio (TG/HDL-C) and insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus.MethodsPatients with newly diagnosed type 2 diabetes mellitus (272 men and 288 women) were enrolled and divided into three groups according to TG/HDL-C tertiles. Insulin resistance was defined by homeostatic model assessment of insulin resistance (HOMA-IR). Demographic information and clinical characteristics were obtained. Spearman's correlation was used to estimate the association between TG/HDL-C and other variables. Multiple logistic regression analyses were adopted to obtain probabilities of insulin resistance. A receiver operating characteristic analysis was conducted to evaluate the ability of TG/HDL-C to discriminate insulin resistance.ResultsTG/HDL-C was associated with insulin resistance in Chinese patients with newly diagnosed T2DM (Spearman's correlation coefficient = 0.21, P < 0.01). Patients in the higher tertiles of TG/HDL-C had significantly higher HOMA-IR values than patients in the lower tertiles [T1: 2.68(1.74-3.70); T2: 2.96(2.29-4.56); T3: 3.09(2.30-4.99)]. Multiple logistic regression analysis showed that TG/HDL-C was significantly associated with HOMA-IR, and patients in the higher TG/HDL-C tertile had a higher OR than those in the lower TG/HDL-C tertile, after adjusting for multiple covariates including indices for central obesity [T1: 1; T2: 4.02 (1.86-8.71); T3: 4.30(1.99-9.29)]. Following stratification of waist circumference into quartiles, the effect of TG/HDL-C on insulin resistance remained significant irrespective of waist circumference.ConclusionsTG/HDL-C was associated with insulin resistance independent of waist circumference. Whether it could be a surrogate marker for insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus still needs to be confirmed by more researches.

OBJECTIVE:Lipid metabolism disturbance can result in insulin resistance and glucose intolerance; however, the features of glucose metabolism are still elusive in different dyslipidemia. Our study intended to explore the characteristics and molecular mechanisms of glucose metabolism abnormal in hypercholesterolemia and hypertriglyceridemia models.METHODS:Two mouse models were used in this study, one was lipoprotein lipase gene-deleted (LPL(+/-)) mice, and the other was high fat dietary (HFD) mice. Levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterin (HDL-c) and low-density lipoprotein-cholesterin (LDL-c) in serum were measured by full-automatic biochemical analyzer. Intraperitoneal glucose tolerance test (IPGTT) was performed to evaluate insulin sensitivity and β-cell function. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) levels in serum were measured by colorimetric determination. mRNA expression of superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase 1 (Gpx1), nuclear factor erythroid 2-related factor 2 (Nrf2a) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) in liver, skeletal muscle, visceral fat and subcutaneous fat were measured by Real-Time PCR.RESULTS:Compared with HFD mice, the levels of serum TG were significantly higher in LPL(+/-) mice, whereas the levels of TC, HDL-c, LDL-c were significantly lower. The plasma glucose levels were increased at each time point of intra-peritoneal glucose tolerance test (IPGTT) in both groups. Furthermore, the level of serum fasting insulin and homeostasis model assessment index-insulin resistance (HOMA-IR) increased with a decreased ISI in both groups. In addition, the plasma MDA of HFD group was higher than that of lipoprotein lipase-deficiency (LPL(+/-)) group, while the activity of T-SOD in HFD group was lower than that in LPL(+/-) group. Real-Time PCR revealed that the expressions of SOD1, CAT and Gpx1 in liver and subcutaneous fat were lower in HFD group than those in LPL(+/-) group, but higher in skeletal muscle and visceral fat.CONCLUSIONS:There are different in glucose metabolism between high TG mice and high TC mice. Impaired insulin sensitivity is more serious in HFD mice than that in LPL(+/-) mice. Oxidative stress could contribute to insulin resistance in hyperlipidemia mice.

