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Inhibition of protein kinase B by Palmitate in the insulin signaling of HepG2 cells and the preventiveeffect of Arachidonic acid on insulin resistance

XIA Yanzhi, WAN Xuedong, DUAN Qiuhong, HE Shansu, WANG Ximing

《医学前沿(英文)》 2007年 第1卷 第2期   页码 200-206 doi: 10.1007/s11684-007-0038-y

摘要: Elevated plasma levels of free fatty acids (FFAs) may contribute to insulin resistance (IR) that is characteristic of type 2 diabetes mellitus. In this study, we investigated the effects of two fatty acids, palmitate (PA) and arach

关键词: palmitate     characteristic     study     plasma     resistance    

Mechanism of insulin resistance in obesity: a role of ATP

《医学前沿(英文)》 2021年 第15卷 第3期   页码 372-382 doi: 10.1007/s11684-021-0862-5

摘要: Obesity increases the risk of type 2 diabetes through the induction of insulin resistance. The mechanism of insulin resistance has been extensively investigated for more than 60 years, but the essential pathogenic signal remains missing. Existing hypotheses include inflammation, mitochondrial dysfunction, hyperinsulinemia, hyperglucagonemia, glucotoxicity, and lipotoxicity. Drug discoveries based on these hypotheses are unsuccessful in the development of new medicines. In this review, multidisciplinary literature is integrated to evaluate ATP as a primary signal for insulin resistance. The ATP production is elevated in insulin-sensitive cells under obese conditions independent of energy demand, which we have named “mitochondrial overheating.” Overheating occurs because of substrate oversupply to mitochondria, leading to extra ATP production. The ATP overproduction contributes to the systemic insulin resistance through several mechanisms, such as inhibition of AMPK, induction of mTOR, hyperinsulinemia, hyperglucagonemia, and mitochondrial dysfunction. Insulin resistance represents a feedback regulation of energy oversupply in cells to control mitochondrial overloading by substrates. Insulin resistance cuts down the substrate uptake to attenuate mitochondrial overloading. The downregulation of the mitochondrial overloading by medicines, bypass surgeries, calorie restriction, and physical exercise leads to insulin sensitization in patients. Therefore, ATP may represent the primary signal of insulin resistance in the cellular protective response to the substrate oversupply. The prevention of ATP overproduction represents a key strategy for insulin sensitization.

关键词: type 2 diabetes     energy expenditure     mitochondria     hyperinsulinemia     hyperglucagonemia     AMPK    

Mechanisms of insulin resistance in obesity

null

《医学前沿(英文)》 2013年 第7卷 第1期   页码 14-24 doi: 10.1007/s11684-013-0262-6

摘要:

Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that, there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy.

关键词: type 2 diabetes     energy expenditure     inflammation     lipotoxicity     mitochondria     hyperinsulinemia     adenosine monophosphate-activated protein kinase (AMPK)    

Insulin resistance and the metabolism of branched-chain amino acids

null

《医学前沿(英文)》 2013年 第7卷 第1期   页码 53-59 doi: 10.1007/s11684-013-0255-5

摘要:

Insulin resistance (IR) is a key pathological feature of metabolic syndrome and subsequently causes serious health problems with an increased risk of several common metabolic disorders. IR related metabolic disturbance is not restricted to carbohydrates but impacts global metabolic network. Branched-chain amino acids (BCAAs), namely valine, leucine and isoleucine, are among the nine essential amino acids, accounting for 35% of the essential amino acids in muscle proteins and 40% of the preformed amino acids required by mammals. The BCAAs are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in insulin resistant conditions and/or insulin deficiency. Although increased circulating BCAA concentration in insulin resistant conditions has been noted for many years and BCAAs have been reported to be involved in the regulation of glucose homeostasis and body weight, it is only recently that BCAAs are found to be closely associated with IR. This review will focus on the recent findings on BCAAs from both epidemic and mechanistic studies.

