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Effects of different free fatty acids on insulin resistance in rats

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Hepatobiliary & Pancreatic Diseases International 2008年第1期7卷 91-96页

作者： Han, Ping Zhang, Yong-Yan Lu, Yan He, Bing Zhang, Wei Xia, Fei China Med Univ Affiliated Shengjing Hosp Dept Endocrinol Shenyang 110004 Peoples R China

BACKGROUND: Much evidence demonstrates that elevated free fatty acids (FFAs) are associated with insulin resistance. However, it is not clear whether different FFAs can cause different degrees of peripheral insulin resistance. This study aimed to investigate the effects of short-term elevation of FFAs on hepatic and peripheral insulin action, and determine whether FFAs with different degrees of saturation have differential effects on hepatic insulin resistance. METHODS: Intralipid+heparin (IH, polyunsaturated fatty acids), oleate (OLE), lard oil+heparin (LOH), and saline (SAL) were separately infused intravenously for 7 hours in normal Wistar rats. During the last 2 hours of the fat/saline infusion, a hyperinsulinemic-euglycemic clamping was performed with [6-H-3] glucose tracer. Plasma glucose was measured using the glucose oxygenase method. Plasma insulin and C-peptide were determined by radioimmunoassays. Plasma FFAs were measured using a colorimetric method. RESULTS: Compared with infusion of SAL, plasma FFA levels were significantly elevated by infusions of IH, OLE, and LOH (Pinsulin resistance. Polyunsaturated fatty acids induced less hepatic insulin resistance than monounsaturated or saturated fatty acids. However, IH, OLE, and LOH infusions induced similar peripheral insulin resistance.

关键词： free fatty acids insulin resistance hepatic glucose production glucose utilization

Expression of matrix metalloproteinase-11 is increased under conditions of insulin resistance

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World Journal of Diabetes 2017年第9期8卷 422-428页

作者： Biagio Arcidiacono Eusebio Chiefari Anna Elisa Laria Sebastiano Messineo Francesco Luciano Bilotta Domenico Britti Daniela Patrizia Foti Anna Foryst-Ludwig Ulrich Kintscher Antonio Brunetti Department of Health Sciences University"Magna Gr█cia"of Catanzaro Institute of Phar-macology Center for Cardiovascular Research

AIM To investigate matrix metalloproteinase-11(MMP-11) expression in adipose tissue dysfunction, using in vitro and in vivo models of insulin resistance.METHODS Culture of mouse 3T3-L1 preadipocytes were induced to differentiation into mature 3T3-L1 adipocytes. Cellular insulin resistance was induced by treating differentiated cultured adipocytes with hypoxia and/or tumor necrosis factor(TNF)-α, and transcriptional changes were analyzed in each condition thereafter. For the in vivo studies, MMP-11 expression levels were measured in white adipose tissue(WAT) from C57BL/6J mice that underwent low fat diet or high-fat feeding in order to induce obesity and obesity-related insulin resistance. Statistical analysis was carried out with GraphP ad Prism Software.RESULTS MMP-11 m RNA expression levels were significantly higher in insulin resistant 3T3-L1 adipocytes compared to control cells(1.46±0.49vs0.83±0.21, respectively;Pinsulin resistance. In particular, MMP-11 m RNA was upregulated in WAT from obese mice compared to lean mice(5.5±2.8vs1.1±0.7, respectively; Pinsulin resistance.

关键词： Metalloproteinase-11 insulin resistance Type 2 diabetes Fibrosis Hypoxia Tumor necrosis factor-α Inflammation

Effect of sodium salicylate on oxidative stress and insulin resistance induced by free fatty acids

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Hepatobiliary & Pancreatic Diseases International 2010年第1期9卷 49-53页

作者： He, Bing Zhao, Sheng Zhang, Wei Li, Yan Han, Ping China Med Univ Shengjing Affiliated Hosp Dept Endocrinol Shenyang 110004 Peoples R China China Med Univ Affiliated Hosp 4 Dept Internal Med Shenyang 110032 Peoples R China

