Insulin Receptor Gene Expression Research Articles

A Neonatal Mild Defect in Brain Insulin Signaling Predisposes a Subclinical Model of Sporadic Alzheimer's to Develop the Disease.

Brain insulin system dysfunction has been proposed as a key player in the pathogenesis of sporadic Alzheimer's disease (sAD). Given this fact, an adult rat model for sAD has been developed by intracerebroventricular injection of a subdiabetogenic streptozotocin dosage (icv-STZ). A low dose of icv-STZ in adult rats leads to a subclinical model of Alzheimer's disease. According to the brain developmental origin for sAD occurrence, the present study evaluated the effect of neonatal injection of icv-STZ on the development and progression of Alzheimer's disease later in the adult animals treated with a low dose of icv-STZ. Although no alteration was observed in the rats receiving an adult low dose of icv-STZ, these animals displayed cognitive deficits if they were also treated neonatally with icv-STZ. These impairments were associated with altered gene expression of insulin receptor, tau and choline acetyltransferase, along with increased astrocyte and dark neuron densities in the hippocampus. This study highlights neonatal brain insulin system dysfunction in the programming of brain insulin signaling sensitivity and provides more evidence for the developmental origin of sAD.

The Effect of Swimming Training and Cinnamon Consumption on the Gene Expression of GLUT4 and Insulin Receptor in the Brown Adipose Tissue of Diabetic Rats

Background: The effect of training on the gene expression of GLUT4 and insulin receptor (IR) has been investigated in some studies, but the simultaneous effect of swimming training along with cinnamon consumption is unknown. Objective: This study aimed to examine the effect of six weeks of swimming training with cinnamon consumption on the gene expression of GLUT4 and IR in the brown adipose tissue of diabetic rats. Methods: In this experimental study, 28 diabetic rats were randomly divided into four groups of seven animals, including 1- control (C), 2- cinnamon (Ci), 3- swimming (S), and 4- swimming plus cinnamon (S + Ci). Rats in groups 3 and 4 trained for six weeks and five sessions. Groups 2 and 4 received 200 mg/kg/day. Data were analyzed using one-way analysis of variance and Tukey’s post hoc test at the level of P ≤ 0.05. Results: The gene expression of GLUT4 and IR in the S, Ci, and S + Ci groups was significantly (P = 0.001) higher than the control group. Also, the gene expression of GLUT4 and IR in the S group was significantly (P = 0.001) higher than the Ci and S + Ci groups. Conclusion: Swimming training and cinnamon consumption and their simultaneous implementation had a significant effect on increasing the gene expression of GLUT4 and IR in the brown adipose tissue of diabetic rats. On the other hand, swimming training alone had a greater effect than cinnamon consumption and swimming plus cinnamon consumption.

Benzyl Butyl Phthalate Induced Early lncRNA H19 Regulation in C3H10T1/2 Stem Cell Line.

Exposure to endocrine-disrupting chemicals used in plastic manufacturing may contribute to the current obesity and diabetes epidemic. Our previous study demonstrated that benzyl butyl phthalate (BBP) induced adipogenesis in the C3H10T1/2 stem cell line. Here we investigated if BBP deregulated long noncoding RNA H19 and its downstream pathway and whether BBP plays a role in the insulin signaling pathway during adipocyte diiferentiation. Cells treated with an 8 day BBP regimen showed that H19 expression was decreased at day 2 with 50 μM BBP exposure (p < 0.05). However, no significant changes were observed from day 4 to day 8. Expression of miRNA-103/107, H19 regulated miRNAs, was upregulated at day 2 (p < 0.05) but not from day 4 to day 8. Similarly, expression of the let-7 family members (a, b, c, d, f, and g) was also significantly increased at day 2 (p < 0.05 or p < 0.01), except for let-7e. Both let-7 and miRNA-103/107 are targets of H19 and play roles in insulin signaling. Insulin receptor substrate (IRS)-1, one of the key insulin signal transduction regulators, was significantly downregulated from day 2 to day 8 (p < 0.05). Gene expression of insulin receptor (IR) and IRS-2 were not altered by BBP exposure. The ratio of IRS1/IRS2 was significantly decreased from day 2 to day 8. On day 4, phospho-Akt protein expression was significantly decreased (p < 0.05). In conclusion, BBP exposure may lead to metabolic dysregulation by altering vital epigenetic regulators such as lncRNA H19 and its target microRNAs at an earlier stage, which further regulates insulin signaling.

