Donohue syndrome caused by mutation of insulin receptor gene: a case report / 中华围产医学杂志

This article reported the comprehensive management and short-term follow-up of a neonate diagnosed with Donohue syndrome. The affected male neonate presented with obvious insulin resistance (uncontrollable hyperglycemia) and unusual facies (more hair and dense, wide eye distance, large ears, etc.). Whole exome sequencing revealed a compound heterozygous variant in the insulin receptor gene [c.3258+4A>G in intron 17 and c.1321T>A (p.W441R) in exon 6], and Sanger sequencing confirmed that the mutation was inherited from both parents, which is likely pathogenic mutation. Based on the genetic test results and clinical manifestation, the neonate had a high probability of being diagnosed with Donohue syndrome. During a follow-up of nine months, the baby showed growth and development retardation, intermittent low-grade fever, and the fasting glucose was around 18 mmol/L.

miR-126-mediated activation of IGF2/IGF1R/IRS1 signaling promotes the Herceptin resistance in ErbB2 positive breast cancer cells / 中国医师杂志

Objective To explore the role of insulin-like growth factor-2/insulin-like growth factor1 receptor/insulin receptor substrate-1 (IGF2/IGF1R/IRS1) signal pathway inducing the chemoresistance of epidermal growth factor receptor 2 (ErbB2) positive breast cancer cells to Herceptin.Methods Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assay were used to determine the expression levels of IGF2,IGF1 R,and IRS1.The direct targets of miR-126 were validated by dual-luciferase reporter gene assay.In SKBR3/pool2 cells,IGF1 R activity was reduced by an inhibitor of IGF1 R,and IRS1 was knocked-down by shRNAs.Furthermore,3-(4,5-dimenthylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was performed to evaluate the sensitivity of these treated cells to Herceptin.Results IGF2,IGF1 R,and IRS1 were significantly higher expressed in SKBR3/pool2 cell compared to that in SKBR3 cell.Western blot assay showed that IGF2/IGF1R/IRS1 was activated in SKBR3/pool2 cells.Bioinformatics analysis combined with luciferase activity suggested that miR-126 directly targeted IRS1.MTS results demonstrated that the chemosensitivity to Herceptin of SKBR3/ pool2 cells with inhibitor of IGF1R or shRNAs targeting IRS1 or overexpressing miR-126 was significantly reduced.Conclusions IGF2/IGF1R/IRS1 signal pathway confers to the chemoresistance of ErbB2 positive breast cancer cells to Herceptin.

Promoting effects of insulin-like growth factor-1 on proliferation of orbital fibroblasts derived from thyroid associated ophthalmopathy / 中华实验眼科杂志

Background Thyroid associated ophthalmopathy (TAO) is an autoimmune disease.Current research on the pathogenesis focuses on common autoantigen.Insulin-like growth factor-1 receptor (IGF-1R) is necessary for the function of IGF-1,also IGF-1 plays an important role in signaling pathway of thyroid stimulating hormone receptor (TSHR).Objective This study was to investigate the effects of IGF-1 on the proliferation,expression of IGF-1R and TSHR on cultured orbital fibroblasts (OFs) derived from TAO.Methods Human orbital tissue was obtained from 17 TAO patients who received orbital adipectomy and 4 normal controls who received cosmetic surgery in West China Hospital from March 2016 to June 2016.OFs were cultured by explant culture with DMEM/F12 containing 5％ fetal bovine serum and identified by immunochemistry.The OFs were treated with different concentrations of IGF-1.IGF-1 at different concentrations (0,50,100,125 μg/L) was added into the medium,respectively,and the proliferation of the cells (absorbancy) was detected by MTS.The percentages of IGF-1R and TSHR expressions in the cells were assayed by flow cytometry.Results Cultured cells appeared to be spindle-like in shape and grew well with abundant cytoplasm.The characteristics of the cells derived from TAO patients were consistant with normal ones.The cells showed the positive response for vimentin and absent respose for desmin,S-100,myoglobin and cytokeratin.The proliferative values of OFs were gradually elevated with the increase of IGF-I dose in both TAO group and normal group (Fgroup =219.639,P＜0.001;F ion =17.752,P＜0.001) with the optimal effects in 100 μg/L IGF-1.The expression levels of IGF-1R in the OFs were (0.009 1 ±0.008 7)％,(0.095 3±0.023 3) ％,(0.083 7±0.022 7) ％ and (0.070 9 ± 0.024 1) ％ in the TAO group,and those in the normal group were (0.0023± 0.0006)％,(0.0093±0.0012)％,(0.0073±0.0015)％ and (0.0083±0.0012)％ after treatment of 50,100,125 μg/L IGF-1.The expression levels of IGF-1 R were significantly higher after treatment of 50,100 and 125 μtg/L IGF-1 than those treatment of 0 μg/L IGF-1 in both TAO group and normal group,and the expression levels of IGF-1R in the OFs were significantly increased in the TAO group compared with the normal group (all at P＜0.05).No statistical difference was seen in the TSHR expression between the TAO group and normal group after treatment of 0,50,100 and 125 μg/L IGF-1 (Fgroup =0.133,P ＞ 0.05;F ion =0.004,P ＞ 0.05).Conclusions IGF-1 can promote the proliferation of OFs and up-regulate the expression of IGF-1R in OFs.However,IGF-1 dose not play a regulating effect on the expression of TSHR in OFs.