关键词: branched-chain amino acids     leucine     isoleucine     valine     insulin resistance    

Role of exercise training on insulin resistance and TNF-α in high-fat diet rats

Hui SUN MD, Xiuling DENG MM, Fangxi XIAO MD, Lulu CHEN MD, Huiqing LI MD,

《医学前沿(英文)》 2009年 第3卷 第4期   页码 403-407 doi: 10.1007/s11684-009-0071-0

摘要: This study investigated the effect of exercise training on insulin resistance and serum and adipose TNF-α in high-fat diet-induced insulin-resistant rats. Thirty male Wistar rats were randomly divided into two groups: normal control group (NC; =8) that accepted normal chow and high-fat diet group (HF; =22) that fed on high-fat diet to induce insulin resistance model. The HF group was randomly assigned to two subgroups after 18 weeks: sedentary group (SE; =10) and exercise training group (ET; =12) that performed swimming exercise training for 6 weeks, while both groups continued high-fat diet. Changes of body weight, lipid profile, and fasting plasma glucose and insulin were measured. The insulin sensitivity index (ISI) was calculated. Serum concentration of TNF-α was detected by ELISA. The expression of TNF-α mRNA and protein in adipose tissue was examined by using real-time fluorescence quantitative polymerase chain reaction (PCR) and Western blot, respectively. After 18 weeks, compared with the NC group, body weight, blood lipid, glucose, and insulin in the HF group were significantly elevated, while the ISI decreased obviously, which suggested that insulin resistance appeared in the HF group. After exercise training for 6 weeks, compared with the SE group, both ISI and serum TNF-α concentration in the ET group were decreased significantly; however, the expression levels of TNF-α mRNA and protein in adipose tissue increased by 27.5% and 20.5%, respectively. In conclusion, exercise training ameliorates insulin resistance. The reduction of the level of serum TNF-α and the increased expression of TNF-α in adipose tissue by exercise training may be involved in this mechanism.

关键词: exercise training     insulin resistance     tumor necrosis factor-α    

Overcoming oral insulin delivery barriers: application of cell penetrating peptide and silica-based nanoporous

Huining HE, Junxiao YE, Jianyong SHENG, Jianxin WANG, Yongzhuo HUANG, Guanyi CHEN, Jingkang WANG, Victor C YANG

《化学科学与工程前沿(英文)》 2013年 第7卷 第1期   页码 9-19 doi: 10.1007/s11705-013-1306-9

摘要: Oral insulin delivery has received the most attention in insulin formulations due to its high patient compliance and, more importantly, to its potential to mimic the physiologic insulin secretion seen in non-diabetic individuals. However, oral insulin delivery has two major limitations: the enzymatic barrier that leads to rapid insulin degradation, and the mucosal barrier that limits insulin’s bioavailability. Several approaches have been actively pursued to circumvent the enzyme barrier, with some of them receiving promising results. Yet, thus far there has been no major success in overcoming the mucosal barrier, which is the main cause in undercutting insulin’s oral bioavailability. In this review of our group’s research, an innovative silica-based, mucoadhesive oral insulin formulation with encapsulated-insulin/cell penetrating peptide (CPP) to overcome both enzyme and mucosal barriers is discussed, and the preliminary and convincing results to confirm the plausibility of this oral insulin delivery system are reviewed. In vitro studies demonstrated that the CPP-insulin conjugates could facilitate cellular uptake of insulin while keeping insulin’s biologic functions intact. It was also confirmed that low molecular weight protamine (LMWP) behaves like a CPP peptide, with a cell translocation potency equivalent to that of the widely studied TAT. The mucoadhesive properties of the produced silica-chitosan composites could be controlled by varying both the pH and composition; the composite consisting of chitosan (25 wt-%) and silica (75 wt-%) exhibited the greatest mucoadhesion at gastric pH. Furthermore, drug release from the composite network could also be regulated by altering the chitosan content. Overall, the universal applicability of those technologies could lead to development of a generic platform for oral delivery of many other bioactive compounds, especially for peptide or protein drugs which inevitably encounter the poor bioavailability issues.