Potential Antidiabetic and Anti-Genotoxic Activities of Silver Nanoparticles of Alkaloid Extract of Rhazya stricta in Rat Animal Model

In most of Arabian courtiers Rhazya stricta is extensively utilized in public medicine for several diseases treatment. In this study, crude alkaloid extract of R. stricta (CAERS) coated with silver nanoparticles (CAERS-AgNPs) as potential treatment against diabetes in DM animal model was evaluated. Swiss albino male rats (n = 80) were injected with STZ to induce Diabetes Mellitus type-2 (DM). DM-rats were injected different doses of CAERS or CAERS-nanoparticles (CAERS-NPs) for 2 months. The results exhibited that mRNA expression of insulin and insulin receptor was down-regulated, activity levels of antioxidant enzymes were decreased, generation of ROS mediated DNA adducts and apoptosis in DM-rats was increased significantly than those in negative control rats. In contrast, the expression of insulin and insulin receptor genes was up-regulated, activity levels of antioxidant enzymes, ROS generation, DNA adducts and apoptosis incidence in DM-rats supplemented with high dose of CAERS and all doses of CAERS-NPs were improved. In conclusion: R. stricta nanoparticles improved the anti-diabetic effect of the plant much more than the powder form of the extract. This action could be attributed to modification of the chemical and physical properties of the plant materials. The properties modification might be improved the ability of plant compounds to penetrate the cell membrane which facilitating release of plant materials into the target cells.

Themis regulates metabolic signaling and effector functions in CD4+ T cells by controlling NFAT nuclear translocation

Themis is a T cell lineage-specific molecule that is involved in TCR signal transduction. The effects of germline Themis deletion on peripheral CD4+ T cell function have not been described before. In this study, we found that Themis-deficient CD4+ T cells had poor proliferative responses, reduced cytokine production in vitro and weaker inflammatory potential, as measured by their ability to cause colitis in vivo. Resting T cells are quiescent, whereas activated T cells have high metabolic demands. Fulfillment of these metabolic demands depends upon nutrient availability and upregulation of nutrient intake channels after efficient TCR signal transduction, which leads to metabolic reprogramming in T cells. We tested whether defects in effector functions were caused by impaired metabolic shifts in Themis-deficient CD4+ T cells due to inefficient TCR signal transduction, in turn caused by the lack of Themis. We found that upon TCR stimulation, Themis-deficient CD4+ T cells were unable to upregulate the expression of insulin receptor (IR), glucose transporter (GLUT1), the neutral amino acid transporter CD98 and the mTOR pathway, as measured by c-Myc and pS6 expression. Mitochondrial analysis of activated Themis-deficient CD4+ T cells showed more oxidative phosphorylation (OXPHOS) than aerobic glycolysis, indicating defective metabolic reprogramming. Furthermore, we found reduced NFAT translocation in Themis-deficient CD4+ T cells upon TCR stimulation. Using previously reported ChIP-seq and RNA-seq data, we found that NFAT nuclear translocation controls IR gene expression. Together, our results describe an internal circuit between TCR signal transduction, NFAT nuclear translocation, and metabolic signaling in CD4+ T cells.

