Insulin Receptor Gene Expression Research Articles

Expression of dopamine signaling genes in the post-mortem brain of individuals with mental illnesses is moderated by body mass index and mediated by insulin signaling genes

Preclinical studies implicate insulin signaling as a modulator of dopamine transmission, but human data is currently limited. We hypothesize that changes in the expression of insulin receptor-related genes in the post-mortem brain tissue of patients with mood and psychotic disorders mediate the expression of dopamine regulation-related genes. From a database containing microarray data from the post-mortem dorsolateral prefrontal cortex (dlPFC) (healthy controls [HC]: n = 209; patients: n = 321) and hippocampus (HC: n = 180; patients: n = 196), we conducted a hypothesis-driven analysis through the a priori selection of 12 dopamine- and 3 insulin-related genes. Mediation and moderated mediation models, accounting for the role of body mass index (BMI), were used. In the dlPFC, expressions of insulin receptor- and dopamine regulation-related genes were moderated by BMI, with significantly lower expression in high BMI patients. In the hippocampus, there were significantly lower expressions of these genes, which were not moderated by BMI. Illnesses by BMI effects on expression of dopamine genes were fully mediated by expression of insulin receptor gene (INSR). Analysis of conditional indirect effects showed interactions between INSR and BMI, indicating significantly stronger indirect effects at higher BMI values. In the hippocampus we observed that expression of insulin receptor substrate 1 and 2 fully mediated the effects of illnesses on expression of dopamine genes. In conclusion, differential expression of dopamine-related genes was related to altered expression of insulin signaling genes. BMI had region-specific effects, supporting the hypothesis that metabolic systems are critical mediators of dopaminergic function.

Ferulic Acid Produced by Lactobacillus fermentum Influences Developmental Growth Through a dTOR-Mediated Mechanism.

The composition and activity of the gut microbiota impacts several energy-regulating conditions including diabetes, obesity and metabolic syndrome; however, the specific mechanisms linking the gut microbiota with the host's energy homeostasis remain elusive. Probiotics are health-promoting bacteria that when consumed, alter the composition and/or metabolism of resident microbiota conferring health benefits. To assess the role of a specific probiotic treatment on microbiota-derived impacts on energy homeostasis in the context of development, Drosophila melanogaster larvae were orally administered the probiotic Lactobacillus fermentum NCIMB 5221 or its metabolic product, ferulic acid: a potent anti-inflammatory and anti-oxidant hydroxycinnamic acid. In Drosophila larvae, both the probiotic and metabolite treatments advanced the nutritionally dependent stages of development in a dose-dependent manner while not affecting the hormonally controlled pupariation stage. These treatments correspondingly accelerated the developmental phase-dependent 20-hydroxyecdysone and insulin receptor gene expression surges and altered the phasic expression of downstream insulin signalling factors including dAkt, dTOR and dFOXO indicating a deep level of nutritionally dependent regulatory control. Administering Drosophilaboth ferulic acid and the TOR inhibitor rapamycin eliminated the physiological and molecular developmental advances indicating that microbial ferulic acid affects energy utilization in a dTOR-dependent manner outlining a potential mechanism of action of L. fermentum NCIMB 5221 on modulating microbiota dynamics to modulate energy homeostasis. TOR conservation from flies to humans indicates that probiotic therapy with L. fermentum NCIMB 5221 has a high therapeutic potential towards several human energy regulatory diseases such as obesity, diabetes and cancer.

Reduced Insulin Receptor Expression and Altered DNA Methylation in Fat Tissues and Blood of Women With GDM and Offspring.

