Insulin signalling downstream of protein kinase B is potentiated by 5′AMP-activated protein kinase in rat hearts in vivo

Aims/hypothesis 5′AMP-activated protein kinase (AMPK) and insulin stimulate glucose transport in heart and muscle. AMPK acts in an additive manner with insulin to increase glucose uptake, thereby suggesting that AMPK activation may be a useful strategy for ameliorating glucose uptake, especially in cases of insulin resistance. In order to characterise interactions between the insulin- and AMPK-signalling pathways, we investigated the effects of AMPK activation on insulin signalling in the rat heart in vivo. Methods Male rats (350–400 g) were injected with 1 g/kg 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or 250 mg/kg metformin in order to activate AMPK. Rats were administered insulin 30 min later and after another 30 min their hearts were removed. The activities and phosphorylation levels of components of the insulin-signalling pathway were subsequently analysed in individual rat hearts. Results AICAR and metformin administration activated AMPK and enhanced insulin signalling downstream of protein kinase B in rat hearts in vivo. Insulin-induced phosphorylation of glycogen synthase kinase 3 (GSK3) β, p70 S6 kinase (p70^S6K)(Thr389) and IRS1(Ser636/639) were significantly increased following AMPK activation. To the best of our knowledge, this is the first report of heightened insulin responses of GSK3β and p70^S6K following AMPK activation. In addition, we found that AMPK inhibits insulin stimulation of IRS1-associated phosphatidylinositol 3-kinase activity, and that AMPK activates atypical protein kinase C and extracellular signal-regulated kinase in the heart. Conclusions/interpretations Our data are indicative of differential effects of AMPK on the activation of components in the cardiac insulin-signalling pathway. These intriguing observations are critical for characterisation of the crosstalk between AMPK and insulin signalling.     

2型糖尿病老年患者应用阿卡波糖联合二甲双胍治疗的效果探析

目的探讨2型糖尿病老年患者应用阿卡波糖联合二甲双胍治疗的效果。方法选择该院80例2017年1月至2019年2月老年2型糖尿病患者。随机分组,二甲双胍治疗组采取二甲双胍治疗,联合药物降糖组则采取阿卡波糖+二甲双胍治疗。比较两组血糖达标率;GLU降低至6.39 mmol/L内时间、PBG降低至7.8 mmol/L内的时间、GHb降低至6.0%时间;治疗前后患者血糖情况;不良反应发生率。结果联合药物降糖组血糖达标率、GLU降低至6.39 mmol/L内时间、PBG降低至7.8 mmol/L内的时间、GHb降低至6.0%时间、血糖情况相比较二甲双胍治疗组更好,差异有统计学意义(P<0.05)。联合药物降糖组不良反应发生率低于二甲双胍治疗组,差异有统计学意义(P<0.05)。结论阿卡波糖+二甲双胍治疗老年2型糖尿病可获得较好预后,可有效改善血糖代谢,且无严重不良反应,安全性高。     

Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells

Objective

Metformin and glucagon like peptide-1 (GLP-1) prevent diabetic cardiovascular complications and atherosclerosis. However, the direct effects on hyperglycemia-induced oxidative stress in endothelial cells are not fully understood. Thus, we aimed to evaluate the effects of metformin and a GLP-1 analog, liraglutide on high glucose-induced oxidative stress.

Methods

Production of reactive oxygen species (ROS), activation of protein kinase C (PKC) and NAD(P)H oxidase, and changes in signaling molecules in response to high glucose exposure were evaluated in human aortic endothelial cells with and without treatment of metformin and liraglutide, alone or in combination. PKC-NAD(P)H oxidase pathway was assessed by translocation of GFP-fused PKCβ2 isoform and GFP-fused p47phox, a regulatory subunit of NAD(P)H oxidase, in addition to endogenous PKC phosphorylation and NAD(P)H oxidase activity.

Results

High glucose-induced ROS overproduction was blunted by metformin or liraglutide treatment, with a further decrease by a combination of these drugs. Exposure to high glucose caused PKCβ2 translocation and a time-dependent phosphorylation of endogenous PKC but failed to induce its translocation and phosphorylation in the cells treated with metformin and liraglutide. Furthermore, both drugs inhibited p47phox translocation and NAD(P)H oxidase activation, and prevented the high glucose-induced changes in intracellulalr diacylglycerol (DAG) level and phosphorylation of AMP-activated protein kinase (AMPK). A combination of these drugs further enhanced all of these effects.