Insulin receptor deficiency reduces lipid synthesis and reproductive function in the insect Rhodnius prolixus

Rhodnius prolixus, a vector of Chagas disease, is a hematophagous insect that feeds exclusively on blood. Each blood meal is digested within the first fourteen days after feeding, providing substrates for lipid synthesis for storage and egg production. These events are precisely regulated and emerging evidence points to a key function of insulin-like peptides (ILPs) in this control. Here we investigated the role of insulin receptor in the regulation of nutrient metabolism in fed adult females. The expression of insulin receptor (RhoprIR) gene was determined in adult organs, and it was highest in ovaries and previtellogenic follicles. We generated insects with RNAi-mediated knockdown of RhoprIR to address the physiological role of this receptor. RhoprIR deficiency improved longevity and reduced triacylglycerol storage in the fat body, whereas blood digestion remained unchanged for seven days after blood meal. The lower lipid content was attributable to decreased de novo lipogenesis as well as reduced incorporation of hemolymph-derived fatty acids into newly synthesized lipids within this organ. Consistent with that, fat bodies from RhoprIR-deficient insects exhibited decreased gene expression levels of lipophorin receptor (RhoprLpR), glycerol-3-phosphate acyltransferase 1 and 4 (RhoprGpat1 and RhoprGpat4), and carnitine palmitoyltransferase 1 (RhoprCpt1). Although hemolymph lipid profile was not affected by RhoprIR disruption, the concentration of circulating vitellogenin was increased. In line with these changes, RhoprIR-deficient females exhibited smaller ovaries and a marked reduction in oviposition. Taken together, these findings support a key role of insulin receptor in nutrient homeostasis, lipid synthesis and egg production following a blood meal.

Ethnic and Adipose Depot Specific Associations Between DNA Methylation and Metabolic Risk.

BackgroundMetabolic risk varies according to body mass index (BMI), body fat distribution and ethnicity. In recent years, epigenetics, which reflect gene-environment interactions have attracted considerable interest as mechanisms that may mediate differences in metabolic risk. The aim of this study was to investigate DNA methylation differences in abdominal and gluteal subcutaneous adipose tissues of normal-weight and obese black and white South African women.MethodsBody composition was assessed using dual-energy x-ray absorptiometry and computerized tomography, and insulin sensitivity was measured using a frequently sampled intravenous glucose tolerance test in 54 normal-weight (BMI 18–25 kg/m2) and obese (BMI ≥ 30 kg/m2) women. Global and insulin receptor (INSR) DNA methylation was quantified in abdominal (ASAT) and gluteal (GSAT) subcutaneous adipose depots, using the Imprint methylation enzyme-linked immunosorbent assay and pyrosequencing. INSR gene expression was measured using quantitative real-time PCR.ResultsGlobal DNA methylation in GSAT varied according to BMI and ethnicity, with higher levels observed in normal-weight white compared to normal-weight black (p = 0.030) and obese white (p = 0.012) women. Pyrosequencing of 14 CpG sites within the INSR promoter also showed BMI, adipose depot and ethnic differences, although inter-individual variability prevented attainment of statistical significance. Both global and INSR methylation were correlated with body fat distribution, insulin resistance and systemic inflammation, which were dependent on ethnicity and the adipose depot. Adipose depot and ethnic differences in INSR gene expression were observed.ConclusionWe show small, but significant global and INSR promoter DNA methylation differences in GSAT and ASAT of normal-weight and obese black and white South African women. DNA methylation in ASAT was associated with centralization of body fat in white women, whereas in black women DNA methylation in GSAT was associated with insulin resistance and systemic inflammation. Our findings suggest that GSAT rather than ASAT may be a determinant of metabolic risk in black women and provide novel evidence that altered DNA methylation within adipose depots may contribute to ethnic differences in body fat distribution and cardiometabolic risk.

