UNIPROT:P30536 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel controlled release formulation has been developed with PEGylated human insulin encapsulated in PLGA microspheres that produces multi-day release in vivo. The insulin is specifically PEGylated at the amino terminus of the B chain with a relatively low molecular weight PEG (5000 Da). Insulin with this modification retains full biological activity, but has a limited serum half-life, making encapsulation necessary for sustained release beyond a few hours. PEGylated insulin can be co-dissolved with PLGA in methylene chloride and microspheres made by a single o/w emulsion process. Insulin conformation and biological activity are preserved after PEGylation and PLGA encapsulation. The monolithic microspheres have inherently low burst release, an important safety feature for an extended release injectable insulin product. In PBS at 37 degrees C, formulations with a drug content of approximately 14% show very low (< 1%) initial release of insulin over one day and near zero order drug release after a lag of 3-4 days. In animal studies, PEG-insulin microspheres administered subcutaneously as a single injection produced < 1% release of insulin in the first day but then lowered the serum glucose levels of diabetic rats to values < 200 mg/dL for approximately 9 days. When doses were given at 7-day intervals, steady state drug levels were achieved after only 2 doses. PEG-insulin PLGA microparticles show promise as a once-weekly dosed, sustained release basal insulin formulation.
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PMID:PEGylated insulin in PLGA microparticles. In vivo and in vitro analysis. 1591 Oct 45

Recent studies have demonstrated that the transplantation of bone marrow cells following diabetes induced by streptozotocin can support the recovery of pancreatic b-cell mass and a partial reversal of hyperglycemia. To address this issue, we examined whether the c-Met/hepatocyte growth factor (HGF) signaling pathway was involved in the recovery of b-cell injury after bone marrow transplantation (BMT). In this model, donor-derived bone marrow cells were positive for HGF immunoreactivity in the recipient spleen, liver, lung, and pancreas as well as in the host hepatocytes. Indeed, plasma HGF levels were maintained at a high value.The frequency of c-Met expression and its proliferative activity and differentiative response in the pancreatic ductal cells in the BMT group were greater than those in the PBS-treated group, resulting in an elevated number of endogenous insulin-producing cells. The induction of the c-Met/HGF signaling pathway following BMT promotes pancreatic regeneration in diabetic rats.
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PMID:Hepatocyte growth factor is constitutively produced by donor-derived bone marrow cells and promotes regeneration of pancreatic beta-cells. 1595 Jan 93

The regional difference in the contribution of the mucous/glycocalyx layers in rat small intestine, as a diffusional or enzymatic barrier, to the absorption of insulin was investigated by in vitro studies. The mucous/glycocalyx layers from the duodenum, the jejunum, and the ileum in rat were successfully removed without damaging membrane integrity, by exposing them to a hyaluronidase solution in situ. In an in vitro transport experiment, the apparent permeability coefficient (P(app)) of insulin for the hyaluronidase-pretreated group was significantly increased compared to the PBS-pretreated (control) group in all small intestinal regions, and the P(app) of insulin in both PBS- and hyaluronidase-pretreated groups increased in the following order: duodenum < jejunum < ileum. On the other hand, irrespective of small intestinal regions, the P(app) of FD-4 and of antipyrine, respectively the passive para- and transcellular permeation marker, exhibited no significant differences between PBS- and hyaluronidase-pretreated group. In addition, a significant amount of insulin was degraded in the mucous/glycocalyx layers compartment removed by hyaluronidase pretreatment, and the degradation activity in the mucous/glycocalyx layers showed regional differences in the following order: duodenum > jejunum > ileum. These findings suggest that, irrespective of small intestinal regions, the mucous/glycocalyx layers contributed to insulin permeation predominantly as an enzymatic barrier, and not as a diffusional barrier. Furthermore, the variation of the enzymatic activities in the mucous/glycocalyx layers and in the brush-border membrane would be one factor that accounts for the regional differences in the transport of insulin.
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PMID:Region-dependent role of the mucous/glycocalyx layers in insulin permeation across rat small intestinal membrane. 1604 94