Potential targets prediction of apigenin via virtual screening / 重庆医学

Objective To predict the potential targets of apigenin by virtual screening .Methods The targets preliminarily forecast by PharmMapper ,were validated by associating data mining and Autodock Vina in PyRx 0 .8 .Subsequently ,receptor‐ligand interactions were analyzed by Discovery Studio 3 .5 .Results The virtual screening by PharmMapper indicated that apigenin coupled well with the disease‐related targets including insulin receptor ,estradiol 17‐beta‐dehydrogenase 1 ,and cathepsin K .According to the data mining ,insulin receptor was found in related experimental researches ,while the other two had few reports previously .And then ,the interactions between apigenin and the target proteins were analyzed by Autodock Vina and Discovery Studio Visualizer 3 .5 ,involving hydrogen bonds ,electrostatic forces ,van der Waals forces etc .Conclusion The most potential targets of apigenin were insulin receptor ,while 17‐beta‐dehydrogenase 1 and cathepsin K were also possible .

Asociación entre periodontitis crónica y altos niveles de glicemia en pacientes no diabético / Association between chronic periodontitis and high blood glucose levels in non-diabetic patients

Fundamento: los mediadores inflamatorios originados por la periodontitis interfieren con la acción de los receptores de la insulina. Objetivo: evaluar la asociación entre periodontitis y niveles de glicemia en sangre en pacientes no diabéticos. Métodos: en el presente estudio de corte transversal, el universo estuvo constituido por 94 pacientes, 80 con periodontitis crónica y 14 controles sin periodontitis. Se realizó un examen periodontal completo que evaluó los parámetros periodontales más importantes. De cada paciente se obtuvo una muestra de sangre en ayunas a través de punción venosa en el brazo derecho, procesada posteriormente para obtener los niveles de glucosa. Resultados: no se observaron individuos con niveles elevados de glicemia en ayunas en el grupo de pacientes sin periodontitis, mientras que en el grupo de pacientes con periodontitis crónica un total de 22 (23 %) individuos presentaron niveles elevados de glicemia (p<0.05). Se observó mayor profundidad al sondaje y mayor pérdida de inserción clínica en los pacientes con periodontitis y glicemia alterada comparados con el grupo de pacientes con periodontitis y glicemia normal. El análisis de regresión logística crudo mostró una asociación estadísticamente significativa entre periodontitis crónica y niveles de glicemia elevados (OR= 1,087; intervalo de confianza del 95 % 1,010-1,168). Esta asociación se conservó después de ajustar por las variables de confusión. Conclusiones: los niveles elevados de glicemia son un factor de riesgo para periodontitis crónica en pacientes no diabéticos en la población estudiada; igualmente estos hallazgos indican la necesidad de implementar exámenes médicos y sanguíneos de rutina en pacientes con periodontitis crónica, con el fin de evaluar signos y síntomas que permitan identificar un metabolismo anormal de la glucosa.

ABSTRACT Background: inflammatory mediators originated by periodontitis interfere with the action of insulin receptors. Objective: to evaluate the association between periodontitis and the blood glucose levels in non-diabetic patients. Method: a cross-sectional study was conducted; the universe was composed of 94 patients: 80 with chronic periodontitis and 14 controls without periodontitis. A complete periodontal exam that evaluated the most important periodontal parameters was made. A fasting blood sample was taken from each patient through a venous puncture in the right arm and subsequently processed to obtain the glucose levels. Results: none of the individuals from the group of patients without periodontitis presented high fasting blood glucose levels; on the other hand, in the group of patients with chronic periodontitis a total of 22 individuals (23 %) presented high blood glucose levels (p<0.05). A greatest depth at probing and a greatest loss of clinical insertion were observed in patients with periodontitis and impaired glucose compared with the group of patients with periodontitis and normal blood glucose levels. The raw logistic regression analysis showed a statistically significant association between chronic periodontitis and high blood glucose levels (OR= 1,087; an interval of trust of 95 % 1,010-1,168). This association was maintained after adjusting by means of the variables of confusion. Conclusions: high blood glucose levels are a risk factor for chronic periodontitis in non-diabetic patients in the studied population. This finds show as well the need of implementing routine medical and blood exams in patients with chronic periodontitis with the aim of evaluating signs and symptoms that allow identifying an abnormal metabolism of the glucose.