关键词: insulin     cell penetrating peptide     mucoadhesive composites     oral delivery    

Lingguizhugan Decoction, a Chinese herbal formula, improves insulin resistance in overweight/obese subjects

《医学前沿(英文)》 2022年 第16卷 第5期   页码 745-759 doi: 10.1007/s11684-021-0880-3

摘要: Lingguizhugan Decoction (LGZG) has been investigated in basic studies, with satisfactory effects on insulin resistance in non-alcoholic fatty liver disease (NAFLD). This translational approach aimed to explore the effect and underlying mechanism of LGZG in clinical setting. A randomized, double-blinded, placebo-controlled trial was performed. A total of 243 eligible participants with NAFLD were equally allocated to receive LGZG (two groups: standard dose and low dose) or placebo for 12 weeks on the basis of lifestyle modifications. The primary efficacy variable was homeostasis model assessment of insulin resistance (HOMA-IR). Analyses were performed in two populations in accordance with body mass index (BMI; overweight/obese, BMI ≥ 24 kg/m2; lean, BMI < 24 kg/m 2). For overweight/obese participants, low-dose LGZG significantly decreased their HOMA-IR level compared with placebo (−0.19 (1.47) versus 0.08 (1.99),P = 0.038). For lean subjects, neither dose of LGZG showed a superior effect compared with placebo. Methylated DNA immunoprecipitation sequencing and real-time qPCR found that the DNA N6-methyladenine modification levels of protein phosphatase 1 regulatory subunit 3A (PPP1R3A) and autophagy related 3 (ATG3) significantly increased after LGZG intervention in overweight/obese population. Low-dose LGZG effectively improved insulin resistance in overweight/obese subjects with NAFLD. The underlying mechanism may be related to the regulation of DNA N6-methyladenine modification of PPP1R3A and ATG3. Lean subjects may not be a targeted population for LGZG.

关键词: insulin resistance     non-alcoholic fatty liver disease     Chinese herbal medicine     randomized controlled trial     DNA N6-methyladenine modification    

Effects of resistin on insulin signaling in endothelial cells

Zhizhen LI, Fangping LI, Jianhong YE, Li YAN, Zuzhi FU

《医学前沿(英文)》 2009年 第3卷 第2期   页码 136-140 doi: 10.1007/s11684-009-0029-2

摘要: The objective of this study was to investigate the effects of resistin on insulin signaling in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with recombinant human resistin (0-100 ng/mL) for 24 h. Akt and endothelial nitric oxide synthase (eNOS) phosphorylation levels of endothelial cells under basal or insulin stimulated conditions were measured by Western blot. Nitric oxide (NO) production of HUVECs was also detected. The results showed that resistin could significantly inhibit Akt and eNOS phosphorylation and NO production in endothelial cells under insulin stimulated conditions ( < 0.05 control). But under basal conditions, treatment with resistin could result in a decrease in eNOS phosphorylation ( < 0.05 control) but had no effect on NO production and Akt phosphorylation levels. These findings suggested that resistin exerted an inhibitory effect on NO production by inhibiting insulin signaling and eNOS phosphorylation in endothelial cells.

关键词: resistin     endothelium     nitric oxide     endothelial nitric oxide synthase     Akt-binding protein     mouse    

用智能药丸提供胰岛素?

Elizabeth K. Wilson

《工程(英文)》 2019年 第5卷 第4期   页码 603-604 doi: 10.1016/j.eng.2019.07.008

Molecular mechanisms of fatty liver in obesity

null

《医学前沿(英文)》 2015年 第9卷 第3期   页码 275-287 doi: 10.1007/s11684-015-0410-2

摘要:

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver disorders ranging from simple steatosis to advanced pathologies, including nonalcoholic steatohepatitis and cirrhosis. NAFLD significantly contributes to morbidity and mortality in developed societies. Insulin resistance associated with central obesity is the major cause of hepatic steatosis, which is characterized by excessive accumulation of triglyceride-rich lipid droplets in the liver. Accumulating evidence supports that dysregulation of adipose lipolysis and liver de novo lipogenesis (DNL) plays a key role in driving hepatic steatosis. In this work, we reviewed the molecular mechanisms responsible for enhanced adipose lipolysis and increased hepatic DNL that lead to hepatic lipid accumulation in the context of obesity. Delineation of these mechanisms holds promise for developing novel avenues against NAFLD.