BACKGROUND: It has been reported that high-dose salicylates improve free fatty acids (FFAs)-induced insulin resistance and beta-cell dysfunction in vitro, but the mechanism remains uncertain. In insulin-resistant rats, we found that the supplementation of sodium salicylate is associated with a reduction of plasma malondialdehyde (MDA), a marker of oxidative stress. Few studies have investigated the effects of salicylates on oxidative stress levels in insulin-resistant animal models. This study aimed to assess the effect of sodium salicylate on insulin sensitivity and to explore the potential mechanism by which it improves hepatic and peripheral insulin resistance. METHODS: Intralipid+heparin (IH), saline (SAL), or intralipid+heparin+sodium salicylate (IHS) were separately infused for 7 hours in normal Wistar rats. During the last 2 hours of the infusion, hyperinsulinemic-euglycemic clamping was 3 performed with [6-(3)H] glucose tracer. Plasma glucose was measured using the glucose oxygenase method. Plasma insulin and C-peptide were determined by radioimmunoassay. MDA levels and glutathione peroxidase (GSH-PX) activity in the liver and skeletal muscle were measured with colorimetric kits. RESULTS: Compared with infusion of SAL, IH infusion increased hepatic glucose production (HGP), and decreased glucose utilization (GU) (Pinsulin resistance by enhancing oxidative stress levels in the liver and muscle. The administration of the anti-inflammatory drug sodium salicylate reduces the degree of oxidative stress, therefore improving hepatic and peripheral insulin resistance. IKK-beta and NF-kappa B provide potential pathogenic links to oxidative stress.

关键词： free fatty acids sodium salicylate oxidative stress insulin resistance hepatic glucose production

Study on insulin resistance and Genetic Polymorphisms in Essential Hypertension Patients of Two Different Kinds of TCM Constitution

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Chinese Journal of Integrative Medicine 2007年第3期13卷 175-179页

作者：钱岳晟周晓鸥张怡高平进张伟忠朱鼎良 Ruijin Hospital Medical School of Shanghai Jiaotong University Shanghai Institute of Hypertension

Objective： To investigate the relationship of insulin resistance and the polymorphisms of insulin receptor-related genes in essential hypertension patients of two different kinds of TCM constitution. Methods： Oral glucose tolerance test （OGTT） and insulin release test （InRT） were conducted in 217 essential hypertensive patients of either sluggish meticulous （SM） constitution （139 cases） or prosperous impetuous （PI） constitution （78 cases）, and the polymorphism of three genes, including insulin-like growth factor-1 receptor （IGF-1R）, insulin receptor substrate-1 （IRS-1） and 2 （IRS-2） genes were detected. Results：（1） OGTT, InRT and insulin resistance index （Homa-IR） were higher and insulin sensitive index （ISI） was lower in the patients of SM constitution than those in patients of PI constitution. （2） Significant difference of ISI and Homa-IR was shown in patients of both constitutions with genotype G of the 3 genes. Conclusion： Decrease of insulin sensitivity and increase of insulin resistance are more obvious in hypertensive patients with genotype G of the 3 genes of SM constitution than in those of PI constitution. Therefore, the difference in constitution might be one of the genetic characteristics for insulin resistance in hypertensive patients.

关键词： essential hypertension insulin resistance constitution classification polymorphism of gene prosperous impetuous constitution sluggish meticulous constitution

Effect of Berberine on Expression of Hepatocyte Nuclear Factor-4α in Rats with Fructose-induced insulin resistance

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2008年第3期28卷 261-265页

作者：高志强冷三华陆付耳谢美娟徐丽君王开富 Institute of Integrated Traditional Chinese and Western Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology

The effects of berberine on the expression of hepatocyte nuclear factor-4α （HNF-4α） in liver of rats with fructose-induced insulin resistance and the molecular mechanism of berberine preventing insulin resistance were investigated. The experimental animals were divided into two groups of 16 animals each. The control group received a control routine diet containing 60% carbohydrate, and the study group a high-fructose diet containing 60% fructose as the sole source of carbohydrate. At the end of 6 weeks these were each subdivided into two groups. One was administered with berberine [187.5 mg/（kg·d） in 5 g/L carboxymethyl cellulose] by intragastric intubation and the other group was treated with a vehicle （5 g/L carboxymethyl cellulose）. The rats were fed on the same dietary regimen for the next 4 weeks. After the experimental period of 10 weeks, plasma glucose, insulin and triglyceride levels were measured. HOMA insulin resistance index （HOMA-IR） was assayed. Immunohistochemistry, semiquantitative RT-PCR and western blot were used to detect the expression of HNF-4α in liver. Compared with control diet, fructose feeding induced hyperinsulinemia, HOMA-IR and increased triglyceride （all P〈0.01）. Berberine prevented the rise in plasma insulin （P〈0.01）, HOMA-IR （P〈0.01） and triglyceride （P〈0.05） in the fructose-fed rats. No change in plasma glucose was seen among these groups. The mRNA and protein expression of HNF-4α was decreased in the fructose-fed rats, but berberine could promote its expression. It was concluded that berberine could prevent fructose-induced insulin resistance in rats possibly by promoting the expression HNF-4α in liver.