Altered expression of the insulin receptor (IR) in adipose tissue (AT) could contribute to gestational diabetes mellitus (GDM) etiopathogenesis. Transcriptional regulation via epigenetic mechanisms (e.g., DNA methylation) may play a critical role. However, the human IR promoter DNA methylation patterns and involvement in gene expression are unknown. We evaluated IR mRNA and protein expression accompanied by targeted DNA methylation analyses in AT and blood cells of women with GDM and their offspring. Prospective observational study. Academic clinic and research unit. GDM-affected (n = 25) and matched control (n = 30) mother-child dyads. Maternal IR gene and protein expression in paired subcutaneous (SAT) and visceral adipose tissue samples (VAT). DNA methylation levels in IR promoter and intronic regions in maternal AT and blood cells of mother-offspring pairs. In SAT and VAT, IR mRNA/protein expressions were significantly reduced in women with GDMs (P < 0.05). The decrease in VAT was more pronounced and independent of maternal body mass index. VAT IR protein levels were inversely associated with key maternal and neonatal anthropometric and metabolic parameters (P < 0.05). DNA methylation patterns were similar across tissues, with significant yet small size alterations between groups in mothers and offspring (P < 0.05). Decreased IR levels in AT may be a relevant pathogenic factor in GDM, affecting materno-fetal metabolism. Further investigation of causal factors for IR dysregulation is necessary, especially in VAT. Potential functional and/or clinical roles of altered DNA methylation also should be evaluated.

Evaluated the Up –regulation in Gene ‎Expression of Hepatic Insulin Gene and ‎Hepatic Insulin Receptor Gene in Type 1 ‎Diabetic Rats Treated with Cuscuta chinesis ‎Lam.‎

This research was conducted to study the hypoglycemic activity of C. chinesis Lam on type 1 diabetic disease and investigate the molecular and histological mechanism of its action .many parameters was investigated , Fasting blood glucose (FBG), Fasting serum insulin,Hepatic Insulin Gene Expression, pancreas Insulin Gene Expression ,Hepatic Insulin Receptors Gene expression and histological sections of pancrease and liver.54 Rattus rattus male rats weighting(180 -200g) were divided into 3 groups: A normal control daily administrated with Dw, B Diabetic control daily administrated with Dw and C diabetic group daily administrated with 400 mg/Kg body weight of C. chinesis Lam. methanolic extract, each group consisted of 18 rats and further divided into (3) sub- groups 1 ,2 and 3. According to the period of administration 30, 60 and 90 days respectively. The results showing the daily administration of 400 mg/Kg body weight of C. chinesis Lam. methanolic extract for 60 day causing significance decrease in FBG and In the other hand each of fasting serum insulin, hepatic Insulin gene expression,pancreas Insulin gene expression and hepatic Insulin receptor gene expression was increased in group C in compare to B group and return all studied parameters involving pancrease and liver texture to the normal state ,which were statically morphologically not appeared any significant difference from A group .this study concluded that the daily administration type 1 diabetic rats with 400 mg/Kg body weight of C. chinesis Lam. extract for 60 day was return fasting serum insulin and FBG to normal value by upregulated the gene expression of hepatic INS Gene ,INSR gene , pancreas INS Gene ,regenerate pancreatic beta- cell and returnthe texture of both liver and pancrease to the normal state

Gene expression of insulin receptor, insulin-like growth factor increases and insulin-like growth factor-binding protein-3 reduces with increase in prostate size in benign prostatic hyperplasia

Introduction: Although the role of insulin in the development of benign prostatic hyperplasia (BPH) is well established, there are no studies regarding alteration in the gene expression of components of insulin-signaling pathway and their association with prostate size in BPH. Hence, the study was designed to analyze the gene and protein expression of insulin receptor and its related components in patients with BPH.Materials and methods: Twenty-seven BPH patients aged between 55 and 75 years were recruited in the study and prostatic tissues were obtained after transurethral resection of the prostate. Gene expression levels of Insulin receptor (IR), insulin receptor substrate (IRS), insulin-like growth factor (IGF) and insulin-like growth factor-binding protein-3 (IGFBP-3) were assessed by q-PCR.Results: Insulin receptor (IR-A and B) and insulin-like growth factors (IGF-1 and IGF-2) gene expression were significantly increased and IGFBP-3 gene expression was reduced in BPH patients with larger prostate size. Also, serum insulin was significantly increased and IGFBP-3 was significantly reduced in patients with larger prostate size.Conclusion: Increased expression of IR-A, B and IGF-1, 2 genes and reduced IGFBP-3 gene expression was associated with larger prostate size in BPH.