Association between single nucleotide polymorphism of rs2252673 of INSR gene and polycystic ovarian syndrome / 中华妇产科杂志

Objective This study is designed to determine whether an association exists between single nucleotide polymorphism (SNP) variant rs2252673 of insulin receptor(INSR) gene and polycystic ovarian syndrome (PCOS) in Han Chinese in order to identify INSR as a genetic susceptibility factor for PCOS.Methods A total of 224 women with PCOS,192 controls and 672 participants consisting of 224 trios (mother,father and offspring with PCOS) were recruited from the Hospital for Reproductive Medicine Affiliated to Shandong University,from July 2007 to April 2013.Genomic DNA was extracted according to the manufacturer' s protocol.SNP rs2252673 of INSR gene was amplified by PCR and then sequenced on an automated sequencer.Moreover,clinical and metabolic features of the patients with PCOS were compared according to the genotypes.The subjects were divided into twot groups according to body mass index (BMI),and then the results were compared between two groups.And the transmitted disequilibrium test (TDT) was applied for data analysis.Results (1) There were three kinds of genotype of CC,CG and GG.Genotype frequencies of rs2252673 were 8.0％,38.8％,53.1％ and 14.6％,42.2％,43.2％ in the PCOS group and the control group,respectively.The allele frequencies of C and G were 27.5％,72.5％ and 35.7％,64.3％ in the PCOS group and the control group,respectively.There were statistical differences in genotype frequencies and allele frequencies between two groups (all P＜0.05).(2)No significant differences were observed in the different genotype according to clinical and metabolic characteristics of women with PCOS (P＞0.05).But when merging the genotype CG and GG,carriers of the CG and GG genotypes in women with PCOS were slightly associated with total cholesterol (TC) levels (t=2.072,P=0.048) and lower high-density lipoprotein (HDL) levels (t=2.274,P=0.026).Although statistical significance was not achieved,there was an increased tendency in fasting blood glucose (FBG) and fasting insulin (FINS) levels in CG and GG genotypes in PCOS cases.(3)Between the obesity and the non-obesity with PCOS,there was no statistical significance in the genotype and allele frequencies (x2=0.054,P=0.974; x2=0.022,P=0.883).(4)The results of families based analysis shown that genotype distribution of the SNP rs2252673 was in Hardy-Weinberg equilibrium (P＞0.05).After the TDT,the G allele in SNP rs2252673 was over transmitted in families (transmitted∶ non-transmitted=120∶ 88; x2=4.923,P=0.027).There was a transmitted disequilibrium in rs2252673,which implies the association of INSR and PCOS were independent of population stratification.Conclusions There were a association between the SNP variant rs2252673 of INSR gene and the susceptibility to PCOS in Han Chinese women,which was independently of body mass index.The carrier of G allele frequency of rs2252673 may have higher risk of PCOS.

Effects of acute knockdown of hepatic insulin receptor on secretion of apolipoprotein B and triglyceride in mice / 中华老年医学杂志

Objective To analyze the effects of acute depletion of liver-specific insulin signaling on secretion of apolipoprotein B (apoB) and triglyceride (TG).Methods Based on Cre-LoxP principle,a promoter of hepatic tissue specific albumin gene was inserted into upstream of the cre recombinase gene.Albumin-Cre adenovirus (Ad-CRE) and GFP adenovirus (Ad-GFP) were amplified in 293A cells and purified before intravenous administration to mice.After adenovirus infection for 2 days,4 days and 6 days,blood samples from mice were collected and hepatic tissues were frozen.The secretion rates of hepatic newly synthesized apoB and very low density lipoprotein (VLDL)-TG were determined by injection of Triton WR-1339.The levels of plasma cholesterol (TC) and TG were measured.The expressions of insulin receptor and other lipoprotein metabolism related proteins in hepatic tissues were analyzed by Western blot.Results After 2 d,4 d and 6 d of the Ad-CRE injection into mice,insulin receptor expression was reduced by 30.50％ (P＜0.05),60.12％ (P＜ 0.01) and 99.54％ (P＜0.001),and VLDL-TG secretion rate was decreased by 20.43％ (P＜0.05),33.63％ (P＜0.05) and 44.21％ (P＜0.01),respectively.Expressions of sterol regulatory binding proteins 1,fatty acid synthase,and the related proteins of VLDL-formation were decreased,but there were no changes in hepatic secretion of apoB100 and hepatic lipids.The hepatic secretion of apoB48 was increased by 35.07％ (P＜0.05) 6 d after Ad-CRE injection.Conclusions Acute depletion of hepatic insulin receptor might reduce VLDL-TG secretion in manner of time-dependent,and increase the assembly and secretion of smaller apoB-containing lipoproteins in mice liver,which is probably associated with decreased lipogenesis.