Bovine Milk Exosome and miRNA-2478 Enhances Insulin Sensitivity by Upregulating Insulin Receptor and Promotes Glycogen Synthesis in HepG2 Cells

Background: Milk and milk products are a sort of mandatory component of diet world-wide. Milk exosome and its bioactive content especially miRNA has been linked with several metabolic regulatory pathways and diseases. However, there is lack of convincing experimental validation. Recently, we have profiled cow milk exosomal miRNAs and in silico analysis identified insulin receptor (INSR) as potential target of miRNA-2478 which one of the candidate miRNA is encapsulated in cow milk exosomes. Down-regulation of insulin receptor (INSR) in peripheral tissues including liver results in the development of pathogenesis of Type II diabetes. However, role of miRNA-2478 in regulation of insulin signaling has not been studied so far. The main aim of the study was to decipher the role of milk exosomal miR-2478 on its target insulin receptor in HepG2 cells. Methods: The effect of miR-2478 mimic on INSR mRNA and protein expression, glycogen content and enrichment of RNA polymerase II at insulin gene promoter in HepG2 cells was analysed. Findings: Results of the current study showed that there was increased expression of insulin receptor gene at both mRNA and protein level with increased abundance of bta-miR-2478 in HepG2 cells. Similarly, glycogen content was also found to be increased in bta-miR-2478 transfected cells. Results of ChIP assay also showed enrichment of RNA polymerase on insulin receptor promoter in miR-2478 transfected cells as compared to control. Interpretation: In conclusion, bovine milk exosomes and miR-2478 enhanced insulin sensitivity through increased expression of insulin receptor and glycogen synthesis in HepG2 cells. Funding Statement: None. Declaration of Interests: All authors declare they have no conflict of interest. Ethics Approval Statement: Cow (Sahiwal) milk was collected from the healthy and early lactating animals of ICAR-National Dairy Research Institute, Karnal as per the Institute Animal Ethics Guidelines.

Effect of Gymnema sylvestre on Insulin Receptor (IR) and Proglucagon Gene Expression in Streptozotocin Induced Diabetic Rats

Effect of Gymnema sylvestre on Insulin Receptor (IR) and Proglucagon Gene Expression in Streptozotocin Induced Diabetic Rats

Maternal obesity modulates sexually dimorphic epigenetic regulation and expression of leptin receptor in offspring hippocampus

Maternal obesity during pregnancy is associated with a greater risk for obesity and neurodevelopmental deficits in offspring. This developmental programming of disease is proposed to involve neuroendocrine, inflammatory, and epigenetic factors during gestation that disrupt normal fetal brain development. The hormones leptin and insulin are each intrinsically linked to metabolism, inflammation, and neurodevelopment, which led us to hypothesise that maternal obesity may disrupt leptin or insulin receptor signalling in the developing brain of offspring. Using a C57BL/6 mouse model of high fat diet-induced maternal obesity (mHFD), we performed qPCR to examine leptin receptor (Lepr) and insulin receptor (Insr) gene expression in gestational day (GD) 17.5 fetal brain. We found a significant effect of maternal diet and offspring sex on Lepr regulation in the developing hippocampus, with increased Lepr expression in female mHFD offspring (p < 0.05) compared to controls. Maternal diet did not alter hippocampal Insr in the fetal brain, or Lepr or Insr in prefrontal cortex, amygdala, or hypothalamus of female or male offspring. Chromatin immunoprecipitation revealed decreased binding of histones possessing the repressive histone mark H3K9me3 at the Lepr promoter (p < 0.05) in hippocampus of female mHFD offspring compared to controls, but not in males. Sex-specific deregulation of Lepr could be reproduced in vitro by exposing female hippocampal neurons to the obesity related proinflammatory cytokine IL-6, but not IL-17a or IFNG. Our findings indicate that the obesity-related proinflammatory cytokine IL-6 during pregnancy leads to sexually dimorphic changes in the modifications of histones binding at the Lepr gene promoter, and concomitant changes to Lepr transcription in the developing hippocampus. This suggests that exposure of the fetus to metabolic inflammatory molecules can impact epigenetic regulation of gene expression in the developing hippocampus.

Indomethacin decreases insulin secretion by reducing KCa3.1 as a biomarker of pancreatic tumor and causes apoptotic cell death.