A transient insulin system dysfunction in newborn rat brain followed by neonatal intracerebroventricular administration of streptozotocin could be accompanied by a labile cognitive impairment

The early postnatal period is a critical period of hippocampus development, which is highly dependent on insulin receptor (IR) signaling and very important in cognitive function. The present study was conducted in order to present a model of neonatal transient brain insulin system dysfunction through finding an appropriate dose of injection of streptozotocin (STZ) during the neonatal period.Sixty male Wistar rat pups were divided into 4 groups of 15 and received intracerebroventricular saline or STZ (icv-STZ) (15, 20 and 25μg/kg) on postnatal day 7. Gene expression of IR and target genes for IR signaling (choline acetyltransferase (ChAT) and Tau) were measured at the ages of 2 and 7 weeks. Behavioral tests were performed at the ages of 3 and 6 weeks to assess short- and long-term cognitive function. 20μg/kg dose of icv-STZ was estimated as the optimal dose causing transient alteration in gene expression of IR, ChAT and Tau. Additionally, cognitive function of the animals restored to normal level at the age of 6 weeks. Therefore, 20μg/kg dose of icv-STZ is proposed as a new approach to generating transient brain insulin system dysfunction associated with transient cognitive impairments at a critical postnatal period of brain development.

Obesity alters the ovarian glucidic homeostasis disrupting the reproductive outcome of female rats

Obesity constitutes a health problem of increasing worldwide prevalence related to many reproductive problems such as infertility, ovulation dysfunction, preterm delivery, fetal growth disorders, etc. The mechanisms linking obesity to these pathologies are not fully understood. Cafeteria diet (CAF) is the animal model used for the study of obesity that more closely reflects western diet habits. Previously we described that CAF induces obesity associated to hyperglycemia, reduced ovarian reserve, presence of follicular cysts and ovulatory impairments. The aim of the present study was to contribute in the understanding of the physiological mechanisms altered as consequence of obesity. For that purpose, female Wistar rats were fed ad libitum with a standard diet (control group) or CAF (Obese group). We found that CAF fed-rats developed obesity, glucose intolerance and insulin resistance. Ovaries from obese rats showed decreased glucose uptake and became insulin resistant, showing decreased ovarian expression of glucotransporter type 4 and insulin receptor gene expression respect to controls. These animals showed an increased follicular nitric oxyde synthase expression that may be responsible for the ovulatory disruptions and for inflammation, a common feature in obesity. Obese rats resulted subfertile and their pups were macrosomic. We conclude that obesity alters the systemic and the ovarian glucidic homeostasis impairing the reproductive outcome. Since macrosomia is a risk factor for metabolic and obstetric disorders in adult life, we suggest that obesity is impacting not only on health and reproduction but it is also impacting on health and reproduction of the offspring.

Effect of Seyoeum on Obesity, Insulin Resistance, and Nonalcoholic Fatty Liver Disease of High-Fat Diet-Fed C57BL/6 Mice.

Background This study was performed to evaluate the effect of Seyoeum (SYE), a novel herbal meal replacement, on insulin resistance and nonalcoholic fatty liver disease (NAFLD) in obese mice fed with a high-fat diet (HFD). Methods SYE contained six kinds of herbal powder such as Coix lacryma-jobi, Oryza sativa, Sesamum indicum, Glycine max, Liriope platyphylla, and Dioscorea batatas. Male C57BL/6 mice were divided into four groups: normal chow (NC), HFD, SYE, and HFD plus SYE (HFD + SYE). The mice in groups other than NC were fed HFD for 9 weeks to induce obesity and then were fed each diet for 6 weeks. Clinical markers related to obesity, diabetes, and NAFLD were examined and gene expressions related to inflammation and insulin receptor were determined. Results Compared with HFD group, body weight, serum glucose, serum insulin, HOMA-IR, total cholesterol, triglyceride, epididymal fat pad weight, liver weight, and inflammatory gene expression were significantly reduced in SYE group. Insulin receptor gene expression increased in SYE group. Conclusions Based on these results, we conclude that SYE improved obesity and insulin resistance in high-fat fed obese mice. Our findings suggest that SYE could be a beneficial meal replacement through these antiobesity and anti-insulin resistance effects.