关键词: nonalcoholic fatty liver disease     insulin resistance     obesity    

Zinc homeostasis in the metabolic syndrome and diabetes

null

《医学前沿(英文)》 2013年 第7卷 第1期   页码 31-52 doi: 10.1007/s11684-013-0251-9

摘要:

Zinc (Zn) is an essential mineral that is required for various cellular functions. Zn dyshomeostasis always is related to certain disorders such as metabolic syndrome, diabetes and diabetic complications. The associations of Zn with metabolic syndrome, diabetes and diabetic complications, thus, stem from the multiple roles of Zn: (1) a constructive component of many important enzymes or proteins, (2) a requirement for insulin storage and secretion, (3) a direct or indirect antioxidant action, and (4) an insulin-like action. However, whether there is a clear cause-and-effect relationship of Zn with metabolic syndrome, diabetes, or diabetic complications remains unclear. In fact, it is known that Zn deficiency is a common phenomenon in diabetic patients. Chronic low intake of Zn was associated with the increased risk of diabetes and diabetes also impairs Zn metabolism. Theoretically Zn supplementation should prevent the metabolic syndrome, diabetes, and diabetic complications; however, limited available data are not always supportive of the above notion. Therefore, this review has tried to summarize these pieces of available information, possible mechanisms by which Zn prevents the metabolic syndrome, diabetes, and diabetic complications. In the final part, what are the current issues for Zn supplementation were also discussed.

关键词: zinc     zinc transporters     metallothionein     diabetes     diabetic complications     insulin resistance     antioxidant    

Xiao Ke Qing improves glycometabolism and ameliorates insulin resistance by regulating the PI3K/Akt pathway

Xiaoqing Li, Xinxin Li, Genbei Wang, Yan Xu, Yuanyuan Wang, Ruijia Hao, Xiaohui Ma

《医学前沿(英文)》 2018年 第12卷 第6期   页码 688-696 doi: 10.1007/s11684-018-0662-8

摘要:

Xiao Ke Qing (XKQ) granule has been clinically used to treat type 2 diabetes mellitus (T2DM) for 10 years in Chinese traditional medication. However, its mechanisms against hyperglycemia remain poorly understood. This study aims to investigate XKQ mechanisms on diabetes and diabetic liver disease by using the KKAy mice model. Our results indicate that XKQ can significantly reduce food and water intake. XKQ treatment also remarkably decreases both the fasting blood glucose and blood glucose in the oral glucose tolerance test. Additionally, XKQ can significantly decrease the serum alanine aminotransferase level and liver index and can alleviate the fat degeneration in liver tissues. Moreover, XKQ can ameliorate insulin resistance and upregulate the expression of IRS-1, PI3K (p85), p-Akt, and GLUT4 in the skeletal muscle of KKAy mice. XKQ is an effective drug for T2DM by ameliorating insulin resistance and regulating the PI3K/Akt signaling pathway in the skeletal muscle.

关键词: XKQ     type 2 diabetes mellitus     KKAy mice     PI3K/Akt pathway     diabetic liver disease    

Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

null

《医学前沿(英文)》 2015年 第9卷 第2期   页码 139-145 doi: 10.1007/s11684-015-0377-z

摘要:

In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 (IL-15) is used as a new example to explain the beneficial effects of the pro-inflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-κB. IL-15 binds to its receptor that contains three different subunits (α, β and γ) to activate JAK/STAT, PI3K/Akt, IKK/NF-κB and JNK/AP1 pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti-obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure.

关键词: inflammation     obesity     cytokine     energy expenditure     insulin resistance    

星突江鲽胰岛素样生长因子I的体外重组表达及生物活性分析

徐永江,臧 坤,柳学周,史 宝,陈圣毅

《中国工程科学》 2015年 第17卷 第1期   页码 67-73

摘要:

为了在蛋白水平认识星突江鲽(Platichthys stellatus)胰岛素样生长因子I(IGF-I)的生长调控作用及机制,采用RT-PCR方法扩增了其成熟肽片段,利用原核表达载体pET-28a成功构建了重组星突江鲽IGF-I/pET-28a质粒,转化至大肠杆菌BL21(DE3)后经IPTG诱导获得了N端含6个组氨酸的重组星突江鲽IGF-I蛋白。获得的重组IGF-I蛋白大小为12.1 kD,37 ℃下用0.5 mmol/L的异丙基-β-D-硫代半乳糖苷(IPTG)诱导3 h时目的蛋白表达量最高,占菌体总蛋白的39.8 %,主要以包涵体形式存在。Western blotting免疫印迹表明星突江鲽IGF-I重组蛋白均可被6×His抗体特异性识别。包涵体经6 mol/L盐酸胍变性、Ni2+离子亲和柱纯化和尿素梯度复性后,可获得高纯度的IGF-I重组蛋白。细胞增殖试验结果显示0.6 μg/mL 的星突江鲽IGF-I重组蛋白能显著促进人胚胎肾细胞HEK293T的增殖而大于1.8 μg/mL时则表现出抑制作用。本研究成功构建了星突江鲽IGF-I体外高效表达系统,并获得具有细胞水平生物活性的星突江鲽IGF-I重组蛋白,结果可为深入探究IGF-I在星突江鲽生长发育中的作用机制及研制高效绿色的促生长制剂提供基础资料。