Objective: To investigate the correlation of hypertriglyceridemia with abnormal glucose metabolism and insulin resistance.Methods: Lipid and glucose metabolism, whole-body and tissue-specific insulin sensitivity, genes and proteins related with oxidative stress and endoplasmic reticulum (ER) stress were compared between LPL+/- and control mice at different weeks of age.Results: 16-50-week LPL+/- mice had increased body weight compared with their respective controls. Fat mass in visceral adipose tissue (VAT) of 16 and 28-week LPL+/- mice were twice more than their control littermates, and 50-week LPL+/- mice showed the same trend of increase. Plasma lipids were higher in 16-50-week LPL+/- mice. 28- and 50-week LPL+/- mice had elevated tissue lipid accumulation (liver, skeletal muscle, pancreas) and impaired glucose tolerance, while 16-week LPL+/- mice showed no differences. Homeostasis model assessment of insulin resistance for 28 and 50-week LPL+/- mice were twofold greater, whereas that for 16-week LPL+/- mice had no change. Insulin-stimulated phosphorylated Akt (Ser473) in VAT of 28- week LPL+/- mice decreased by 80.6% (p = 0.001), and that in liver and skeletal muscle decreased by 62.4% (P < 0.001) and 51.8% (p = 0.005) respectively. Then we found that plasma malondialdehyde and reactive oxygen species levels in liver and skeletal muscle of LPL+/- mice were elevated. Increased ER stress biomarkers were also detected in liver and VAT of 28-week LPL+/- mice.Conclusions: Systemic LPL deletion results in impaired glucose tolerance, whole-body and tissue-specific insulin resistance, which is associated with tissue lipid deposition in various insulin target tissues. Furthermore, the activation of oxidative stress and ER stress may play an important role in the development of tissue-specific and systemic insulin resistance. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Objective To investigate the glucolipid metabolism in lipoprotein lipase (LPL) gene knockout mice, and to explore the possible mechanisms of insulin resistance. Methods 16- and 40-week old LPL gene knockout heterozygous mice( LPL + / -) and wild type ( WT) C57 mice were selected and divided into 4 groups:16-week LPL+ / -(n=6), 16-week WT(n = 6), 40-week LPL+ / -(n = 6), and 40-week WT(n = 6) group. LPL activity of post-heparin serum was examined. Serum triglyceride( TG) and free fatty acid( FFA) were measuzed. Intraperitoneal glucose tolerance test(IPGTT) in 4 groups of mice were performed. The glucose area under the curve (AUCG) and homeostasis model assessment for insulin resistance index and β-cell function index ( HOMA-IR, HOMA-β) were calculated to evaluate insulin sensitivity and the function of islet β-cells. Serum malondialdehyde (MDA) and total antioxidant capacity ( TAOC) levels were determined by means of colorimetric method. Using dihydroethidium( DHE) fluorescent staining method, reactive oxygen species ( ROS) levels in liver and skeletal muscle were determined. Results LPL activity levels of both 16- and 40-week LPL+ / - mice were significantly lower than that in WT mice of the same age. Serum TG and FFA of 40-week old LPL+ / - mice were significantly higher than those in WT mice of the same age(P<0. 05), and they were also higher than those of 16-week old LPL+ / - mice(P<0. 05). IPGTT showed that compared with WT mice, blood glucose level in LPL+ / - mice was significantly higher than that in WT group at 30 and 120 minute(P<0. 05), and fasting insulin and HOMA-IR were increased significantly(P<0. 05). Serum MDA of 40-week old LPL+ / - mice was evidently higher than that in WT mice by the same week(P<0. 05), while TAOC level was lower than that of WT mice (P<0. 05). ROS in skeletal muscle of 16-week old LPL+ /- mice was significantly increased. Meanwhile, ROS in both liver and skeletal muscle of 40-week old LPL+ / - mice was significantly higher than that in WT mice of the same age. Conclusion As time goes by, lipid and glucose disorders of LPL+ / - mice are aggravating, and insulin resistance develops evidently. Insulin resistance in LPL+ / -mice with dyslipidemia may be related to oxidative stress.