The effect of high-glucose-high-fat diet in male SD rats on methylation of INSR gene in F1 offspring

Objective To study the effect of high-glucose-high-fat diet on expression and methylation of insulin receptor(INSR)gene in F1 offspring. Methods Sixty 5-week-old male SD rats were randomly divided into two groups: normal diet group and high-glucose-high-fat diet group. After rats were fed for three months, all male rats were performed to copulate with normal female rats. The body weight, blood glucose, and blood insulin of neonatal rats of F1 offspring were measured. The genome DNA, total RNA, and total protein were extracted from livers, brains, and muscles of neonatal rats. Relative expression of INSR in both mRNA level and protein level were detected using a realtime PCR test and a Western blot test respectively. Methylation of INSR promoter was analyzed by a methylation specific PCR(MSP). Results Both body weight and fasting glucose were without significant difference in two groups. In high-glucose-high-fat diet group, both the glucose tolerance and insulin tolerance of neonatal rats in F1 offspring were significantly decreased. Except that in brains, the expressions of INSR gene in livers and in muscles of neonatal rats in high-glucose-high-fat diet group were down-regulated in mRNA(realtime PCR)and protein levels(Western blot)compared to the normal diet group. Meanwhile, the methylation of INSR gene in livers and muscles were strengthened in high-glucose-high-fat diet group. Conclusion A high-glucose-high-fat diet fed to male SD rats leads to the decrease in glucose tolerance, insulin tolerance, and the inhibition of expression of hepatic and muscle INSR gene in neonatal offspring. The methylation of INSR gene could be involved in this phenomenon. (Chin J Endocrinol Metab, 2016, 32: 1010-1014) Key words: Methylation; Insulin receptor gene; F1 offspring; High-glucose-high-fat diet; Male; Sprague Dawley rats

Transcriptional Control of Glucose and Energy Supply Prevents Oncogenic Signaling and B Cell Transformation

Background and Hypothesis: B-cell identity is determined by a set of B-cell transcription factors including PAX5, IKZF1 and EBF1. However, B-lineage leukemia clones often carry secondary genetic lesions that result in reduced activity or inactivation of these transcription factors. Studying patient samples from clinical trials for B-lineage childhood (P9906; n=187) and adult (MDACC; n=92) leukemia, we found that genetic defects in one or more B-cell transcription factors represent near-obligate lesions in human acute lymphoblastic leukemia (209 of 279 B-lineage ALL cases). While previously of unknown significance, we found that adult ALL cases with known lesions in one or more of these transcription factors had higher activity of lactate dehydrogenase, and phospho-states indicated higher activity of IRS1, PDK1, and AKT, which contribute to glucose uptake. For this reason, we investigated whether B-cell transcription factors set metabolic constraints of oncogenic signaling in leukemia.Results: Reconstitution of wildtype PAX5 and IKZF1 in patient-derived B-lineage ALL cells carrying PAX5 and IKZF1deletions decreased phospho-AKT levels. Furthermore, protein levels of multiple positive regulators involved in glucose uptake and metabolism (including insulin receptor, glucose transporters and hexokinases) were downregulated upon reconstitution of PAX5 and IKZF1. Conversely, protein levels of negative regulators of glucose uptake and metabolism including NR3C1 and TXNIP were upregulated upon reinstatement of PAX5 and IKZF1 function. Analysis of ChIPseq data of human B cells revealed binding of multiple B-cell transcription factors including PAX5, IKZF1 and EBF1 to promoter regions of genes encoding positive regulators of glucose uptake and metabolism. Binding peaks for B-cell transcription factors were also observed at genes that encode negative regulators of glucose uptake and metabolism (NR3C1 and TXNIP). In addition, direct recruitment of PAX5 was confirmed by single-locus quantitative chromatin immunoprecipitation (qChIP).Reconstitution of wildtype PAX5 and IKZF1 in patient-derived B-lineage ALL cells caused depletion from the cell culture in competitive growth assays, in parallel with reduced glucose consumption and depletion of cellular ATP levels. On the contrary, overexpression of dominant-negative PAX5-ETV6 and IK6 in patient-derived B-lineage ALL cells expressing wildtype PAX5 and IKZF1 resulted in a net survival advantage, concomitant with increases in both glycolytic activity and cellular ATP levels. PAX5-mediated impaired survival fitness was significantly rescued by CRISPR-based activation of gene expression of insulin receptor, glucose transporter and hexokinases in patient-derived B-lineage ALL cells. Conversely, CRISPR/Cas9-mediated deletion of NR3C1 and TXNIP largely reversed the effects of PAX5. Finally, reduced survival fitness upon reconstitution of wild-type PAX5 and IKZF1 in patient-derived pre-B ALL cells was mostly rescued by metabolites that can enter the TCA cycle and thus provide ATP.Conclusions: In summary,B-cell-specific restriction of glycolytic energy supply represents a previously unrecognized metabolic barrier against malignant transformation. Our findings suggest a causative link between impaired glucose uptake and metabolism caused by B-cell transcription factors as well as cell death, and the known tumor suppressive function of PAX5 and IKZF1 in B-lineage ALL. DisclosuresNo relevant conflicts of interest to declare.