Insulinomas originate from pancreatic β cells and it is the most widely known tumor. Indomethacin is a nonsteroidal anti-inflammatory drug, which is used for blocking the production of some natural substances that cause inflammationand decreasepain. In this study, Iaimed to investigate the effects of indomethacin on rat insulinoma INS-1 cells. The relationship between cell death and insulin metabolism was determined with the administration of indomethacin.The cell viability by WST-1; the apoptosis and necrosis levels by ELISA kits; malondialdehyde levels by spectrophotometer;andbeclin, intracellular insulin, insulin secretion, KCa3.1, insulin receptor (IR), glucose transporter type 2 (GLUT2), activating transcription factor 2 (ATF2), Elk1, c-Jun, Akt and phosphorylated ATF2, Elk1, c-Jun, Akt, intracellular betacellulin and betacellulin secretion levels by Western blot analysis investigated.The Ins1, Ins2, IR, GLUT2, ATF2, Elk1, c-Jun, Akt, and Betacellulin gene expression levels were determined by the real-time quantitative reverse transcription-polymerase chain reaction method. Apoptotic cell death was observed with the administration of indomethacin. The insulin secretion and Ins1, Ins2 gene expression levels decreased. The insulin receptor and GLUT2 levels increased, while KCa3.1 (KCNN4) levels decreased with the administration of indomethacin to insulinoma INS-1 cells. A decrease was observed in the total c-Jun, phosphorylated ATF2, Elk1, c-Jun, and Akt levels. Betacellulin secretion levels increased. In insulinoma INS-1 cells, apoptotic cell death occurred in the following manner: (i) indomethacin might decrease insulin secretion by reducing KCa3.1, (ii) might inactivate the JNK/ERK pathway with the inactivity of transcription factors.

Overfeeding During Lactation in Rats is Associated with Cardiovascular Insulin Resistance in the Short-Term.

Childhood obesity is associated with metabolic and cardiovascular comorbidities. The development of these alterations may have its origin in early life stages such as the lactation period through metabolic programming. Insulin resistance is a common complication in obese patients and may be responsible for the cardiovascular alterations associated with this condition. This study analyzed the development of cardiovascular insulin resistance in a rat model of childhood overweight induced by overfeeding during the lactation period. On birth day, litters were divided into twelve (L12) or three pups per mother (L3). Overfed rats showed a lower increase in myocardial contractility in response to insulin perfusion and a reduced insulin-induced vasodilation, suggesting a state of cardiovascular insulin resistance. Vascular insulin resistance was due to decreased activation of phosphoinositide 3-kinase (PI3K)/Akt pathway, whereas cardiac insulin resistance was associated with mitogen-activated protein kinase (MAPK) hyperactivity. Early overfeeding was also associated with a proinflammatory and pro-oxidant state; endothelial dysfunction; decreased release of nitrites and nitrates; and decreased gene expression of insulin receptor (IR), glucose transporter-4 (GLUT-4), and endothelial nitric oxide synthase (eNOS) in response to insulin. In conclusion, overweight induced by lactational overnutrition in rat pups is associated with cardiovascular insulin resistance that could be related to the cardiovascular alterations associated with this condition.

Detrimental Effects of Sodium Fluoride on the Expression of Insulin Receptor in the Olfactory Bulb and Hippocampus of Male Mice.