The role of gut-liver axis in the restriction of intrauterine growth in a model of experimental gastroschisis / O papel do eixo intestino-fígado na restrição de crescimento intra-uterino em um modelo de gastrosquise experimental

PURPOSE: To evaluate the intrauterine growth restriction (IUGR) by the expression of IR-β, IRS-1, IRS-2, IGF-IRβ and Ikappaβ in experimental model of gastroschisis. METHODS: Pregnant rats at 18.5 days of gestation were submitted to surgery to create experimental fetal gastroschisis (term = 22 days) were divided in three groups: gastroschisis (G), control (C) and sham (S). Fetuses were evaluated for body weight (BW), intestinal (IW), liver (LW) and their relations IW/BW and LW/BW. IR-β and IGF-IRβ receptors, IRS-1 and IRS-2 substrates and Ikappaβ protein were analyzed by western blotting. RESULTS: BW was lower in G, the IW and IW / BW were greater than C and S (p<0.05) groups. The liver showed no differences between groups. In fetuses with gastroschisis, compared with control fetuses, the expression of IGF-IRβ (p<0.001) and Ikappaβ (p<0.001) increased in the liver and intestine, as well as IR-β (p<0.001) which decreased in both. In contrast to the intestine, IRS-1 (p<0.001) increased in the liver and IRS-2 decreased (p<0.01). CONCLUSION: The axis of the intestine liver has an important role in inflammation, with consequent changes in the metabolic pathway of glucose can contribute to the IUGR in fetuses with gastroschisis.

OBJETIVO: Avaliar a restrição de crescimento intra-uterino (RCIU) pela expressão de IR-β, IRS-1, IRS-2, IGF-IRβ e a via inflamatória do Ikappaβ no modelo de gastrosquise experimental. MÉTODOS: Ratas grávidas com 18,5 dias de gestação foram submetidas a cirurgia experimental para criar gastrosquise fetal (termo = 22 dias) e os fetos foram divididos em três grupos: gastrosquise (G), controle (C) e sham (S). Os fetos foram avaliados quanto ao peso corporal (BW), intestinal (IW), fígado (LW) e suas relações IW/BW e LW/BW. Os receptores IR-β e IGF-IRβ, os substratos IRS-1 e IRS-2 e a proteína Ikappaβ foram analisados por western blotting. RESULTADOS: O BW de G foi menor, o IW e IW/BW foram superiores a C e S (p < 0.05). O fígado não apresentou diferenças entre os grupos. Nos fetos com gastrosquise, quando comparados com fetos controles, a expressão de IGF-IRβ (p<0.001) e Ikappaβ (p<0.001) aumentou no fígado e intestino, assim como IR-β (p<0.001) que diminuiu em ambos. Inversamente ao intestino, IRS-1 (p<0.001) aumentou no fígado e IRS-2 diminuiu (p<0.01). CONCLUSÃO: O eixo do intestino fígado tem um papel importante na inflamação, com consequentes alterações na via metabólica de glicose que pode contribuir para a RCIU em fetos com gastrosquise.

Preliminary investigation of the expression and functions of insulin receptor isoforms in endometrial carcinoma / 中华妇产科杂志