关键词: 星突江鲽;胰岛素样生长因子I;原核表达;生物活性    

Metformin and metabolic diseases: a focus on hepatic aspects

null

《医学前沿(英文)》 2015年 第9卷 第2期   页码 173-186 doi: 10.1007/s11684-015-0384-0

摘要:

Metformin has been widely used as a first-line anti-diabetic medicine for the treatment of type 2 diabetes (T2D). As a drug that primarily targets the liver, metformin suppresses hepatic glucose production (HGP), serving as the main mechanism by which metformin improves hyperglycemia of T2D. Biochemically, metformin suppresses gluconeogenesis and stimulates glycolysis. Metformin also inhibits glycogenolysis, which is a pathway that critically contributes to elevated HGP. While generating beneficial effects on hyperglycemia, metformin also improves insulin resistance and corrects dyslipidemia in patients with T2D. These beneficial effects of metformin implicate a role for metformin in managing non-alcoholic fatty liver disease. As supported by the results from both human and animal studies, metformin improves hepatic steatosis and suppresses liver inflammation. Mechanistically, the beneficial effects of metformin on hepatic aspects are mediated through both adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. In addition, metformin is generally safe and may also benefit patients with other chronic liver diseases.

关键词: metformin     diabetes     hepatic steatosis     inflammatory response     insulin resistance    

标题 作者 时间 类型 操作

Inhibition of protein kinase B by Palmitate in the insulin signaling of HepG2 cells and the preventiveeffect of Arachidonic acid on insulin resistance

XIA Yanzhi, WAN Xuedong, DUAN Qiuhong, HE Shansu, WANG Ximing

期刊论文

Mechanism of insulin resistance in obesity: a role of ATP

期刊论文

Mechanisms of insulin resistance in obesity

null

期刊论文

Insulin resistance and the metabolism of branched-chain amino acids

null

期刊论文

Role of exercise training on insulin resistance and TNF-α in high-fat diet rats

Hui SUN MD, Xiuling DENG MM, Fangxi XIAO MD, Lulu CHEN MD, Huiqing LI MD,

期刊论文

Overcoming oral insulin delivery barriers: application of cell penetrating peptide and silica-based nanoporous

Huining HE, Junxiao YE, Jianyong SHENG, Jianxin WANG, Yongzhuo HUANG, Guanyi CHEN, Jingkang WANG, Victor C YANG

期刊论文

Lingguizhugan Decoction, a Chinese herbal formula, improves insulin resistance in overweight/obese subjects

期刊论文

Effects of resistin on insulin signaling in endothelial cells

Zhizhen LI, Fangping LI, Jianhong YE, Li YAN, Zuzhi FU

期刊论文

用智能药丸提供胰岛素?

Elizabeth K. Wilson

期刊论文

Molecular mechanisms of fatty liver in obesity

null

期刊论文

Zinc homeostasis in the metabolic syndrome and diabetes

null

期刊论文

Xiao Ke Qing improves glycometabolism and ameliorates insulin resistance by regulating the PI3K/Akt pathway

Xiaoqing Li, Xinxin Li, Genbei Wang, Yan Xu, Yuanyuan Wang, Ruijia Hao, Xiaohui Ma

期刊论文

Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

null

期刊论文

星突江鲽胰岛素样生长因子I的体外重组表达及生物活性分析

徐永江,臧 坤,柳学周,史 宝,陈圣毅

期刊论文

Metformin and metabolic diseases: a focus on hepatic aspects

null

期刊论文