Insulin-like growth factor (IGF)-I is a polypeptide that mediates the growth-promoting action of growth hormone in postnatal animals. The present study was conducted to examine whether orally administered IGF-I would be absorbed into the general circulation and also whether ingested IGF-I would enhance the growth of whole body as well as internal organs, and tissues in 3-week-old ICR-strain female weanling mice. In experiment (Exp) 1, a total of 70 mice received IGF-I orally at 1 microg.g-1 in 0.2-ml PBS or the vehicle alone. Concentrations of IGF-I and glucose in heart blood were measured after killing 5 animals in each group every fourth hour during a 24-hour period. In Exp 2, a total of 40 mice received oral IGF-I administration at 1 microg.g-1 or vehicle every third day beginning from day 0 for a 13-day period. Half the animals were killed at day 7 and the other half at day 13. Weights of whole body and organs/tissues (small intestine, liver, thigh muscle, and brain) were measured every day and at slaughter, respectively. In Exp 1, following the oral IGF-I administration, serum IGF-I concentration increased at hour 4 (p<0.01) and returned to the hour 0 level by hour 8, whereas glucose concentration was lowest at hour 4 and returned to the hour 0 level by hour 16. In the PBS-fed group, neither IGF-I nor glucose concentration changed during the 24-hour period. In Exp 2, weight of small intestine increased (p<0.05) in response to the oral IGF-I, whereas weights of liver and thigh muscle of the IGF-I-fed group were greater (p<0.01) and tended to be greater (p=0.06), respectively, than those of the PBS-fed only at day 13. However, brain weight and serum concentrations of IGF-I and IGF-II were not affected by oral IGF-I administration. Results suggest that although orally administered IGF-I mainly acts at the intestine, a portion of ingested IGF-I is absorbed into the general circulation to enhance the growth of selective organs/tissues in weanling mice.
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PMID:Effects of oral administration of insulin-like growth factor-I on circulating concentration of insulin-like growth factor-I and growth of internal organs in weanling mice. 1629 62

Glucagon-like peptide-1 (GLP-1) increases beta-cell function and growth through protein kinase A- and phosphatidylinositol-3-kinase (PI3-K)/protein kinase B, respectively. GLP-1 acts via a G protein-coupled receptor, and PI3-Kgamma is known to be activated by G(betagamma.) Therefore, the role of PI3-Kgamma in the chronic effects of GLP-1 on the beta-cell was investigated using PI3-Kgamma knockout (KO) mice treated with the GLP-1 receptor agonist, exendin-4 (Ex4; 1 nmol/kg sc every 24 h for 14 d). In vivo, glucose and insulin responses were similar in PBS- and Ex4-treated KO and wild-type (WT) mice. However, glucose-stimulated insulin secretion was markedly impaired in islets from PBS-KO mice (P < 0.05), and this was partially normalized by chronic Ex4 treatment (P < 0.05). In contrast, insulin content was increased in PBS-KO islets, and this was paradoxically decreased by Ex4 treatment, compared with the stimulatory effect of Ex4 on WT islets (P < 0.05-0.01). Transfection of INS-1E beta-cells with small interfering RNA for PI3-Kgamma similarly decreased glucose-stimulated insulin secretion (P < 0.01) and increased insulin content. Basal values for beta-cell mass, islet number and proliferation, glucose transporter 2, glucokinase, and insulin receptor substrate-2 were increased in PBS-KO mice (P < 0.05-0.001) and, although they were increased by Ex4 treatment of WT animals (P < 0.05), they were decreased in Ex4-KO mice (P < 0.05-0.01). These findings indicate that PI3-Kgamma deficiency impairs insulin secretion, resulting in compensatory islet growth to maintain normoglycemia. Chronic Ex4 treatment normalizes the secretory defect, thereby relieving the pressure for expansion of beta-cell mass. These studies reveal a new role for PI3-Kgamma as a positive regulator of insulin secretion, and reinforce the importance of GLP-1 for the maintenance of normal beta-cell function.
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PMID:Role of phosphatidylinositol 3-kinasegamma in the beta-cell: interactions with glucagon-like peptide-1. 1657 89