Conclusions

Metformin and liraglutide ameliorate high glucose-induced oxidative stress by inhibiting PKC-NAD(P)H oxidase pathway. A combination of these two drugs provides augmented protective effects, suggesting the clinical usefulness in prevention of diabetic vascular complications.     

多烯磷脂酰胆碱联合二甲双胍和非诺贝特治疗NAFLD患者血清Pygo2和血脂水平变化*

目的 探讨应用多烯磷脂酰胆碱联合二甲双胍和非诺贝特治疗非酒精性脂肪性肝病(NAFLD)患者血清人尾肢同源蛋白2(Pygo2)和血脂水平的变化。方法 2015年3月 ~2019年6月我院收治的NAFLD患者64例,被随机分为对照组32例和观察组32例。给予对照组二甲双胍片和非诺贝特胶囊口服治疗,观察组在此治疗的基础上加用多烯磷脂酰胆碱口服,两组均连续治疗12周。采用放射免疫分析法检测血清透明质酸(HA)和层黏蛋白(LN)水平,采用ELISA法检测血清Pygo2、高迁移率族蛋白B1(HMGB1)和白细胞介素-17(IL-17)。结果 在治疗结束时,观察组血甘油三酯(TG)水平为(1.8±0.1)mmol/L,显著低于对照组【(2.7±0.4)mmol/L,P＜0.05】,总胆固醇(TC)水平为(4.6±0.4)mmol/L,显著低于对照组【(5.8±0.6)mmol/L,P＜0.05】,而血高密度脂蛋白胆固醇(HDL-C)水平为(1.9±0.5)mmol/L,显著高于对照组【(1.5±0.4)mmol/L,P＜0.05】;观察组血清丙氨酸氨基转移酶(ALT) 水平为(28.4±3.2)U/L,显著低于对照组【(35.9±4.1)U/L,P＜0.05】,天冬氨酸氨基转移酶(AST) 水平为(22.1±2.0)U/L,显著低于对照组【(32.6±3.4)U/L,P＜0.05】,血清HMGB1 水平为(13.7±1.5)μg/L,显著低于对照组【(20.2±2.4)μg/L,P＜0.05】,IL-17水平为(75.6±7.8)pg/mL,显著低于对照组【(90.7±10.2)pg/mL,P＜0.05】;观察组血清HA水平为(84.5±9.2)mg/L,显著低于对照组【(117.6±10.3)mg/L,P＜0.05】, LN水平为(91.2±10.2)μg/L,显著低于对照组【(108.7±11.3)μg/L,P＜0.05】,Pygo2水平为(37.5±4.1)μg/L,显著低于对照组【(42.4±5.0)μg/L,P＜0.05】。结论 在运动和饮食控制的基础上,应用多烯磷脂酰胆碱联合二甲双胍和非诺贝特治疗可显著改善NAFLD患者脂代谢,抑制炎症反应和肝纤维化程度,短期临床疗效显著。     

盐酸二甲双胍对原发性高血压伴糖耐量减低患者的疗效观察

目的 :观察二甲双胍对原发性高血压 (EH)伴糖耐量减低 (IGT)患者糖代谢、胰岛素敏感性的影响。方法 :4 3例EH伴IGT患者分组进行非诺地平降压治疗 (Ⅰ组 )和非诺地平降压加二甲双胍治疗 (Ⅱ组 ) ,比较两组患者治疗前后糖代谢、胰岛素敏感性、脂代谢和体重指数的变化。结果 :Ⅱ组患者IGT、胰岛素敏感性明显改善 ,与Ⅰ组比较 ,差异有统计学意义 (P <0 .0 5 ) ;血脂水平、体重指数较Ⅰ组也有所下降 ,但两组比较差异无统计学意义 (P >0 .0 5 )。结论 :二甲双胍能较好地用于EH伴IGT患者的干预治疗     

Stent thrombosis is not increased following percutaneous coronary intervention in patients with non-insulin dependent diabetes mellitus taking metformin

Objective

Recent studies have suggested that metformin may inhibit endothelialization following limus-eluting stent (LES) placement and may increase the risk of stent thrombosis. Therefore, we assessed the impact of metformin on stent thrombosis and major adverse cardiovascular events (MACE) in non-insulin-dependent diabetes mellitus (NIDDM) patients who receive drug-eluting stents (DES).

