Insulin Receptor Gene Expression Research Articles

Mitogenic Effect of the Insulin Analogue Glargine in Malignant Cells in Comparison with Insulin and IGF-I

The aim of the study was to investigate if the insulin analogue glargine, with an increased affinity for the IGF-I receptor (IGF-IR), affects the cell growth to a larger extent than human insulin in malignant cells expressing IGF-IRs. The breast cancer cell lines MCF-7 and SKBR-3, and the osteosarcoma cell line SaOS-2 were used. Gene expression was determined by real-time RT-PCR and receptor protein quantified by ELISAs. Receptor phosphorylation was assessed by immunoprecipitation and Western blot. Mitogenic effect was determined as (3)H-thymidine incorporation into DNA. The gene expression of insulin receptor (IR) varied between 4.3-7.5 x 10(-3) and the expression of IGF-IR between 7.7-147.7 x 10(-3) in relation to GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Insulin receptor and IGF-IR protein varied between 2.0-4.1 ng/mg protein and 2.0-40.4 ng/mg protein, respectively. The IGF-IR was phosphorylated by IGF-I at a concentration of 10(-10)-10(-9) M. All three polypeptides stimulated DNA synthesis in MCF-7, SKBR-3, and SaOS-2 cells. SaOS-2 cells were more sensitive to IGF-I than to insulin and glargine. MCF-7 cells were more sensitive to des(1-3)IGF-I than to IGF-I. In SKBR-3 and SaOS-2 cells, glargine tended to be more potent than human insulin to stimulate DNA synthesis. Our results suggest that glargine, compared to human insulin, has little or no increased mitogenic effect in malignant cells expressing IGF-IRs.

Genomic actions of 1,25-dihydroxyvitamin D3 on insulin receptor gene expression, insulin receptor number and insulin activity in the kidney, liver and adipose tissue of streptozotocin-induced diabetic rats

Backgroundthis study set out to examine the effects of the treatment with 1,25-dihydroxyvitamin D3 (1,25D3) [150 IU/Kg (3.75 μg/Kg) one a day, for 15 days] to non-diabetic rats and in rats rendered diabetic by a single injection of streptozotocin [65 mg/kg].Resultstreatment with 1,25D3 to non-diabetic rats did not affect the biochemical parameters measured in the plasma and urine of these animals. Likewise, insulin receptor expression in the kidney, liver, or adipose tissue and insulin-stimulated glucose transport in adipocytes from these animals were not affected either. Treatment with 1,25D3 to streptozotocin-induced diabetic rats did not correct the hyperglycemia, hypoinsulinemia, glycosuria or ketonemia induced by the diabetes, although it partially reversed the over-expression of the insulin receptor gene in the liver and adipose tissue, without altering the normal expression of this gene in the kidney. These effects were accompanied by a normalization of the number of insulin receptors without altering receptor affinity but improving the insulin response to glucose transport in adipocytes from these diabetic animals. Moreover, a computer search in the rat insulin receptor promoter revealed the existence of two candidate vitamin D response element (VDRE) sequences located at -256/-219 bp and -653/-620 bp, the first overlapped by three and the second by four AP-2-like sites.Conclusionthese genomic actions of 1,25D3 could represent beneficial effects associated with the amelioration of diabetes via mechanisms that possibly involve direct transcriptional activation of the rat insulin receptor gene. The candidate VDREs identified may respond to 1,25D3 via activation of the vitamin D receptor, although this remains to be investigated.

Testosterone deficiency impairs glucose oxidation through defective insulin and its receptor gene expression in target tissues of adult male rats

Testosterone and insulin interact in their actions on target tissues. Most of the studies that address this issue have focused on the physiological concentration of testosterone, which maintains normal insulin sensitivity but has deleterious effects on the same when the concentration of testosterone is out of this range. However, molecular basis of the action of testosterone in the early step of insulin action is not known. The present study has been designed to assess the impact of testosterone on insulin receptor gene expression and glucose oxidation in target tissues of adult male rat. Adult male albino rats were orchidectomized and supplemented with testosterone (100 μg/100 g b. wt., twice daily) for 15 days from the 11th day of post orchidectomy. On the day after the last treatment, animals were euthanized and blood was collected for the assay of plasma glucose, serum testosterone and insulin. Skeletal muscles, such as gracilis and quadriceps, liver and adipose tissue were dissected out and used for the assay of various parameters such as insulin receptor concentration, insulin receptor mRNA level and glucose oxidation. Testosterone deprivation due to orchidectomy decreased serum insulin concentration. In addition to this, insulin receptor number and its mRNA level and glucose oxidation in target tissues were significantly decreased ( p < 0.05) when compared to control. However, testosterone replacement in orchidectomized rats restored all these parameters to control level. It is concluded from this study that testosterone deficiency-induced defective glucose oxidation in skeletal muscles, liver and adipose tissue is mediated through impaired expression of insulin and its receptor gene.