With the aim of developing a serum-free, cell-free culture system for embryo development, in vitro-matured (IVM) and -fertilized (IVF) bovine oocytes were cultured in TCM 199 with the following supplements: 1) BSA alone (10 mg/ml); 2) BSA with ITS (5 mug/ml insulin, 5 mug/ml transferrin and 5 ng/ml selenium; BSAITS medium); 3) estrous cow serum alone (ECS; 10%); or 4) ECS with BOEC (bovine oviduct epithelial cells) (Experiment 1). In Experiment 2, embryos were cultured in BSAITS medium with or without feeding with fresh medium on Day 4 (day of insemination = Day 0). Embryos were evaluated on Day 2 for first cleavage, on Day 7 for morulae and blastocysts, and on Day 8 for blastocysts. Blastocysts from Experiment 1 were frozen in 10% glycerol in PBS, thawed and further cultured in ECS medium with BOEC for 48 h, and evaluated for formation of a distinct blastocoel, or expansion and hatching of blastocysts. In vivo-developed, Grade-1 and Grade-2, 7-d-old embryos served as control for the freezing, thawing and subsequent culture procedures. The percentage of first cleavage did not differ between the treatments (74 to 79% in Experiment 1 and 80 to 83% in Experiment 2). The percentage of blastocysts developed in BSAITS medium did not differ from that in ECS medium whether BOEC were present or not. However, medium with BSA alone had fewer blastocysts than any other culture system (P<0.05). Feeding embryos with fresh BSAITS medium on Day 4 did not lead to any further increase in the proportion of blastocysts. The culture systems had a significant effect on the post-thaw viability of blastocysts developed in them (P<0.001). Blastocysts developed in BSAITS medium had better (P<0.05) viability (14/38) than those from medium with ECS alone (1/27) or with ECS and BOEC (3/37). The post-thaw survival of control embryos was 80% (n=30). One of the three transfers of BSAITS-treated, frozen-thawed blastocysts resulted in a pregnancy. The results indicate that a serum-free, cell-free culture system can support the development of IVM-IVF bovine oocytes up to the blastocyst stage with better viability than a complex co-culture system.
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PMID:A serum-free, cell-free culture system for development of bovine one-cell embryos up to blastocyst stage with improved viability. 1672 56

We report the encapsulation of MIN6 cells, a pancreatic beta-cell line, using thermally induced gelable materials. This strategy uses aqueous solvent and mild temperatures during encapsulation, thereby minimizing adverse effects on cell function and viability. Using a 2:1 mixture of PNIPAAm-PEG-PNIPAAm tri-block copolymer and PNIPAAm homopolymer that exhibit reversible sol-to-gel transition at approximately 30 degrees C, gels were formed that exhibit mechanical integrity, and are stable in H(2)O, PBS and complete DMEM with negligible mass loss at 37 degrees C for 60 days. MTT assays showed undetectable cytotoxicity of the polymers towards MIN6 cells. A simple microencapsulation process was developed using vertical co-extrusion and a 37 degrees C capsule collection bath containing a paraffin layer above DMEM. Spherical capsules with diameters ranging from 500 to 900 microm were formed. SEM images of freeze-dried capsules with PBS as the core solution showed homogenous gel capsule membranes. Confocal microscopy revealed that the encapsulated cells tended to form small aggregates over 5 days, and staining for live and dead cells showed high viability post-encapsulation. A static glucose challenge with day-5 cultured microencapsulated cells exhibited glucose-dependent insulin secretion comparable to controls of free MIN6 cells grown in monolayers. These results demonstrate the potential use of these thermo-responsive polymers as cell encapsulation membranes.
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PMID:Thermally induced gelable polymer networks for living cell encapsulation. 1689 33