Is the canine corpus luteum an insulin-sensitive tissue?

This study aimed to determine in the canine corpus luteum throughout the dioestrus (1) the influence of insulin on glucose uptake; (2) the regulation of genes potentially involved; and (3) the influence of hypoxia on glucose transporter expression and steroidogenesis, after treatment with cobalt chloride (CoCl2). Glucose uptake by luteal cells increased 2.7 folds (P < 0.05) in response to insulin; a phenomenon related to increased expression of glucose transporter (GLUT) 4 and phosphorylation of protein kinase B (AKT). The gene expression of insulin receptor and SLC2A4 (codifier of GLUT4) genes after insulin stimulation increased on day 20 post ovulation (p.o.) and declined on day 40 p.o. (P < 0.05). Regarding potentially involved molecular mechanisms, the nuclear factor kappa B gene RELA was upregulated on days 30/40 p.o., when SLC2A4 mRNA was low, and the interleukin 6 (IL6) gene was upregulated in the first half of dioestrus, when SLC2A4 mRNA was high. CoCl2 in luteal cell cultures increased the hypoxia-inducible factor HIF1A/HIF1A and the SLC2A4/GLUT4 expression, and decreased progesterone (P4) production and hydroxyl-delta-5-steroid dehydrogenase 3 beta (HSD3B) mRNA expression (P < 0.05). This study shows that the canine luteal cells are responsive to insulin, which stimulates glucose uptake in AKT/GLUT4-mediated pathway; that may be related to local activity of RELA and IL6. Besides, the study reveals that luteal cells under hypoxia activate HIF1A-modulating luteal function and insulin-stimulated glucose uptake. These data indicate that insulin regulates luteal cells' glucose disposal, participating in the maintenance and functionality of the corpus luteum.

Evaluation of Neuropathological Effects of a High-Fat Diet in a Presymptomatic Alzheimer's Disease Stage in APP/PS1 Mice.

Alzheimer's disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders. The results showed that the hippocampus from APP/PS1 mice fed with a HFD had an early significant decrease in Aβ signaling pathway specifically in the insulin degrading enzyme protein levels, an enzyme involved in (Aβ) metabolism, and α-secretase. These changes were accompanied by a significant increase in the occurrence of plaques in the hippocampus of these mice. Furthermore, APP/PS1 mice showed a significant hippocampal decrease in PGC-1α levels, a cofactor involved in mitochondrial biogenesis. However, HFD does not provoke changes in neither insulin receptors gene expression nor enzymes involved in the signaling pathway. Moreover, there are no changes in any enzymes (kinases) involved in tau phosphorylation, such as CDK5, and neither in brain oxidative stress production. These results suggest that early changes in brains of APP/PS1 mice fed with a HFD are mediated by an increase in Aβ1‒42, which induces a decrease in PKA levels and alterations in the p-CREB/ NMDA2B /PGC1-α pathway, favoring early AD neuropathology in mice.