Photoperiodic changes in hypothalamic insulin receptor gene expression are regulated by gonadal testosterone

In order to adapt to seasonal changes, animals exhibit robust changes in their reproductive status, body weight, and molt. However, the molecular mechanisms regulating such seasonal changes in physiology and behavior are not fully understood. Here, we report the photoperiodic regulation of the insulin receptor ( IR) gene in the infundibular nucleus (anatomically homologous to the mammalian arcuate nucleus) of the Japanese quail. When the birds were transferred from short-day to long-day conditions, a significant increase in the level of IR mRNA was observed on the 10th long day, whereas that in testicular length was observed on the 5th long day. Castration abolished IR mRNA expression induced by long-day conditions, whereas the testosterone administration mimicked induction of IR mRNA expression induced by long-day conditions. These results suggested that the photoperiodic regulation of the IR mRNA in the infundibular nucleus is mediated by testosterone from the testes. It has been known that the central administration of insulin increases luteinizing hormone (LH) secretion, and neuron-specific disruption of IR gene causes impaired gonadal function due to the dysregulation of LH and increased food intake and body weight. Together with these results, the photoperiodic regulation of the IR mRNA in the hypothalamus may enhance the effect of long days in the seasonal response of reproduction and body weight changes.

Innate Immune Pathway Links Obesity to Insulin Resistance

See related article, pages 1589–1596 The prevalence of obesity, especially among adolescents, has increased considerably over the past 20 years because of increased caloric intake and reduced physical activity. It has been estimated that 20% of the world’s population is overweight and nearly 300 million are obese (BMI >30 kg/m2).1,2 Excess body weight and obesity are associated with the development of metabolic syndrome and type II diabetes, both of which are associated with insulin resistance and increased risk of cardiovascular complications.1,2 Atherothrombotic vascular disease, resulting from a complex interplay between dyslipidemia and vascular immunoinflammatory processes, is responsible for a majority of the excess morbidity and mortality that characterizes metabolic syndrome and type II diabetes.1,2 Several studies have shown that obesity is associated with activation of inflammatory pathways and that inflammatory responses are associated with impaired insulin signaling and insulin resistance.3–8 Considerable progress has been made in the last 2 decades in our understanding of molecular events that link obesity to inflammation, insulin resistance, type II diabetes, and enhanced vascular disease. Obesity-mediated skeletal muscle insulin resistance has been linked to defects in cellular signaling events triggered by insulin.3–8 In obesity, the skeletal muscle levels of several kinases such as protein kinase C isoforms (PKC), I Kappa B Kinase-β …

Involvement of insulin and growth hormone (GH) during follicular development in the bovine ovary

Insulin and growth hormone (GH) play critical roles in the process of follicular development and maturation. However, the involvement of insulin receptor (IR) and GH receptor (GHR) during follicular development is not well understood. The aim of this study was to investigate the expression of IR and GHR mRNAs in the granulosa cells (GCs) and theca tissues (TCs) of the follicle at different developmental stages (preovulatory dominant follicles, POFs; estrogen-active dominant follicles, EADs; estrogen-inactive dominant follicles, EIDs; and small follicles, SFs), and second, to examine the effects of follicle-stimulating hormone (FSH) and estradiol (E2) on the expression of IR and GHR genes in cultured bovine GCs. Although the concentration of insulin in follicular fluid (FF) was constant at all developmental stages, the GH concentration in FF was significantly increased in the EAD and POF compared with the EID. IR mRNA in GCs and TCs was significantly increased in the POF compared with other follicles. Regarding GHR expression, significant increases of mRNA expression were observed in GCs of EAD compared to those of SF, EID and POF. GHR mRNA in TCs was significantly decreased in the SF compared with other follicles. In cultured GCs, FSH, but not E2, stimulated the expression of IR and GHR genes. Our results suggest that the increase in the expression of GHR may be a turning point for follicles to enter the ovulatory phase during final follicular development and that the insulin system may support the maturation of preovulatory follicles.

Fatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase Cε

It is known that free fatty acid (FFA) contributes to the development of insulin resistance and type2 diabetes. However, the underlying mechanism in FFA-induced insulin resistance is still unclear. In the present investigation we have demonstrated that palmitate significantly (p < 0.001) inhibited insulin-stimulated phosphorylation of PDK1, the key insulin signaling molecule. Consequently, PDK1 phosphorylation of plasma membrane bound PKCε was also inhibited. Surprisingly, phosphorylation of cytosolic PKCε was greatly stimulated by palmitate; this was then translocated to the nuclear region and associated with the inhibition of insulin receptor (IR) gene transcription. A PKCε translocation inhibitor peptide, εV1, suppressed this inhibitory effect of palmitate, suggesting requirement of phospho-PKCε migration to implement palmitate effect. Experimental evidences indicate that phospho-PKCε adversely affected HMGA1. Since HMGA1 regulates IR promoter activity, expression of IR gene was impaired causing reduction of IR on cell surface and that compromises with insulin sensitivity.

Molecular mechanism of insulin resistance

Free fatty acids are known to play a key role in promoting loss of insulin sensitivity,thereby causing insulin resistance and type 2 diabetes.However,the underlying mechanism involved is still unclear.In searching for the cause of the mechanism,it has been found that palmitate inhibits insulin receptor (IR)gene expression,leading to a reduced amount of IR protein in insulin target cells. PDK1-independent phosphorylation of PKC(eta) causes this reduction in insulin receptor gene expression.One of the pathways through which fatty acid can induce insulin resistance in insulin target cells is suggested by these studies.We provide an overview of this important area,emphasizing the current status.

Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein

The intracerebroventricular (icv) application of streptozotocin (STZ) in low dosage was used in 3-month-old rats to explore brain insulin system dysfunction. Three months following STZ icv treatment, the expression of insulin-1 and -2 mRNA was significantly reduced to 11% in hippocampus and to 28% in frontoparietal cerebral cortex, respectively. Insulin receptor (IR) mRNA expression decreased significantly in frontoparietal cerebral cortex and hippocampus (16% and 33% of control). At the protein/activity level, different abnormalities of protein tyrosine kinase activity (increase in hippocampus), total IR beta-subunit (decrease in hypothalamus) and phosphorylated IR tyrosine residues (increase) became apparent. The STZ-induced disturbance in learning and memory capacities was not abolished by icv application of glucose transport inhibitors known to prevent STZ-induced diabetes mellitus. The discrepancy between reduced IR gene expression and increase in both phosphorylated IR tyrosine residues/protein tyrosine kinase activity may indicate imbalance between phosphorylation/dephosphorylation of the IR beta-subunit causing its dysfunction. These abnormalities may point to a complex brain insulin system dysfunction after STZ icv application, which may lead to an increase in hyperphosphorylated tau-protein concentration. Brain insulin system dysfunction is discussed as possible pathological core in the generation of hyperphosphorylated tau protein as a morphological marker of sporadic Alzheimer's disease.

Photoperiodic regulation of insulin receptor mRNA and intracellular insulin signaling in the arcuate nucleus of the Siberian hamster,Phodopus sungorus

During the last 5 years it has been well established that photoperiod-induced changes in body weight in the seasonal hamster, Phodopus sungorus, are accompanied by a marked seasonal cycle in leptin sensitivity. In the present study, we investigated the possible involvement of insulin signaling in seasonal body weight regulation. We analyzed the expression pattern and relative intensity of insulin receptor (IR), phosphatidylinositol 3-kinase (PI3-kinase), and protein tyrosine phosphatase 1B (PTP1B) mRNAs by in situ hybridization in the brains of juvenile female hamsters acclimated to either long- (LD) or short-day length (SD) for 8 wk, with or without superimposed food deprivation for 48 h. Furthermore, the hypothalamic concentration and distribution of phospho-AKT, a marker of PI3-kinase activity was determined by immunoblotting and immunohistochemistry. Eight weeks of acclimation to SD led to a substantial downregulation of IR, PTP1B gene expression, and phospho-AKT concentration in this brain region, whereas PI3-kinase mRNA was unchanged. Food deprivation induced a decrease in PTP1B and a trend toward lowered IR gene expression in LD but not in SD. Additionally, a striking increase in PTP1B gene expression in the thalamus was observed after food deprivation in both photoperiods. The direction of change in neuronal insulin signaling contrasts to the central catabolic nature of this pathway described in other species. SD-induced reduction in insulin signaling may be due to decline in body fat stores mediated by enhanced central leptin sensitivity. Increased anorexigenic tone of leptin may overwrite central insulin signaling to prevent catabolic overdrive.