Objective To investigate the expression of insulin receptor isoforms(IR,including IR-A and IR-B)in endometrial carcinoma(EC),and explore the role of IR-A in the growth of endometrial carcinoma cells.Methods The expression of IR isoforms were detected by reverse transcription(RT)-PCR and real-time PCR in 4 different endometrial cancer cell lines(HEC-1-A,Ishikawa,RL95-2 and KLE),with human breast cancer cell line MCF-7 cells and hepatocellular carcinoma cell line Hep-G2 as positive control and in the endometrial cancer tissue specimens of 42 cases,admitted in Peking University People's Hospital from November 2007 to July 2009,with normal endometrial tissues from 15 cases of ovarian neoplasms at the same period as controls.The relationships among the expression of IR,IR-A isoforms and the clinicopathological parameters of EC tissues were analyzed by Spearman rank correlation analysis.An eukaryotic IR-A expression plasmid was constructed and transfected into RL95-2 cells[RL95-2(IR-A)]for overexpression of IR-A in RL95-2 cells,in which the expression of IR-A originally was low.Non radioactive cell proliferation assay—MTS was used to determine the proliferation curves in the four EC cells listed above and in RL95-2 or RL95-2(IR-A).Results(1)There were two isoforms of IR-A and IR-B coexpressed were detected in EC cells and EC tissues.Among four kinds of EC cell lines,the expression level of IR mRNA in RL95-2 cells was the highest,followed by Ishikawa,KLE and HEC-1-A cells,in which the relative IR mRNA expression levels were(26.54 ± 1.82)× 10-4,(15.44 ± 3.29)× 10-4,(10.14 ±0.10)× 10-4 and(2.63 ±0.23)× 10-4,respectively(P ＜0.01).The expression level of IR-A mRNA was the highest in Ishikawa cells,followed by KLE,RL95-2 and HEC-1-A cells,with the relative expression levels were(12.07 ±3.31)× 10-4,(4.68 ±0.63)× 10-4,(3.03 ±0.22)× 10 4 and(1.46 ±0.03)×10-4,respectively(P ＜0.01).The relative expression level of IR and IR-A mRNA were 0.017 ±0.013 and 0.011 ±0.010 in the EC tissues,respectively,compared with 0.015 ± 0.014 and 0.010 ± 0.012 in the controls,in which there were no significant differences in the expression level of IR or IR-A mRNA between EC tissues and the control(P =0.662,P =0.780).The expression of IR and IR-A in EC tissues had no significant relevance with International Federation of Gynecology and Obstetrics(FIGO)stage,cell differentiation,depth of myometrial invasion,invasion of lymph-vascular space,lymph nodes metastasis,the expression status of estrogen receptor,human progesterone receptor,and PTEN gene(all P ＞ 0.05).The expression of IR-A mRNA in EC patients with type 2 diabetes mellitus(DM)was significantly higher than that in patients without type 2 DM(P =0.031),while there were no statistical correlation between the expression of IR mRNA and type 2 DM(P =0.438).(2)The proliferation rates of the four kinds of EC cells was positively related with the IR-A expression ratio,with the most growth potential in Ishikawa,followed by HEC-1-A,KLE and RL95-2 cells.The overexpression of IR-A in RL95-2(IR-A)cells showed a significant proliferation-promoting effect than that in control RL95-2 cells(P ＜ 0.01).Conclusion There are two isoforms of IR-A and IR-B co-expressed in EC.The overexpression of IR-A may promote the proliferation of EC cells.

Changes in expression of insulin receptor, insulin receptor substrate- Ⅰ and protein kinase B in Alzheimer's disease model rats / 中华神经科杂志

ObjectiveTo investigate the effect of soluble β-amyloid protein (Aβ) oligomers on the expression levels of insulin signaling transduction cascades-associated proteins including insulin receptor ( InsR),insulin receptor substrate-Ⅰ( IRS-Ⅰ) and protein kinase B (PKB) of rat hippocampal neurons,and the pathogenesis of Alzheimer's disease (AD) in depth.MethodsSoluble Aβ oligomers (5 μl) were injected into the lateral ventriculus of the AD group by a microinjector under the stereotaxic apparatus.Normal saline solution ( NS,5 μl) was injected into the NS group in the same way,and the control group received the puncture without injection. It was repeated after 1 week and the behavior of all rats was evaluatedbyY-mazetestafter2weeks.Thenhippocampuswasremovedandunderwent immunohistochemical staining to detect the expression of proteins associated.ResultsCompared with the other groups,learning and memory ability of the Aβ-treated rats were impaired.To be specific,the times of learning were increased and the times of memory were decreased. However,there was no significant difference between the NS group and the control group.Besides,the expression levels of InsR,IRS-Ⅰ,and PKB were decreased in AD group showing that a mean optical density of staining on these proteins ( InsR:0.12 ± 0.0l ; IRS-Ⅰ:0.14 ± 0.02; PKB:0.12 ± 0.03 ) was reduced in contrast with that in the NS group and the control group.Whereas there was no significant difference between the NS group (0.40 ± 0.02,0.39 ± 0.06,0.38 ± 0.03,mean difference:- 0.13,- 0.13,- 0.17,all P ＜ 0.05 ) and the control group (0.38 ± 0.07,0.35 ± 0.03,0.35 ± 0.06,mean difference:- 0.15,- 0.07,- 0.73,all P ＜ 0.05 ).ConclusionsSoluble Aβ1-42 induced learning and memory disability of the rats.The mechanism might be that Aβ can lead to disorders of the insulin signaling transduction pathway of hippocampal neurons and decrease the expression levels of the proteins in the pathway.