Insulin Therapy Improves Adeno-Associated Virus Transduction of Liver and Skeletal Muscle in Mice and Cultured Cells.

Adeno-associated virus (AAV) gene transfer is a promising treatment for genetic abnormalities. Optimal AAV vectors are showing success in clinical trials. Gene transfer to skeletal muscle and liver is being explored as a potential therapy for some conditions, that is, α1-antitrypsin (AAT) disorder and hemophilia B. Exploring approaches that enhance transduction of liver and skeletal muscle, using these vectors, is beneficial for gene therapy. Regulating hormones as an approach to improve AAV transduction is largely unexplored. In this study we tested whether insulin therapy improves liver and skeletal muscle gene transfer. In vitro studies demonstrated that the temporary coadministration (2, 8, and 24 hr) of insulin significantly improves AAV2-CMV-LacZ transduction of cultured liver cells and differentiated myofibers, but not of lung cells. In addition, there was a dose response related to this improved transduction. Interestingly, when insulin was not coadministered with the virus but given 24 hr afterward, there was no increase in the transgene product. Insulin receptor gene (INSR) expression levels were increased 5- to 13-fold in cultured liver cells and differentiated myofibers when compared with lung cells. Similar INSR gene expression profiles occurred in mouse tissues. Insulin therapy was performed in mice, using a subcutaneously implanted insulin pellet or a high-carbohydrate diet. Insulin treatment began just before intramuscular delivery of AAV1-CMV-schFIX or liver-directed delivery of AAV8-CMV-schFIX and continued for 28 days. Both insulin augmentation therapies improved skeletal muscle- and liver-directed gene transduction in mice as seen by a 3.0- to 4.5-fold increase in human factor IX (hFIX) levels. The improvement was observed even after the insulin therapy ended. Monitoring insulin showed that insulin levels increased during the brief period of rAAV delivery and during the entire insulin augmentation period (28 days). This study demonstrates that AAV transduction of liver or skeletal muscle can be improved by insulin therapy.

Erratum to: Evidence for decreased expression of APPL1 associated with reduced insulin and adiponectin receptors expression in PCOS patients.

To investigate the expression of Adaptor protein containing a PH domain, PTB domain and leucine zipper motif 1 (APPL1), insulin receptor (INSR), adiponectin and adiponectin receptors (adipoR1 and R2) and their possible associations in granulosa cells (GCs) of 22 polycystic ovary syndrome (PCOS) women compared to the 22 non-PCOS controls with normal ovulatory function matched for BMI (body mass index). In this study, 44 infertile women aged 18-40 years undergoing in vitro fertilization (IVF) protocol were recruited. After follicular fluid collection, GCs were isolated and then purified with MACS (Micro Beads conjugated to monoclonal anti-human CD45 antibodies). RNA was extracted from GCs and quantitative real-time PCR (qRT-PCR) was performed to assess APPL1 gene expression. Expression of APPL1, insulin receptor and adiponectin system genes was significantly decreased in PCOS group compared to the controls. Reduction of APPL1, insulin receptor and adiponectin system genes in GCs could be involved in the development of PCOS.

Nigella sativa Relieves the Altered Insulin Receptor Signaling in Streptozotocin-Induced Diabetic Rats Fed with a High-Fat Diet.

The black cumin (Nigella sativa) “NS” or the black seeds have many pharmacological activities such as antioxidant, anticarcinogenic, antihypertensive, and antidiabetic properties. In this work, streptozotocin-induced diabetic rats fed with a high-fat diet were treated daily with NS oil (NSO) in order to study the effect on the blood glucose, lipid profile, oxidative stress parameters, and the gene expression of some insulin receptor-induced signaling molecules. This treatment was combined also with some drugs (metformin and glimepiride) and the insulin receptor inhibitor I-OMe-AG538. The administration of NSO significantly induced the gene expression of insulin receptor compared to rats that did not receive NSO. Also, it upregulated the expression of insulin-like growth factor-1 and phosphoinositide-3 kinase, whereas the expression of ADAM-17 was downregulated. The expression of ADAM-17 is corroborated by the analysis of TIMP-3 content. In addition, the NSO significantly reduced blood glucose level, components of the lipid profile, oxidative stress parameters, serum insulin/insulin receptor ratio, and the tumor necrosis factor-α, confirming that NSO has an antidiabetic activity. Thus, the daily NSO treatment in our rat model indicates that NSO has a potential in the management of diabetes as well as improvement of insulin-induced signaling.