Methods

We assessed the impact of metformin and stent type on stent thrombosis, MACE, and death in NIDDM patients following DES placement. Of the 1201 patients included, 74.8% received LES, 25.2% received paclitaxel-eluting stents (PES), and 55% were taking metformin.

Results

There was no difference in stent thrombosis, regardless of stent type or metformin use. While Kaplan–Meier curves demonstrated reduced MACE (p = 0.007) and death (p = 0.006) with metformin use, multivariate analysis demonstrated that stent type and metformin use were not associated with outcome.

Conclusion

In NIDDM patients, metformin use or stent type following DES placement did not increase stent thrombosis and MACE rates.     

二甲双胍联合奥沙利铂抗肿瘤作用

目的:探究二甲双胍联合奥沙利铂对结肠癌移植瘤小鼠的抗肿瘤作用。方法:32只BALB/C雄性小鼠左前肢腋下接种c26小鼠结肠腺癌细胞,随机分为恶病质组、二甲双胍组、奥沙利铂组以及联合组,另外8只小鼠作为正常组。奥沙利铂组小鼠每周1次腹腔注射奥沙利铂注射液0.01 mg/g,同时每日灭菌蒸馏水0.1 m L/g灌胃;二甲双胍组小鼠每日给予二甲双胍0.2 mg/g灌胃,同时每周1次腹腔注射生理盐水0.02 m L/g;联合组小鼠每日给予二甲双胍0.2 mg/g灌胃,同时每周1次腹腔注射奥沙利铂注射液0.01 mg/g;正常组和恶病质组小鼠每日灭菌蒸馏水0.1 m L/g灌胃,同时每周1次腹腔注射生理盐水0.02 m L/g。每日检测小鼠体重、肿瘤大小、自发性活动、精神毛发等。连续给药42 d后,颈椎脱臼法处死小鼠,解剖分离并称重右下肢腓肠肌组织,ELISA法检测腓肠肌组织炎症因子水平,HE染色观察腓肠肌形态。结果:荷瘤小鼠体重、腓肠肌质量、腓肠肌横切面积较正常组均明显降低(均P0.05),奥沙利铂组和联合组小鼠肿瘤重量及体积均明显减少,且联合组减少最为明显(均P0.05),各荷瘤小鼠腓肠肌组织中IL-6及TNF-α水平较正常组均明显升高,其中二甲双胍组及联合组较恶病质组则明显下降(均P0.05)。结论:二甲双胍联合奥沙利铂能够抑制肿瘤生长,且能延缓癌性恶液质的发生。     

Hyperthyroxinemia is positively associated with prevalent and incident type 2 diabetes mellitus in two population-based samples from Northeast Germany and Denmark

Background and Aims

A potential causal relationship between thyroid function and type 2 diabetes mellitus is currently under debate, but the current state of research is limited. Our aim was to investigate the association of thyroid hormone levels with prevalent and incident type 2 diabetes mellitus (T2DM) in two representative studies.

The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy

AIM: To determine if the risk of developing heart failure (HF) is associated with the use of sulfonylurea or metformin in patients with diabetes. METHODS: Retrospective cohort study of all adults without HF newly treated with oral antidiabetic drugs in Saskatchewan, Canada between 1991 and 1999. RESULTS: Of 5,631 diabetic subjects (mean age 66+/-13 years) newly treated with a single oral agent and followed for 4.7 (+/-2.2) years, 981 developed HF (4.1 cases per 100 patient years). The incidence of HF was greater in patients using sulfonylurea monotherapy (4.4 cases per 100 treatment years) than those taking metformin monotherapy (3.3 cases per 100 years), and users of high-dose sulfonylureas were more likely to develop incident HF than users of high-dose metformin (adjusted HR 1.24, 95% CI 1.01-1.54). Users of high-dose sulfonylureas were also more likely to develop HF (HR 1.38, 95% CI 1.20-1.60) than users of low-dose sulfonylureas; no such association existed for metformin users (HR 1.06, 95% CI 0.81-1.41). CONCLUSIONS: Users of higher doses of sulfonylurea exhibited a greater risk of developing HF. Clinicians should carefully weigh the need for high-dose sulfonylurea therapy in diabetic subjects with, or at high risk of, HF.