关键词： insulin resistance berberine liver HNF-4α high fructose diet

Genistein Reverses Free Fatty Acid-induced insulin resistance in HepG2 Hepatocytes through Targeting JNK

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2011年第2期31卷 185-189页

作者：雷红伟陆付耳董慧徐丽君汪健红赵炎黄召谊 Institute of Integrated Traditional Chinese and Western Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Pharmacy College of Hubei University of Chinese Medicine

This study investigated the effects and molecular mechanisms of genistein in improving insulin resistance induced by free fatty acids （FFAs） in HepG2 hepatocytes. A model of insulin resistance in HepG2 cells was established by adding palmitic acid （0.5 mmol/L） to the culture medium and the cells were treated by genistein. Glucose consumption of HepG2 cells was determined by glucose oxidase method. The levels of c-jun N-terminal kinase （JNK） phosphorylation, insulin receptor substrate-1 （IRS-1） Ser307 phosphorylation, JNK, IRS-1, phosphatidylinositol-3-kinase p85 （PI-3K p85） and glucose transporter 1 （GLUT1） proteins were detected by Western blotting. The results showed that after the treatment with palmitic acid for 24 h, the insulin-stimulated glucose transport in HepG2 cells was inhibited, and the glucose consumption was substantially reduced. Meanwhile, the expressions of IRS-1, PI-3K p85 protein and GLUT1 were obviously reduced, while the levels of JNK phosphorylation and IRS-1 Ser307 phosphorylation and the expression of JNK protein were significantly increased, as compared with cells of normal control. However, the aforementioned indices, which indicated the existence of insulin resistance, were reversed by genistein at 1-4 μmol/L in a dose-dependent manner. It was concluded that insulin resistance induced by FFAs in HepG2 hepatocytes could be improved by genistein. Genistein might reverse FFAs-induced insulin resistance in HepG2 cells by targeting JNK.

关键词： Genistein insulin resistance c-jun N-terminal kinase free fatty acids

Relationship between Calpain-10 Gene Polymorphism and insulin resistance Phenotypes in Chinese

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2004年第5期24卷 452-455页

作者：郑涓陈璐璐黎慧清 Department of Endocrinology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China

In order to determine whether the variations in the calpain-10 gene constitutes risk of type 2 diabetes (T2DM) in Chinese, the frequency of UCSNP-43, 44 in 268 adults newly diagnosed with T2DM (according to the 1999 ADA criteria) and 153 non-diabetic control subjects was investigated. For all subjects, the height, weight, waist-to-hip ratio (W/H) and blood pressure, as well as following parameters were measured: (1) 75-g oral glucose tolerance test with insulin, C-peptide, HbA1c and blood lipid profiles; (2) Genomic DNA extracted from peripheral blood lymphocytes was genotyped for UCSNP-43 (calpain-10-g.4852 G/A) and UCSNP-44 (calpain-10-g.4841 T/C) by sequencing a polymerase chain reaction (PCR)-amplified fragment. PCR product was selected by single strand conformation polymorphism (SSCP) and then sequenced. The results showed that there was significant difference between T2DM group and normal control group in allele frequencies, haplotype frequencies, or haplotype combinations of UCSNP-43 and -44 either. But in newly diagnosed T2DM group, it was found that the individuals with the genotype UCSNP-44 T/C+C/C had significantly increased fasting and post-challenge insulin levels (FIns and P2hIns), consistent with reduced insulin sensitivity. In the BMI>25 subgroup, the differences were even more significant. It was demonstrated that the Calpain-10 gene polymorphism UCSNP-44 was associated with insulin sensitivity and FIns and P2hIns in newly diagnosed T2DM, although Calpain-10 doesn't appear as a major diabetes susceptible gene in this population.