Puerarin reduces blood sugar in the diabetic mice and improves hyperlipidemia in rats

The present study was undertaken to observe effects of puerarin (C21H20O9), a component of traditional Chinese drug Gegen (Pueraria root), on hyperlipidemia, blood sugar and sugar tolerance. Methods: 50 male rats were divided into control, hyperlipidemia, hyperlipidemia and Xuezhikang capsule, hyperlipidemia and low dose puerarin, hyperlipidemia and high dose puerarin groups. The hyperlipidemia was induced by high fat diet for 30 days. The levels of serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and HDL/TC were measured. 50 mice were divided into control, diabetes, diabetes and glybenzcyclamide, diabetes and low dose puerarin, diabetes and high dose puerarin groups. The diabetes mice were induced by i.p. alloxan (200mg/kg) for 5 days. Fasting serum sugar, sugar tolerance and insulin receptor gene were measured. The results indicate that puerarin reduced (n=10, P<0.01) levels of serum TG, TC and LDL in rats. Puerarin also increased the level of HDL in rats. It also decreased (n=10, P<0.01) fasting serum sugar in mice and increased (n=10, P<0.01) the sugar tolerance in the diabetic mice. Puerarin increased (n=10, P<0.05) the expression of insulin receptor gene in the diabetic mice. Conclusion: The results suggest that puerarin reduces insulin resistance, and puerarin increasing the expression of insulin receptor gene contributes to its effect of insulin resistance.

Insulin receptor signaling in long-term memory consolidation following spatial learning

Evidence has shown that the insulin and insulin receptor (IR) play a role in cognitive function. However, the detailed mechanisms underlying insulin's action on learning and memory are not yet understood. Here we investigated changes in long-term memory-associated expression of the IR and downstream molecules in the rat hippocampus. After long-term memory consolidation following a water maze learning experience, gene expression of IR showed an up-regulation in the CA1, but a down-regulation in the CA3 region. These were correlated with a significant reduction in hippocampal IR protein levels. Learning-specific increases in levels of downstream molecules such as IRS-1 and Akt were detected in the synaptic membrane accompanied by decreases in Akt phosphorylation. Translocation of Shc protein to the synaptic membrane and activation of Erk1/2 were also observed after long-term memory formation. Despite the clear memory-correlated alterations in IR signaling pathways, insulin deficits in experimental diabetes mellitus (DM) rats induced by intraperitoneal injections of streptozotocin resulted in only minor memory impairments. This may be due to higher glucose levels in the DM brain, and to compensatory mechanisms from other signaling pathways such as the insulin-like growth factor-1 receptor (IGF-1R) system. Our results suggest that insulin/IR signaling plays a modulatory role in learning and memory processing, which may be compensated for by alternative pathways in the brain when an insulin deficit occurs.

Obesity induced during sexual maturation is linked to LDL-triacylglycerols in Yucatan miniature swine

The incidence of childhood obesity is rising dramatically throughout industrialised countries. To evaluate and study the impact of childhood obesity on lipoprotein metabolism, we developed a new animal model of premature obesity. Yucatan mini-pigs aged 4 months were studied over a 12-month period from childhood to adulthood. Animals were divided into two groups: the first group were overfed a Western misbalanced diet; the second group were normally fed a recommended human-type diet. Cholesterol and triacylglycerol concentrations in VLDL-, LDL- and HDL-lipoproteins were followed from baseline to adulthood by fast protein liquid chromatography. At 10 (the end of sexual maturation) and 16 months old (adulthood), liver, visceral and subcutaneous adipose tissues were sampled. Real-time RT-PCR was performed in order to compare apo AI, apo B, apo C-III, PPAR-alpha, insulin receptor and lipoprotein lipase gene expression between groups and ages. Differences between groups were observed only after sexual maturity. Adult overfed mini-pigs had a higher LDL-cholesterol:HDL-cholesterol ratio (P < 0.05; 0.55 (SE 0.06) for overfed v. 0.42 (SE 0.04) for normally fed pigs at the tenth month of the study). In both groups, VLDL-triacylglycerol decreased (P < 0.05). VLDL-triacylglycerol evolution in the overfed group was associated with an increase in LDL-triacylglycerol plasma concentrations (P < 0.05) after sexual maturation. LDL-triacylglycerol concentration in overfed mini-pigs went from an average of 0.28 mmol/l before sexual maturation to reach an average concentration of 0.56 mmol/l afterwards. This phenomenon has never been observed in similar studies when obesity is induced in adult mini-pigs and may represent a specific hallmark of an obesity induced during sexual maturity.

Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

The insulin receptor (IR) occurs as two alternatively spliced isoforms, IR-A (exon 11-) and IR-B (exon 11+), which exhibit functional differences and are expressed in a tissue-specific manner. The IR substrate (IRS) proteins 1, 2 and 3 also differ in function and tissue distribution. Here we show the differential gene expression of IRs and IRSs in several rat target tissues of insulin action. IR-B is significantly higher than IR-A in epididymal white adipose tissue and adipogenesis induces a shift in the alternatively spliced species of IR from the A to the B isoform. Moreover, since aging in the rat is associated with the development of insulin resistance we looked for alterations of expression of these proteins in adipocytes from old rats. Our results reveal that there is a specific decrease in the expression of the IR-B isoform, as well as both mRNA and protein levels of IR, IRS-1 and IRS-3 being significantly decreased, in epididymal adipose tissue from old compared with adult rats. It is concluded that the down-regulation of early components of the insulin transduction pathway in a primary insulin target tissue could be related to the insulin resistance of aging.

IGF-I/insulin hybrid receptors in human endothelial cells

Vascular complications are common in diabetes. IGF-I receptors (IGF-IR) and insulin receptors (IR) in endothelial cells might respond to altered levels of IGF-I and insulin, resulting in altered endothelial function in diabetes. We therefore studied IGF-IR and IR gene expression, ligand binding, receptor protein, and phosphorylation in human umbilical vein endothelial cells (HUVEC). IGF-IR mRNA was more abundant than IR mRNA in freshly isolated HUVEC (IGF-IR/IR ratio 7.1 ± 1.5) and in cultured HUVEC (ratio 3.5 ± 0.51). Accordingly, specific binding of 125I-IGF-I (0.64 ± 0.25%) was higher than that of 125I-insulin (0.25 ± 0.09%). Protein was detected for both receptors and IGF-I/insulin hybrid receptors. IGF-IR phosphorylation was stimulated by 10 −10 to 10 −8 M IGF-I. IR were activated by 10 −9 to 10 −8 M insulin and IGF-I. We conclude that HUVEC express more IGF-IR than IR, and also express hybrid receptors. Both IGF-I and insulin phosphorylate their own receptors but only IGF-I seems to phosphorylate hybrid receptors.

17β-Estradiol transcriptionally represses human insulin receptor gene expression causing cellular insulin resistance

In this study, we demonstrate that 17β-estradiol (E 2) inhibits human insulin receptor (IR) gene expression in a dose- and time-dependent manner in U-937 human promonocytic cells. Using cells transfected with the −1819 to −271 bp fragment of the human IR promoter (wild type promoter) and treated with E 2, we show that this repression is regulated at the transcriptional level. The steroid was also found to diminish the insulin responsiveness of the cells in terms of cell survival, DNA synthesis, glucose transport, and glucose oxidation, this last effect possibly involving reduced phosphatidylinositol 3-kinase (PI3-kinase) activity. These data provide new information on the molecular mechanisms of estrogen-inducing insulin resistance in human cells.

Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells.

Micro- and macroangiopathy are major causes of morbidity and mortality in patients with diabetes. Our aim was to characterize IGF-I receptor (IGF-IR) and insulin receptor (IR) in human micro- and macrovascular endothelial cells. Cultured human dermal microvascular endothelial cells (HMVEC) and human aortic endothelial cells (HAEC) were used. Gene expression was measured by quantitative real-time RT-PCR and receptor protein by ligand-binding assay. Phosphorylation of IGF-IR beta-subunit was analyzed by immunoprecipitation and Western blot. Glucose metabolism and DNA synthesis was assessed using [(3)H]glucose and [(3)H]thymidine incorporation, respectively. We detected gene expression of IGF-IR and IR in HAEC and HMVEC. IGF-IR gene expression was severalfold higher than that of IR. The specific binding of (125)I-IGF-I was higher than that of (125)I-insulin in HAEC and HMVEC. Insulin and the new, long-acting insulin analog glargine interacted with the IGF-IR with thousand- and hundred-fold less potency than IGF-I itself. Phosphorylation of the IGF-IR beta-subunit was shown in HAEC for IGF-I (10(-8) M) and insulin (10(-6) M) and in HMVEC for IGF-I and glargine (10(-8) M, 10(-6) M). IGF-I 10(-7) M stimulated incorporation of [(3)H]thymidine into DNA, and 10(-9)-10(-7) M also the incorporation of [(3)H]glucose in HMVEC, whereas glargine and insulin had no significant effects at 10(-9)-10(-7) M. Human micro- and macrovascular endothelial cells express more IGF-IR than IR. IGF-I and high concentrations of glargine and insulin activates the IGF-IR. Glargine has a higher affinity than insulin for the IGF-IR but probably has no effect on DNA synthesis at concentrations reached in vivo.