Two Novel Insulin Receptor Gene Mutations in a Patient with Rabson-Mendenhall Syndrome: The First Korean Case Confirmed by Biochemical, and Molecular Evidence

Rabson-Mendenhall syndrome (RMS) is a rare syndrome manifested by extreme insulin resistance with hyperinsulinemia, acanthosis nigricans, tooth dysplasia and growth retardation. Our patient was first noted at the age of 8 months due to pigmentations on skin-folded areas. Initial laboratory tests showed normal fasting glucose (69 mg/dL). Fasting insulin level was severely elevated, up to 554.6 microIU/mL, and c-peptide level was increased, up to 13.81 ng/mL. However, hemoglobin A1c was within normal range (4.8%). He is now 11 yr old. His growth development followed the 5-10th percentile and oral hypoglycemic agents are being administered. The last laboratory results showed insulin 364.1 microIU/mL, C-peptide 4.30 ng/mL, and hemoglobin A1c 7.6%. The boy was a compound heterozygote for the c.90C > A and c.712G > A mutations of the insulin receptor gene, INSR, which are nonsense and missense mutations. In summary, we report the first Korean case of RMS, which was confirmed by two novel mutations of the INSR.

Insulin stimulation of Akt/PKB phosphorylation in the placenta of preeclampsia patients / Estimulação com insulina da fosforilação da Akt/PKB em placenta de pacientes com pré-eclâmpsia

CONTEXT AND OBJECTIVE: Preeclampsia is a multi-systemic disease and one of the most frequent severe health problems during pregnancy. Binding of insulin triggers phosphorylation and activates cytoplasmic substrates such as phosphatidylinositol 3 kinase (PI3K). Phosphorylation of membrane phosphoinositide 2 (PIP2) to phosphoinositide 3 (PIP3) by PI3K starts Akt/PKB activation. Defects in phosphorylation of the insulin receptor and its substrates have an important role in insulin resistance. Studies have shown that insulin resistance is associated with preeclampsia and its pathophysiology. The aim here was to investigate insulin stimulation of the Akt/PKB pathway in the placenta, in normal and preeclampsia parturients. DESIGN AND SETTING: Cross-sectional study in a tertiary public university hospital. METHODS: Placentas were collected from 12 normal and 12 preeclampsia patients. These were stimulated and analyzed using Western blot to quantify the Akt/PKB phosphorylation. RESULTS: The insulin stimulation was confirmed through comparing the stimulated group (1.14 ± 0.10) with the non-stimulated group (0.91 ± 0.08; P < 0.001). The phosphorylation of Akt/PKB did not differ between the placenta of the normal patients (1.26 ± 0.16) and those of the preeclampsia patients (1.01 ± 0.11; P = 0.237). CONCLUSIONS: In vitro insulin stimulation of the human placenta has been well established. There was no difference in Akt/PKB phosphorylation, after stimulation with insulin, between placentas of normal and preeclampsia patients. Nevertheless, it cannot be ruled out that the Akt/PKB signaling pathway may have a role in the pathophysiology of preeclampsia, since the substrates of Akt/PKB still need to be investigated.

CONTEXTO E OBJETIVO: Pré-eclâmpsia (PE) é uma doença multissistêmica das mais frequentes e graves durante a gestação. A ligação da insulina inicia a fosforilação e ativação de substratos citoplasmáticos, tais como fosfatidil-inositol 3 quinase (PI3K). A fosforilação do fosfoinositol 2 (PIP2) da membrana em fosfoinosiltol 3 (PIP3) pela PI3K inicia a ativação da Akt/PKB. Defeitos na fosforilação do receptor de insulina e seus substratos têm papel importante na resistência à insulina. Estudos demonstraram que resistência à insulina está associada com pré-eclâmpsia e sua patofisiologia. O objetivo foi investigar a via de estimulação com insulina da Akt/PKB em placenta de parturientes normais e com pré-eclampsia. TIPO DE ESTUDO E LOCAL: Estudo do tipo transversal em um hospital universitário público de nível terciário. MÉTODOS: Vinte e quatro placentas (12 normais, 12 com PE) foram coletadas, estimuladas e analisadas por Western blot para quantificar a fosforilação da Akt/PKB. RESULTADOS: A estimulação com insulina foi confirmada comparando os grupos estimulados (1,14 ± 0,10) e não estimulados (0.91 ± 0.08; P < 0.001). A fosforilação de Akt/PKB não foi diferente na placenta de pacientes normais (1,26 ± 0,16) e com PE (1,01 ± 0,11; P = 0,237). CONCLUSÕES: A estimulação in vitro da placenta humana com insulina foi bem estabelecida. Não houve diferença na fosforilação da Akt/PKB após estimulação em placentas de pacientes normais e PE. Contudo, não é possível descartar a participação desta via de sinalização na patofisiologia da PE, uma vez que os substratos da Akt/PKB ainda precisam ser investigados.