Insulin Resistance in Pregnancy Is Correlated with Decreased Insulin Receptor Gene Expression in Omental Adipose: Insulin Sensitivity and Adipose Tissue Gene Expression in Normal Pregnancy

Aims: To determine correlations of insulin sensitivity to gene expression in omental and subcutaneous adipose tissue of non-obese, non-diabetic pregnant women. Methods: Microarray gene profiling was performed on subcutaneous and omental adipose tissue from 14 patients and obtained while fasting during non-laboring Cesarean section, using Illumina HumanHT-12 V4 Expression BeadChips. Findings were validated by real-time PCR. Matusda-Insulin sensitivity index (IS) and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated from glucose and insulin levels obtained from a frequently sampled oral glucose tolerance test, and correlated with gene expression. Results: Of genes differentially expressed in omental vs. subcutaneous adipose, in omentum 12 genes were expressed toward insulin resistance, whereas only 5 genes were expressed toward insulin sensitivity. In particular, expression of the insulin receptor gene (INSR), which initiates the insulin signaling cascade, is strongly positively correlated with IS and negatively with HOMA-IR in omental tissue (r = 0.84). Conclusion: Differential gene expression in omentum relative to subcutaneous adipose showed a pro-insulin resistance profile in omentum. A clinical importance of omental adipose is observed here, as downregulation of insulin receptor in omentum is correlated with increased systemic insulin resistance.

Anti-obesity and anti-hyperglycemic effects of cinnamaldehyde via altered ghrelin secretion and functional impact on food intake and gastric emptying.

Cinnamon extract is associated to different health benefits but the active ingredients or pathways are unknown. Cinnamaldehyde (CIN) imparts the characteristic flavor to cinnamon and is known to be the main agonist of transient receptor potential-ankyrin receptor 1 (TRPA1). Here, expression of TRPA1 in epithelial mouse stomach cells is described. After receiving a single-dose of CIN, mice significantly reduce cumulative food intake and gastric emptying rates. Co-localization of TRPA1 and ghrelin in enteroendocrine cells of the duodenum is observed both in vivo and in the MGN3-1 cell line, a ghrelin secreting cell model, where incubation with CIN up-regulates expression of TRPA1 and Insulin receptor genes. Ghrelin secreted in the culture medium was quantified following CIN stimulation and we observe that octanoyl and total ghrelin are significantly lower than in control conditions. Additionally, obese mice fed for five weeks with CIN-containing diet significantly reduce their cumulative body weight gain and improve glucose tolerance without detectable modification of insulin secretion. Finally, in adipose tissue up-regulation of genes related to fatty acid oxidation was observed. Taken together, the results confirm anti-hyperglycemic and anti-obesity effects of CIN opening a new approach to investigate how certain spice derived compounds regulate endogenous ghrelin release for therapeutic intervention.

Effects of aPueraria lobata-root based combination supplement containingRehmannia glutinosaand aerobic exercise on improvement of metabolic dysfunctions in ovariectomized rats