Fluoride exposure is associated with lowered cognitive function ability, intelligence quotient, and mental decline, especially in children. The brain insulin receptor (IR) signaling system is related to neuronal plasticity and consequent cognitive ability. In our previous study, NaF exposure decreased IR expressions in olfactory bulb (OB) and hippocampus after Y-maze test in male mice. In order to further explore whether the Y-maze test affected IR gene and protein expression levels in the OB and hippocampus under the NaF exposure, healthy male mice were randomly allotted into four groups and challenged with 0, 50, 100, and 150mg/L NaF for three continuous months. The results showed that femur fluorine content of the NaF-exposed groups increased significantly in a dose-dependent manner. NaF significantly decreased brain protein content and organ coefficient of the treated male mice. The protein and mRNA expression levels of the IR were significantly decreased in the OB and hippocampus of the NaF-treated mice. Interestingly, indicators (brain protein content and organ coefficient) measured in the present study were significantly lower than our previous study indicators (mice tested Y-maze test), especially the expression levels of IR protein and mRNA in the same concentration groups. Taken together, these results indicated that Y-maze test could promote the expression levels of IR protein and mRNA in the OB and hippocampus, while NaF had a stronger inhibitory effect, which resulted in adverse effects on the expression levels of IR in the OB and hippocampus of male mice.

Ficus deltoidea extract down-regulates protein tyrosine phosphatase 1B expression in a rat model of type 2 diabetes mellitus: a new insight into its antidiabetic mechanism.

Ficus deltoidea var. deltoidea Jack (FD) is a well-known plant used in Malay folklore medicine to lower blood glucose in diabetic patients. For further research of the antihyperglycemic mechanisms, the protein tyrosine phosphatase 1B (PTP1B)-inhibitory effect of FD was analysed both in vitro and in vivo. To optimise a method for FD extraction, water, 50, 70, 80, 90 and 95% ethanol extracts were prepared and determined for their total phenolic and triterpene contents, and PTP1B-inhibition capacity. Among the tested extracts, 70% ethanol FD extract showed a significant PTP1B inhibition (92·0% inhibition at 200 µg/ml) and high phenolic and triterpene contents. A bioassay-guided fractionation of the 70% ethanol extract led to the isolation of a new triterpene (3β,11β-dihydroxyolean-12-en-23-oic acid; F3) along with six known compounds. In vivo, 4 weeks' administration of 70% ethanol FD extract (125, 250 and 500 mg/kg/d) to streptozotocin-nicotinamide-induced type 2 diabetic rats reversed the abnormal changes of blood glucose, insulin, total Hb, GLUT2, lipid profile, and oxidative stress in liver and pancreas. Moreover, FD reduced the mRNA expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose 6-phosphatase) and restored insulin receptor and GLUT2 encoding gene (Slc2a2) expression. In addition, FD significantly down-regulated the hepatic PTP1B gene expression. These results revealed that FD could potentially improve insulin sensitivity, suppress hepatic glucose output and enhance glucose uptake in type 2 diabetes mellitus through down-regulation of PTP1B. Together, our findings give scientific evidence for the traditional use of FD as an antidiabetic agent.

Exercise Intensity Alter Insulin Receptor Gene Expression in Diabetic Type - 2 Rat Model.

AIM:To analyse the differential expression of the insulin receptor (IR) gene between moderate continuous and severe continuous training in the T2DM rat model.METHODS:This was an experimental study. Healthy male Wistar was used in this study, which divided into sedentary, moderate continuous training, and severe continuous training. Treated groups were assigned to run on the treadmill three times a week for eight weeks consequently.RESULTS:The result shown that expression of mRNA IR gene in treated groups decline compared to control. There was a difference mRNA IR gene expression after eight weeks of exercise between MCT and control, SCT and control so are MCT and SCT. IR expression on skeletal muscle in treated groups was different compared with control. The distribution of IR on skeletal muscles in treatment groups was significantly increased compared control, but there was no significant difference distribution between MCT and SCT. HOMA-IR post-test in SCT was lower than MCT but FBG post-test lower in MCT than SCT.CONCLUSION:The intensity of exercise makes a difference in IR gene expression between moderate continuous training and severe continuous training after eight weeks of assigned exercise in T2DM rat models.