The changes of insulin secretion in type A insulin resistance syndrome: a 7-year follow up / 中华内科杂志

Objective A previously reported female diagnosed with type A insulin resistance syndrome bearing a heterozygous missense mutation of R1174W in the insulin receptor gene was followed for 7 years since the age of 16 years. Methods Five-hour oral glucose tolerance tests (OGTT) were done on baseline, the 3rd, 6th and 7th year respectively, with serum insulin and C-peptide measured at the same time points. Areas under of curve (AUC) of glucose, insulin and C-peptide were compared between the years.Acute insulin response (AIR) was determined at baseline and the 7th year. The dose response were insulin secretion rates at each time point during OGTT being plotted over the corresponding glucose levels, and the slopes of which quantified the insulin secretion responding to glucose. Results The follow up data showed that the glucose metabolism of the subject did not deteriorate over time with yearly glycosylated hemoglobin A1c (HbAlc) being normal (4.6%-5.5%), and hyperinsulinemic hypoglycemia was a persistent phenomenon observed at 4-5 hours post-load. The fasting and AUCs of serum insulin and C-peptide tended to decline without simultaneously increase of those of plasma glucose. The AIR decreased by 56% as compared to baseline. The dose response curves shifted downward as years went by. Conclusions It supports that with the alleviation of physiological insulin resistance after puberty, the gross hyperinsulinemia tends to ameliorate, and β-cell secretion does not deteriorate over time as glucose homeostasis maintains.

Effect of Acupuncture on Expressions of InsR-β mRNA and Protein in the Liver of Rats with Insulin Resistance / 针灸推拿医学（英文版）

Objective: To observe the effect of acupuncture on the expressions of insulin receptor β (InsR-β) mRNA and protein in the liver of experimental rats with insulin resistance (IR). Method: Twenty-four rats were randomly divided into 3 groups, control group (n=8),model group (n=8) and acupuncture group (n=8). Rats in the control group were fed with conventional food, and the other rats were induced into insulin resistance model with high fat-sugar-salt food. Once model was induced successfully, rats in the control group were fed with conventional food continually, rats in the model group were fed with high fat-sugar-salt food continually, and rats in the acupuncture group were fed with high fat-sugar-salt food, and treated with acupuncture for 2 weeks. The expression of InsR-β mRNA was detected by real-time fluorescent quantitative RT-PCR, and the expression of InsR-β protein was detected by Western blot. Result: Expressions of InsR-β mRNA and protein in the model group were significantly lower than those in the control group (P<0.01), and those in the acupuncture group were higher than those in the model group (P<0.01, P<0.05). The expressions of InsR-β mRNA and protein between the acupuncture and control group had no significant difference. Conclusion:Acupuncture treatment can increase the expressions of InsR-β mRNA and protein in IR rats'liver to improve insulin resistance.

Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle

It is well known that exercise can have beneficial effects on insulin resistance by activation of glucose transporter. Following up our previous report that caveolin-1 plays an important role in glucose uptake in L6 skeletal muscle cells, we examined whether exercise alters the expression of caveolin-1, and whether exercise-caused changes are muscle fiber and exercise type specific. Fifity week-old Sprague Dawley (SD) rats were trained to climb a ladder and treadmill for 8 weeks and their soleus muscles (SOL) and extensor digitorum longus muscles (EDL) were removed after the last bout of exercise and compared with those from non-exercised animals. We found that the expression of insulin related proteins and caveolins did not change in SOL muscles after exercise. However, in EDL muscles, the expression of insulin receptor beta (IRbeta) and glucose transporter-4 (GLUT-4) as well as phosphorylation of AKT and AMPK increased with resistance exercise but not with aerobic exercise. Also, caveolin-1 and caveolin-3 increased along with insulin related proteins only in EDL muscles by resistance exercise. These results suggest that upregulation of caveolin-1 in the skeletal muscle is fiber specific and exercise type specific, implicating the requirement of the specific mode of exercise to improve insulin sensitivity.