Using preadipocyte implantation methods, we recently demonstrated that adipocytes in the visceral area change their function, as the expression of tumor necrosis factor-alpha (TNF-alpha) increases, thereby causing insulin resistance. In order to clarify the mechanism for changes in the function of adipocytes in visceral area, we examined the mRNA expression profiles in visceral fat tissue specimens. Four weeks after cell implantation, we performed a microarray analysis using the RNA of fat tissue specimens implanted either with 3T3-L1 cells or PBS alone. Sixty-three genes were thus isolated and the expression of matrix metalloproteinase-3 (MMP-3) mRNA was found to dramatically increase in the fat tissue specimens. The neutralization of MMP-3 protein inhibited adipogenesis and the free fatty acid-induced TNF-alpha secretion in 3T3-L1 adipocytes. These results suggest a potential role of MMP-3, which promotes the TNF-alpha secretion, thus contributing to the disturbance of the functions in the adipocytes which accumulate in the visceral area.
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PMID:Increased matrix metalloproteinase-3 mRNA expression in visceral fat in mice implanted with cultured preadipocytes. 1701 Mar 13

The present study was conducted to investigate the long-term effects of subchronic elevation of central leptin levels on the expression of corticotropin-releasing factor (CRF) and its types 1 and 2 receptors in the brain of rats subjected to treadmill running-induced stress. PBS or recombinant murine leptin was infused continuously for a period of 5 days into the third ventricle of rats with the aid of osmotic minipumps at a delivery rate of 2 mug/day. On the fifth day of infusion, rats were killed under resting conditions or after a session of treadmill running, which is known to induce a stress response in rats. Leptin treatment significantly decreased food intake, body weight, white adipose tissue weight, glucose and insulin plasma contents, and blunted the treadmill running-induced elevation in plasma levels of corticosterone. Leptin infusion prevented stress-induced de novo synthesis of CRF in the paraventricular hypothalamic nucleus (PVN), which was measured using the intronic probe for CRF heteronuclear RNA. The induction of the type 1 CRF receptor (CRF(1)R) in the PVN and supraoptic nucleus in running rats was also significantly blunted by leptin. In contrast, leptin treatment strongly increased the expression of type 2 CRF receptor (CRF(2)R) in the ventromedial hypothalamic nucleus (VMH). The present results suggest that subchronic elevation of central levels of leptin blunts treadmill running-induced activation of the hypothalamic-pituitary-adrenal axis through the inhibition of activation of the CRFergic PVN neurons, and potentially enhances the anorectic CRF effects via the stimulation of expression of CRF(2)R in the VMH.
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PMID:Regulation of corticotropin-releasing factor and its types 1 and 2 receptors by leptin in rats subjected to treadmill running-induced stress. 1706 1

Administration of autoantigen can be of value for prevention of autoimmune diabetes and it has been speculated that the control point of dendritic cells (DC) for the induction of peripheral tolerance may be highly relevant. We examined the properties of DC associated with immune suppression in NOD mice by insulin injection subcutaneously and the ability of which to suppress diabetes transfer by diabetogenic effector cells in secondary NOD-SCID recipients. Our data showed that the surface expressions of MHC II and CD86 on NOD-derived DC were increased after insulin treatment compared with those on PBS controlled mice. The dendritic cells with a mature phenotype and increased MLR stimulation adoptively transferred immune tolerogenic effects in secondary NOD-SCID mice, which were associated with significant greater IL-10, TGF-beta production and CD4(+)CD25(+)T differentiation from splenocytes compared with NOD-SCID control recipients. Moreover, treatment with DC remarkably decreased the incidence of diabetes in secondary recipients. These results suggest that a subtype of DC generated by insulin subcutaneous treated NOD mice confers potential protection from diabetes through polarizing the immune response towards a Th2 regulatory pathway.
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PMID:Insulin administration confers diabetes-preventive properties to NOD mice derived dendritic cells. 1807 57

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