Effect of Epigallocatechin Gallate and Catechin on Overexpression of GSK-3β and IR Genes Induced by Streptozotocin in Rat Brain

Background: Type 2 diabetes mellitus (T2DM) is one of the significant risk factors for Alzheimer disease (AD). Defects in insulin signaling pathway induce AD hallmarks mainly through activation of glycogen synthase kinase-3β (GSK-3β) pathway. Objectives: In this study, we investigated the expression of GSK-3β and insulin receptor (IR) genes in the hippocampi of an animal model of sporadic AD and assessed the preventive effect of Catechin (CAT) and epigallocatechin gallate (EGCG) on their expression. Materials &amp; Methods: Adult male Wistar rats were treated by intracerebroventricular streptozotocin (STZ) injection (3 mg/kg) at day 1 and 3 after cannulation. CAT was administered at a dose of 40 mg/kg for 10 days per gavage, and EGCG was administered at a dose of 3 mg/kg for 14 days into drinking water. Then the animals were decapitated, and their hippocampi were removed. Real-time Polymerase Chain Reaction (PCR) was used to evaluate the alteration in gene expression. Results: There was overexpression in GSK-3β gene in STZ-treated rats (P≤0.05), which was brought back to normalcy by EGCG (P≤0.01). The IR gene also increased after STZ treatment, but CAT reduced IR expression (P≤0.05). However, the suppressive effect of EGCG on IR expression was stronger (P≤0.01). Conclusion: The neuroprotective activity of EGCG might be due to its influence on IR and GSK-3β expression.

Effects of nano-curcumin on gene expression of insulin and insulin receptor

BackgroundThis study investigates the effects of nano-curcumin on gene expression of insulin and insulin receptor in diabetic rats. Forty female rats were divided into four groups (ten rats for each). The first group was non-diabetic rats acting as negative control and rats of the second group were rendered diabetic by STZ served as positive controls. The third one was induced diabetic and received oral Diamicron for 3 weeks. The fourth was rendered diabetic and administrated oral nano-curcumin for 3 weeks.ResultsA significant increase of blood glucose was showed in diabetic rats with significant reduction of insulin level compared to non-diabetic controls. The gene expression of insulin and insulin receptor were more significant in diabetic untreated rats compared to the control non-diabetic group. The induction of curcumin as well as Diamicron to diabetic rats normalized significantly their blood sugar level. Also, curcumin-treated rats indicated significant higher in gene expression of insulin and insulin receptor than positive and negative controls.ConclusionThe results suggest that nano-curcumin could be used as antidiabetic therapy, induced hypoglycemia, and increase the gene expression of insulin and insulin receptor in STZ-induced diabetic rats. More studies are needed to illustrate the definite mechanism of action of nano-curcumin concerning the upregulation of gene expression of the above-mentioned genes.

Impaired insulin signaling in the B10.D2-Hc0 H2d H2-T18c/oSnJ mouse model of complement factor 5 deficiency.

Given the chemoattractant potential of complement factor 5 (C5) and its increased expression in adipose tissue (AT) of obese mice, we determined whether this protein of the innate immune system impacts insulin action. C5 control (C5cont) and spontaneously C5-deficient (C5def, B10.D2-Hc0 H2d H2-T18c/oSnJ) mice were placed on low- and high-fat diets to investigate their inflammatory and metabolic phenotypes. Adenoviral delivery was used to evaluate the effects of exogenous C5 on systemic metabolism. C5def mice gained less weight than controls while fed a high-fat diet, accompanied by reduced AT inflammation, liver mass, and liver triglyceride content. Despite these beneficial metabolic effects, C5def mice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5def mice also exhibited decreased expression of insulin receptor (INSR) gene and protein, as well as improper processing of pro-INSR. These changes were not due to the C5 deficiency alone as other C5-deficient models did not recapitulate the INSR processing defect; rather, in addition to the mutation in the C5 gene, whole genome sequencing revealed an intronic 31-bp deletion in the Insr gene in the B10.D2-Hc0 H2d H2-T18c/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5cont and C5def mice, indicating an insulin-sensitizing function of C5.

