Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The potential use of embryonic stem (ES) cells for cell therapy of diabetes requires improved methods for differentiation and isolation of insulin-producing beta-cells. The signal transduction protein SHB may be involved in both angiogenesis and beta-cell development. Here we show that cells expressing the pancreatic endodermal marker PDX-1 appear in the vicinity of vascular structures in ES cell-derived embryoid bodies (EBs) cultured in vitro. Moreover, overexpression of SHB as well as culture of EBs in presence of the angiogenic growth factors PDGF or VEGF enhanced the expression of PDX-1 and/or insulin mRNA. Finally, expression of GFP under control of the PDX-1 promoter in EBs allowed for the enrichment by FACS of cells expressing PDX-1, C-peptide, and insulin as determined by immunofluorescence. It is concluded that SHB and angiogenic factors promote the development of cells expressing PDX-1 and insulin in EBs and that such cells can be separated by FACS.
 ...
PMID:SHB and angiogenic factors promote ES cell differentiation to insulin-producing cells. 1663 May 61

Normal blood microvessels are lined by pericytes, which contribute to microvessel development and stability through mechanisms that are poorly understood. Pericyte deficiency has been implicated in the pathogenesis of microvascular abnormalities associated with diabetes and tumors. However, the unambiguous identification of pericytes is still a problem because of cellular heterogeneity and few available molecular markers. Here we describe an approach to identify pericyte markers based on transcription profiling of pericyte-deficient brain microvessels isolated from platelet-derived growth factor (PDGF-B)-/- and PDGF beta receptor (PDGFRbeta)-/- mouse mutants. The approach was validated by the identification of known pericyte markers among the most down-regulated genes in PDGF-B-/- and PDGFRbeta-/- microvessels. Of candidates for novel pericyte markers, we selected ATP-sensitive potassium-channel Kir6.1 (also known as Kcnj8) and sulfonylurea receptor 2, (SUR2, also known as Abcc9), both part of the same channel complex, as well as delta homologue 1 (DLK1) for in situ hybridization, which demonstrated their specific expression in brain pericytes of mouse embryos. We also show that Kir6.1 is highly expressed in pericytes in brain but undetectable in pericytes in skin and heart. The three new brain pericyte markers are signaling molecules implicated in ion transport and intercellular signaling, potentially opening new windows on pericyte function in brain microvessels.
 ...
PMID:Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes. 1680 74

Diabetic nephropathy (DN) is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor-beta1 (TGF-beta-RII), platelet-derived growth factor (PDGF-R), and insulin-like growth factor (IGF1-R). These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACEI) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remain uncertain, we investigated the effect of ACEI on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-beta-RII and activation of IRS1, Erk 1/2, and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACEI stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased ANG II production but also increased bradykinin bioavailability by reducing its degradation. Thus the involvement of the bradykinin pathway was investigated using coadministration of HOE-140, a highly specific nonpeptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACEI were abolished by HOE-140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACEI to reduce albuminuria was also prevented by HOE-140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation.
 ...
PMID:ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats. 1759 23

Pericytes are distinctive regulators of angiogenesis and are adumbrated to provide vessel stability and control of endothelial proliferation. The present article spotlights the persona of pericytes in physiological angiogenesis, recruitment of pericytes and different mechanisms of pericyte depletion. Developing retina appears particularly dependent on pericytes, and pericyte loss is considered as hallmark of early diabetic retinopathies. Several factors are contemplated to be engaged in pericyte conscription including angiopoietin-1 and its receptor tyrosine kinase Tie-2, vascular endothelial growth factor-A and its receptor flk-1 and the platelet-derived growth factor PDGF-B/PDGF-beta system. At present, the mechanisms by which diabetes persuade apoptosis in the retinal microvasculature remain indecisive, albeit oxidative stress, formation of advanced glycation end products , upregulation of protein kinase C, increased polyol pathway flux and focal leukostasis may be important. In this context, accelerated microvascular cell death may become a constructive surrogate end-point in pharmacological studies of experimental diabetic.
Diabetes Obes Metab 2008 Jan
PMID:Importance of pericytes and mechanisms of pericyte loss during diabetes retinopathy. 1794 74