Relationship between insulin resistance and serum levels of adiponectin,leptin and erythrocyte membrane insulin receptor in patients with gestational diabetes / 中华全科医师杂志

Objectives To investigate changes in serum levels of adiponectin,leptin and erythrocyte membrane insulin receptor among patients with gestational diabetes (GDM),and to study their relation to insulin resistance.Methods Fasting plasma glucose (FPG),fasting serum insulin (FINS), serum levels of adiponeetin and leptin,indices of lipid metabolism,2 h plasma glucose during oral glucose tolerance test (2 h PG),2 h serum insulin during oral glucose tolerance test (2 h INS),as well as number of erythrocyte membrane insulin receptors with high and low appetency and its constants,were determined in 40 patients with GDM and 34 controls with normal glucose tolerance.Insulin resistance index (IRI) was calculated.Results ① Serum levels of leptin and adiponectin were (11.7?2.8) ?g/L and (7.8?1.6) ?g/L,respectively,and number of high appeteney erythrocyte membrane insulin receptor (R_1) and low appetency erythrocytemembrane insulin receptor (R_2) was (43?9) / red cell and (2297?525) / red cell,respectively.Serum level of leptin was significantly higher in those with GDM than those of normal controls (P

The relationship between insulin resistance and erythrocyte insulin receptors in patients with gout as- sociated with macroalbruminuria / 中华风湿病学杂志

Objective To investigate the relationship between insulin resistance and erythrocyte in- sulin receptors in patients with gout associated with macroalbruminuria(MAU).Methods FBG,PBG,FINS, P2hINS,CH,TG,HDL,LDL-c,UA and erythrocyte insulin receptors were determined in 44 patients with MAU,62 patients with normal MAU(NMAU).Results In MAU,the levels of FINS,TG,LDL-c and HOMA-IR were(16?4)mU/L,(2.5?0.6)retool/L,(3.2?0.5)mmol/L and 3.6~1.2 respectively.While they were(13?3) mU/L,(2.3?0.8)mmol/L,(3.0?0.5)mmol/L and 3.0~0.4 in NMAU group.The levels of FINS,TG,LDL-c and HOMA-IR were significantly higher in the MAU patients than those in NMAU patients(P

The Levels of Plasma Insulin and Erythrocyte Insulin Receptors in Children with Acanthosis Nigricans Associated with Obesity / 中华皮肤科杂志

Objective To investigate the role of insulin resistance in the pathogenesis of childhood benign acanthosis nigricans with obesity and the relationship between insulin resistance and insulin receptors.Methods Fasting plasma insulin and the amount of erythrocyte insulin receptors were determined among17children with benign acanthosis nigricans with obesity(CBANO),with16cases of simple adiposis and15healthy children as controls.Results The levels of plasma insulin were higher in CBANO than those in sim-ple adiposis and healthy controls;however,the amount of erythrocyte insulin receptors was lower in CBANO than that in simple adiposis and healthy controls.Conclusion Insulin resistance caused by diminished in-sulin receptors may play an important role in pathogenesis of CBANO.

The Molecular Mechanism of Glucocorticoid-Induced Insulin Resistance / 中国医师杂志

Objective To explore the effect of glucocorticoid on glucose transport activity and the expression of insulin signaling peptides in the primary cultured rat adipocytes .Methods Isolated rat adipocytes were cultured for 2h,8h,16h and 24h respectively at 5 mmol glucose with dexamethasone (Dex) 0 3?mol. Then the glucose uptake, cellular contents of insulin receptor substrate (IRS) 1/2, phosphatidylinositol 3-kinase 85 subunit (p85) and protein kinase B(PKB)were measured by Western blotting.Results These adipocytes treated with Dex have shown to impair the basal and insulin-induced glucose uptake with a maximum inhibition at 2h and 24h respectively; Dex down-regulated IRS1 protein expression in a time-dependent manner and up-regulated IRS2 content. The cellular p85 and PKB contents were also decreased by Dex. Conclusion Chronic exposure to glucocorticoid can inhibit glucose uptake and induce insulin resistance. The mechanism may be involved in affecting the expression of insulin signaling peptides.

Polymorphism in insulin receptor gene exon 17 in women with polycystic ovary syndrome / 中华妇产科杂志

Objective To investigate insulin receptor (INSR) genotype exon 17 frequencies in women with polycystic ovary syndrome(PCOS) and to elucidate its role in the pathogenesis of PCOS. Methods The study involved 33 women with PCOS and 28 healthy control women who were genotyped for polymorphism of INSR gene exon 17 by single strand conformation polymorphism (SSCP) analysis. Body mass index (BMI), insulin sensitive index (ISI), the expression of INSR beta subunit, and serum concentration of luteinizing hormone(LH), total testosterone between the genotypes were compared. Results (1) The T -to- C mutation was observed in the INSR gene exon 17 (1008 bp). The frequency of the C/C genotype was significantly higher in patients (39%) than in the controls (11%) (P