To explore clinical characteristics and beta cell function in Chinese patients with newly diagnosed drug naive type 2 diabetes mellitus (T2DM) with different levels of serum triglyceride (TG).

Objective To compare the differences in responsive ability and oxidative stress damage between type 2 diabetic rats and normal rats under acute sepsis associated with stress hyperglycemia.Methods GK rats with type 2 diabetes and Wistar rats were established critical ill models of sepsis by intraperitoneal injection of 5 mg/kg lipopolysaccharide(LPS).Before and after LPS injection,serum levels of proinflammatory cytokines tumor necrosis factor α (TNF-α),interleukin (IL)-1β3,and IL-6,and anti-inflammatory cytokine IL-10 were determined.Malondialdehyde (MDA) and total antioxidative capacity (T-AOC) levels in serum and tissues (lung,liver,kidney,heart) were measured by colorimetric determination.Results Before LPS injection,serum levels of TNF-α,IL-6,and IL-10 in GK rats were higher than those of Wistar rats.The serum levels of TNF-α,IL-6,and IL-10 after LPS injection were raised in both GK rats and Wistar rats (all P＜0.05).At baseline,serum MDA level of GK rats was higher than that of Wistar group [(25.76 vs 12.71) μmol/L,P＜0.05],while T-AOC level were lower [(0.60 vs 2.8) U/ml,P＜0.05].One hour after LPS injection,the serum MDA level in two kinds of rats significantly increased compared with those of their baseline levels [(32.30 and 20.19) μmol/L,both P＜0.05],while their serum T-AOC level decreased [(0.20 and 2.08) U/ml,P＜0.05]).There were no signigicant differences in the change trend of serum MDA and T-AOC between the two kinds of rats.MDA and T-AOC levels in tissues had no significant difference before and after LPS injection in GK and Wistar rats (P＞0.05).Conclusions The rats with type 2 diabetes had lowered level of proinflammatory factors and raised level of anti-inflammatory factors under acute sepsis,presenting better tolerance and lowered probability of inflammatory diffusion compared with normal rats.

他汀类药物:降低胆固醇 他汀类药物主要适用于高胆固醇血症或者以胆固醇增高为主的混合型高脂血症患者,为目前临床上应用最广泛的一类调脂药物.主要包括阿托伐他汀、洛伐他汀、辛伐他汀、普伐他汀以及氟伐他汀.常用剂量下(如口服立普妥10 mg/日),他汀类药物能使总胆固醇(TC)下降30％,低密度脂蛋白胆固醇(LDL-C)下降25％～50％,甘油三酯(TG)中等度下降,高密度脂蛋白胆固醇(HDL-C)轻微上升.

Small ubiquitin-related modifier(SUMO),as a family of proteins expressing in various organs of the body,can modify transcription factors,enzymes,proteins in many cells.They affect islet β cell development,maturation,and increase insulin secretion.Meanwhile,they suppress autoimmune responses and reduce islet β cells apoptosis to slow down the development of type 1 diabetes.Further investigations of these proteins and their modification processes provide new insights into type 1 diabetes mellitus.

近年的临床干预试验表明,恰当的生活方式改变对多数血脂异常者能起到与降脂药相近似的治疗效果,且无论是否进行药物调脂治疗都必须坚持改善生活方式,其在有效控制血脂的同时可以有效减少心血管事件的发生. 改变生活方式的四大内容 饮食:控制总热量,限制脂肪根据《中国成人血脂异常防治指南(2007年)》推荐,高脂血症患者饱和脂肪酸的摄入应小于总热量的7％,胆固醇的摄入每天应＜ 200 mg,食盐应＜6g.