关键词： Calpain-10 UCSNP-43 UCSNP-44 insulin resistance

Analysis of Phosphatidylinositol 3-kinase Activation in the Adipose Tissue of Gestational Diabetes Mellitus Patients and insulin resistance

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2010年第4期30卷 505-508页

作者：初永丽刘文娟崔青冯桂姣王彦姜学强 Department of Obestetrics and Gynecology Yantai Yuhuangding Hospital Central Hospital of Laiyang

The P85 regulatory subunit protein and gene expression and P110 catalylic subunit activity of phosphatidylinositol 3-kinase (PI-3K) were investigated in adipose tissue of patients with gestational diabetes mellitus (GDM) in order to explore the molecular mechanisms of insulin resistance (IR) of GDM. Samples from patients with GDM (n=50), and controls (n=50) were collected. Fasting insulin (FIN) was determined by radioimmunoassay. Fasting plasma glucose (FPG) was measured by oxidase assay. Western blot technique was used to detect the levels of PI-3K P85 subunit in adipose tissues of patients with GDM. The mRNA expression of PI-3K P85 subunit was detected by reverse transcription polymerase chain reaction (RT-PCR) method in the adipose tissue. PI-3K activity was examined by immunoprecipitation, thin-layer chromatography and gamma scintillation counting. The results were analyzed statistically. It was found that the levels of FPG, FIN and HOMA-IR in GDM group were significantly higher than those in control group (all P0.05). PI-3K activity was significantly decreased to 82.89% in GDM group as compared with control group (Pinsulin signaling pathway, resulting in IR of GDM.

关键词： gestational diabetes mellitus insulin resistance phosphatidylinositol 3-kinase

Relationship between Tyrosine Phosphorylation and Protein Expression of insulin Receptor and insulin resistance in Gestational Diabetes Mellitus

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2014年第3期34卷 393-397页

作者：初永丽宫玉典苏志慧于洪娜崔青姜海洋曲洪美 Department of Obstetrics and Gynecology the Affiliated Yantai Yuhuangding Hospital of Qingdao University Medical College Yantai Psychological Rehabilitation Hospital

Summary： The relationship between tyrosine phosphorylation （TP） and protein expression of insulin receptor （InsR） and insulin resistance （IR） in patients with gestational diabetes mellitus （GDM） was investigated. The InsR expression and TP in skeleton muscle tissue were determined by Western blotting and immunoprecipitation in women with GDM （GDM group, n=22）, normal pregnant women （normal pregnancy group, n=22） and normal non-pregnant women （normal non-pregnant group, n=13）. Fasting plasma glucose （FPG） and fasting insulin （FINS） were measured by oxidase assay and immunoradioassay. The results showed that the levels of FPG （5.61±0.78 mmol/L）, FINS （15.42±5.13 mU/L） and Ho- meostasis model assessment-IR （HOMA-IR）（1.21±0.52） in GDM group were significantly higher than those in normal pregnancy group （4.43±0.46 mmol/L, 10.56±3.07 mU/L and 0.80±0.31 respectively）（P〈0.01）. The levels of FINS and HOMA-IR in normal pregnancy group were significantly higher than those in normal non-pregnant group （7.56±2.31 mU/L and 0.47±0.26 respectively）（P〈0.01）. There was no significant difference in the InsR expression level among the three groups （P〉0.05）. TP of InsR with insulin stimulation was significantly decreased in GDM group （0.20±0.05） as compared with normal pregnancy group （0.26±0.06）（P〈0.01）. TP of InsR with insulin stimulation in normal pregnancy group was lower than that in normal non-pregnant group （0.31±0.06）（P〈0.01）. TP of InsR with insulin stimu- lation was negatively related with HOMA-IR in GDM group （r=-0.525, P〈0.01）. There was no correlation between the protein expression of InsR and HOMA-IR in GDM group （r=-0.236, P〉0.05）. It was suggested that there is no significant correlation between the protein expression of InsR in skeletal muscle and IR in GDM, but changes in TP of InsR are associated with IR in GDM.

关键词： gestational diabetes mellitus insulin resistance tyrosine phosphoproteins phosphorylation