Gene expression and tyrosine kinase activity of insulin receptor in uterine leiomyoma and matched myometrium.

Our objective was to determine the insulin receptor (IR) mRNA levels and IR tyrosine kinase activity in normal myometrium and leiomyoma. Experimental study. Academic research center. Five women with leiomyoma submitted to hysterectomy. Plasma membrane fraction of human myometrium and leiomyoma were prepared and samples were incubated with and without insulin. mRNA was isolated and RT-PCR with specific primers was performed. Western blots of plasma membranes incubated with and without insulin were performed. Chemoluminescent methods followed by densitometry were used to assess IR autophosphorylation. RT-PCR with specific primers for IR gene sequences was used to determine IR mRNA levels. IR mRNA levels in myometrium (0.634+/-0.038) and in leiomyoma (0.649+/-0.047; p=0.813) were not different. The degree of insulin-stimulated IR autophosphorylation (relative optical density of the 95 kDa band) was also not different between myometrium (1.496+/-0.310) and leiomyoma (1.593+/-0.129; p=0.650). There was no difference in IR receptor expression and IR autophosphorylation between normal myometrium and leiomyoma. Other steps of insulin signaling chain may participate in the altered proliferation of leiomyomas.

Signaling cross-talk between hypoxia and glucose via hypoxia-inducible factor 1 and glucose response elements

The substrates oxygen and glucose are important for the appropriate regulation of metabolism, angiogenesis, tumorigenesis and embryonic development. The knowledge about an interaction between these two signals is limited. We demonstrated that the regulation of glucagon receptor, insulin receptor and L-type pyruvate kinase (L-PK) gene expression in liver is dependent upon a cross-talk between oxygen and glucose. The periportal to perivenous drop in O2 tension was proposed to be an endocrine key regulator for the zonated gene expression in liver. In primary rat hepatocyte cultures, the expression of the glucagon receptor and the L-PK mRNA was maximally induced by glucose under arterial pO2 whereas the insulin receptor was maximally induced under perivenous pO2. It was demonstrated for the L-PK gene that the modulation by O2 of the glucose-dependent induction occured at the glucose-responsive element (GlcPKRE) in the L-PK gene promoter. The reduction of the glucose-dependent induction of the L-PK gene expression under venous pO2 appeared to be mediated via an interference between hypoxia-inducible factor 1 (HIF-1) and the glucose-responsive transcription factors at the GlcPKRE. The glucose response element (GlcRE) also functioned as a hypoxia response element and, vice versa, a hypoxia-responsive element was functioning as a GlcRE. Thus, our findings implicate that the cross-talk between oxygen and glucose might have a fundamental role in the regulation of several physiological and pathophysiological processes.

Effects of pregnancy on insulin receptor in liver, skeletal muscle and adipose tissue of rats

The mechanism responsible for insulin resistance during pregnancy remains unclear. Considerable evidence indicates that the insulin receptor plays an important role in insulin sensitivity. It seems possiblethat the hormonal milieu during gestation could have an effect on the insulin receptor. In the present study, measurements of tyrosine phosphorylation and protein content of the insulin receptor and expressionof its gene in liver, skeletal muscle and adipose tissue indicate that during pregnancy significant changes occur in these parameters. We found that at the end of early gestation (day 10), muscle and adiposetissue are very sensitive to insulin action because the amount, phosphorylation and gene expression of insulin receptor is higher than in late gestation (days 15–20), while the tissue which is mostsensitive to insulin action in late gestation is the liver. Our hypothesis is that these results are connected with changes in the concentrations of estradiol and progesterone observed during pregnancy.In conclusion, our previous and present findings seem to demonstrate that the different concentrations of gestational hormones play an important role in insulin sensitivity in this period and that eachtissue responds in the most appropriate manner to guarantee the gestation in its entirety.