Rice bran oil ameliorates hepatic insulin resistance by improving insulin signaling in fructose fed-rats.

Insulin resistance is an inadequate metabolic response of the peripheral tissue to circulating insulin. It plays an important pathophysiological role in type 2 diabetes mellitus. The purpose of the study was to investigate the molecular effects of rice bran oil (RBO) on the gene expression of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), glucose transporters-4 and 5 (GLUT-4 and 5) in insulin-resistant rats induced by high fructose diet (HFD). Rats were divided into six groups (10 rats each) as follows: Groups 1 and 2: rats received a standard diet with corn oil or RBO (as the sole source of fat), respectively. Group 3: animals fed on HFD, which was furtherly divided into 2 sub-groups: rats fed HFD either for one (HFD1) or for 2months (HFD2). Group 4, rats fed HFD containing RBO for 1 month (HFD1 + RBO), while rats in group 5 fed HFD for 30days then RBO was added to the diet for another 30days (HFD2 + RBO). Serum levels of glucose and insulin, as well as hepatic gene expression of insulin receptors and glucose transporters were determined. Livers were isolated for histopathological study. HFD induced insulin resistance with a reduction in the hepatic level of insulin receptor and glucose transporters at both protein and molecular levels. Addition of RBO improved the insulin sensitivity and up-regulated the expression of the tested genes. HFD impaired the insulin sensitivity of the hepatocytes by down-regulating the insulin receptor genes. Addition of RBO alleviated all the hazardous effects.

Glycogen metabolism in mink uterine epithelial cells and its regulation by estradiol, progesterone and insulin

Glycogen content in mink uterine glandular and luminal epithelia (GE and LE) is maximal during estrus and is depleted before implantation while embryos are in diapause. Uterine glycogen synthesis in vivo is stimulated by estradiol (E2) while its mobilization is induced by progesterone (P4). Nevertheless, treatment of an immortalized mink uterine epithelial cell line (GMMe) with E2 did not affect glycogen production. Interestingly, insulin alone significantly increased synthesis of the nutrient and glycogen content in response to insulin + E2 was greater than for insulin alone. Our objectives were to determine: 1) If insulin receptor protein (INSR) is expressed by mink uterine GE and LE in vivo and if the amount differs between estrus, diapause and pregnancy; 2) if E2, P4 or insulin regulate insulin receptor gene (Insr) expression by GMMe cells, and 3) if E2 and P4 act independently to regulate glycogen metabolism by GMMe cells and/or if their effects are mediated in part through the actions of insulin. The mean (±S.E.) percent INSR content of uterine epithelia was greatest during diapause (GE: 15.65 ± 0.06, LE:16.56 ± 1.25), much less during pregnancy (GE: 2.53 ± 0.60, LE:2.25 ± 0.32) and barely detectable in estrus (GE: 0.03 ± 0.01, LE:0.02 ± 0.01). Glycogen concentrations in GMMe cells increased 10-fold in response to insulin and 20-fold with insulin + E2 when compared to controls. Expression of Insr was increased 2-fold by insulin and insulin + E2 when compared to controls and there was no difference between the two hormone treatments, indicating that E2 does not increase Insr expression in insulin-treated cells. To simulate E2-priming, cells were treated with Insulin + E2 for 24 h, followed by the same hormones + P4 for the second 24 h (Insulin + E2 → P4) which resulted in Insr and glycogen levels not different from controls. Similarly, cells treated with Insulin + P4 resulted in glycogen concentrations not different from controls. We conclude that the glycogenic actions of E2 on GMMe cells are due to increased responsiveness of the cells to insulin, but not as a result of up-regulation of the insulin receptor. Glycogen mobilization in response to P4 was the result of decreased glycogenesis and increased glycogenolysis occurring concomitantly with reduced Insr expression. Mink uterine glycogen metabolism appears to be regulated in a reproductive cycle-dependent manner in part as a result of the actions of E2 and P4 on cellular responsiveness to insulin.