目的 比较由高脂膳食诱发肥胖的非糖尿病和2型糖尿病大鼠对急性炎症刺激的反应能力.方法 对2型糖尿病GK大鼠(GK组)和Wistar大鼠(Wistar组)进行高脂饲料喂养14周,观察两组大鼠体质量的变化情况.按随机数字表法将高脂饲料喂养14周后的大鼠再分为GK高脂喂养基线组(GK+ HFF组)、Wistar+HFF组、GK高脂喂养后内毒素(LPS)注射组(GK+ HFF+LPS组)和Wistar+ HFF+ LPS组,每组6只.取GK+ HFF+ LPS组和Wistar+ HFF+LPS组大鼠,分别以5 mg/kg LPS经腹腔注射建立脓毒血症危重病模型,观察大鼠血糖波动情况,Real-Time PCR检测肝脏、肺脏、肾脏和心肌组织中肿瘤坏死因子α(TNF-α)、白介素1β (IL-1β)、IL-6和IL-10等炎症细胞因子mRNA的表达.结果 高脂喂养14周后,Wistar组大鼠的体质量明显大于GK组(P＜0.05),GK组大鼠血糖浓度显著高于Wistar组(P＜0.05).LPS注射后,CK+ HFF+ LPS组大鼠血糖浓度上升趋势明显,而Wistar+ HFF+ LPS组大鼠的血糖浓度无明显变化.炎症细胞因子mRNA表达的检测结果显示:Wistar+ HFF+LPS组显著高于Wistar +HFF组(P＜0.05),GK+ HFF+ LPS组显著高于GK+ HFF组(P＜ 0.05)；Wistar+ HFF+ LPS组炎症细胞因子mRNA表达的上升幅度与GK+ HFF+ LPS组比较,差异无统计学意义(P＞0.05).结论 正常大鼠经高脂膳食诱发肥胖后,对急性炎症刺激出现一定的耐受性,且较2型糖尿病大鼠更为显著.

Objective To investigate the incidence and severity of adverse events in Han pateints with advanced digestive tumor treated with irinotecan-based chemotherapy, and their relationship with UGT1A1 gene promoter polymorphism. Methods Sixty-six advanced digestive tumor patients treated with irinotecan-based chemotherapy were enrolled, and the adverse events during chemotherapy, the pretreatment bilirubin level, and the time to the occurrence of degree Ⅲ toxicity were observed. Genomic DNA was extracted from peripheral blood to examine the frequency of UGT1A1 TATA box thymine-adenine (TA) repeats, and its relationship with adverse events was analyzed. The differences of the pretreatment bilirubin level and the time to the occurrence of severe toxicity were also compared. Results Fifty-five patients (83.3%) were identified with (TA)6/(TA)6 genotype, and eleven patients (16.7%) with UGT1A1*28/*1 polymorphism [thymine-adenine (TA)6/(TA)7 genotype, no (TA)7/(TA)7 genotype was found]. In the two groups, 26 and 5 patients (47.3% vs 45.5%,P=1.000) had grade 3 and 4 neutropenia and 5 and 4 patients (9.1% vs 36.4%,P=0.036) had grade 3 and 4 diarrhea, respectively. The pretreatment bilirubin levels of the two groups were (15.1±1.1) μmol/L and (20.8±5.1) μmol/L, respectively (P =0.09). The time to occurrence of severe toxicity of the two groups were 9 weeks and 3 weeks of postchemotherapy, respectively (P=0.186). Conclusions The marked increase in grade 3 or 4 diarrhea, but not in grade 3 or 4 neutropenia may occur in patients treated with irinotecan-based chemotherapy who had (TA)6/(TA)7 genotype.

<正>病例:女,75岁,因中上腹闷胀不适伴烧心感近1个月、发热2周就诊。体检:中上腹及右上腹轻压痛,无反跳痛及肌卫,肝右肋下3cm、剑突下8cm,肝区叩痛阳性。B超示肝多发实性占位,伴部分液化;CT示肝内多发实性占位,转移

<正>伊立替康自20世纪90年代问世以来,已广泛应用于结肠直肠癌、肺癌等实体瘤治疗,可明显提高病人的总生存期,但因其毒性较大(Ⅲ～Ⅳ度腹泻和粒细胞缺乏),应用受到限制。伊立替康毒性与其主要的药物代谢酶UGT1A1有