Purpose: There is a fair amount of evidence indicating that increased risk of obesity and insulin resistance is associated with postmenopausal state, but can be modulated by diet and exercise. In this study, we explored whether a Pueraria lobata root-based supplement containing Rehmannia glutinosa (PR) and/or aerobic treadmill exercise can modify the metabolic changes associated with estrogen deficiency. Methods: Seventy rats were randomly assigned to the following groups for 8 weeks (n=10 per group): SHAM, sham-operated; PR0, ovariectomized (OVX) control; PR200, OVX with PR200 ㎎/㎏ B.W; PR400, OVX with PR400 ㎎/㎏ B.W; EPR0, OVX with exercise; EPR200, OVX with exercise and PR200 ㎎/㎏ B.W; EPR400, OVX with exercise and PR400 mg/kg B.W. Results: OVX induced significant increases in body weight, food intake, fat mass, LDL-cholesterol, and fasting blood glucose, confirming induction of menopausal symptoms. PR supplementation or exercise significantly suppressed the above mentioned changes through different regulatory elements in adipose tissue: PR supplement upregulated adiponectin gene expression and aerobic exercise upregulated adiponectin and insulin receptor gene expression and a combination of PR supplement and aerobic exercise showed an additive effect on adiponectin gene expression. Conclusion: Taken together, the results of this study suggest that PR supplement has a potential to provide health benefits in OVX rats through leptin and adiponectin secretion. In addition, the data suggest that combination of exercise and PR would have additive effects on metabolic dysfunction associated with estrogen deficiency.

Gender differences in the myocardial response to dietary CLA isomers during diabetes

This study was undertaken to examine if conjugated linoleic acid (CLA) isomers c9,t11 and t10,c12, provide protection against cardiac dysfunction in diabetic male and female rats. Diabetes was induced by an intravenous injection of streptozotocin (65 mg/kg body weight) in male and female rats. Four wks after the induction of diabetes, the animals were treated daily for 4 wks with or without 0.5% of each CLA isomer by oral gavage. Eight wks diabetes was associated with elevated levels of plasma total cholesterol, HDL-cholesterol, triglycerides and glucose as well as depressed rate of cardiac relaxation (-dP/dt) in both male and female animals. However, unlike females, male diabetic rats showed an increase in heart weight: body weight ratio and decreased rates of cardiac contraction (+dP/dt) and fractional shortening (FS). Both CLA isomers improved the lipid profile in male diabetic rats, whereas only CLA c9,t11 isomer improved the lipid profile in females. CLA intervention did not affect blood glucose levels in male or female diabetic animals. While CLA c9,t11 isomer improved ± dP/dt in the male rats, a deterioration of +dP/dt and -dP/dt in the female diabetic rats was observed. Although FS was normalized by both CLA isomers in males, CLA t10,c12 isomer depressed FS in the female diabetic rats. CLA treatment normalized GLUT 4 gene expression levels, but markedly increased insulin receptor gene expression in the heart of male diabetic rats. These data suggest that, unlike females, improved myocardial function in male diabetic rats in response to CLA may be related to a favorable shift in myocardial energetics.

Hyperglycemia induces memory impairment linked to increased acetylcholinesterase activity in zebrafish (Danio rerio)

Diabetes mellitus, which causes hyperglycemia, affects the central nervous system and can impairs cognitive functions, such as memory. The aim of this study was to investigate the effects of hyperglycemia on memory as well as on the activity of acethylcholinesterase. Hyperglycemia was induced in adult zebrafish by immersion in glucose 111mM by 14 days. The animals were divided in 4 groups: control, glucose-treated, glucose-washout 7-days and glucose-washout 14-days. We evaluated the performance in inhibitory avoidance task and locomotor activity. We also determined acethylcholinesterase activity and gene expression from whole brain. In order to counteract the effect of hyperglycemia underlined by effects on acethylcholinesterase activity, we treated the animals with galantamine (0.05ng/g), an inhibitor of this enzyme. Also we evaluated the gene expression of insulin receptor and glucose transporter from zebrafish brain. The hyperglycemia promoted memory deficit in adult zebrafish, which can be explained by increased AChE activity. The ache mRNA levels from zebrafish brain were decrease in 111mM glucose group and returned to normal levels after 7 days of glucose withdrawal. Insulin receptors (insra-1, insra-2, insrb-1 and insrb-2) and glut-3 mRNA levels were not significantly changed. Our results also demonstrated that galantamine was able to reverse the memory deficit caused by hyperglycemia, demonstrating that these effects involve modulation of AChE activity. These data suggest that the memory impairment induced by hyperglycemia is underlined by the cholinergic dysfunction caused by the mechanisms involving the control of acetylcholinesterase function and gene expression.