Obesity is a risk factor for asthma. The purpose of this study was to determine whether metformin, an agent used in the treatment of an obesity-related condition (type II diabetes), might have therapeutic potential for modifying the effects of obesity on airway smooth muscle (ASM) function. Metformin acts via activation of AMP-activated protein kinase (AMPK), a cellular sensor of energy status. In cultured murine ASM cells, metformin (0.2-2 mM) caused a dose-dependent inhibition of cell proliferation induced by PDGF (10(-8) M) and serotonin (10(-4) M). Another AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-Driboruranoside (AICAR), also inhibited PDGF-induced proliferation. Furthermore, cells treated with metformin or AICAR, also exhibited an attenuation in the rate of cytoskeletal remodeling, as quantified by spontaneous nanoscale motions of microbeads tightly anchored to the cytoskeleton (CSK) of the ASM cell. ASM cells treated with metformin or AICAR, however, exhibited no appreciable differences in stiffness as measured by optical magnetic twisting cytometry (OMTC) or their abilities to stiffen in response to contractile agonist serotonin. Taken together, these findings suggest that metformin, probably through activation of AMPK, reduces the rate of ongoing reorganization of the CSK and inhibits ASM cell proliferation.
 ...
PMID:Airway smooth muscle proliferation and mechanics: effects of AMP kinase agonists. 1832 Sep 1

Phosphorylation of alpha-tocopherol produces an entity with enhanced antiatherogenic properties. Troglitazone, an alpha-tocopherol derivative of a 2,4-thiazolidinedione nucleus, is an antidiabetic agent that shows fatal idiosyncratic hepatotoxicity, a property not shared by later agents. We investigated the effects of phosphorylation of troglitazone (to yield "phosphoglitazone") on the biochemical pharmacologic properties of troglitazone. We investigated its ability to act as a PPARgamma agonist and to inhibit 2 atherogenic properties of vascular smooth muscle cells (vSMC)-proliferation and proteoglycan synthesis. PPARgamma activity was assessed in a transfection assay. Proliferation was assessed by [H]-thymidine incorporation and cell counting and proteoglycan synthesis by [S]-sulfate incorporation using human vSMCs stimulated with platelet-derived growth factor (PDGF; 50 ng/mL) and transforming growth factor (TGF)-beta (2 ng/mL). Phosphoglitazone was a full agonist for PPARgamma with a potency and efficacy similar to troglitazone. Phosphoglitazone also inhibited cell proliferation and proteoglycan synthesis with potency similar to troglitazone. We conclude that phosphorylation retains the pharmacologic activity of troglitazone while decreasing its lipophilicity and therefore potentially its toxicity. A phosphorylated derivative of a 2,4-thiazolidinedione warrants further investigation as a potential new therapeutic agent for the treatment of insulin resistance and Type 2 diabetes.
 ...
PMID:Phosphorylated troglitazone activates PPARgamma and inhibits vascular smooth muscle cell proliferation and proteoglycan synthesis. 1835 92

3-Hydroxy-3-methyl-glutaryl CoA reductase inhibitors, or statins, have pleiotropic effects and can protect the vasculature in a manner independent of their lipid-lowering effect. The effectiveness of statins in reducing the risk of coronary events has been shown even in patients with diabetes, and their effects on diabetic complications have been reported. Using a model of severe hindlimb ischemia in streptozotocin-induced diabetic mice (STZ-DM), we investigated the effects and mechanisms of statin therapy in diabetic angiopathy in ischemic hindlimbs. As a result, STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Supplementation with statins significantly prevented autoamputation. We previously showed that diabetic vascular complications are caused by impaired expression of PDGF-BB, but statin therapy did not enhance PDGF-BB expression. Statins helped enhance endogenous endothelial nitric oxide (NO) synthase (eNOS) expression. Furthermore, the inhibition of NO synthesis by the administration of N(omega)-nitro-l-arginine methyl ester impaired the ability of statins to prevent STZ-DM mouse limb autoamputation, indicating that the therapeutic effect of statins in hindlimb ischemia in STZ-DM mice occurs via the eNOS/NO pathway. A combination therapy of statins and PDGF-BB gene supplementation was more effective for diabetic angiopathy than either therapy alone. In conclusion, these findings indicate that statin therapy might be useful for preventing intractable diabetic foot disease in patients with diabetic angiopathy.
 ...
PMID:Statins restore ischemic limb blood flow in diabetic microangiopathy via eNOS/NO upregulation but not via PDGF-BB expression. 1844 Dec 6

Bone marrow stem cells participate in tissue repair processes and may have a role in wound healing. Diabetes is characterised by delayed and poor wound healing. We investigated the potential of bone marrow-derived mesenchymal stromal cells (BMSCs) to promote healing of fascial wounds in diabetic rats. After manifestation of streptozotocin (STZ)-induced diabetic state for 5 weeks in male adult Sprague-Dawley rats, healing of fascial wounds was severely compromised. Compromised wound healing in diabetic rats was characterised by excessive polymorphonuclear cell infiltration, lack of granulation tissue formation, deficit of collagen and growth factor [transforming growth factor (TGF-beta), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor PDGF-BB and keratinocyte growth factor (KGF)] expression in the wound tissue and significant decrease in biomechanical strength of wounds. Treatment with BMSC systemically or locally at the wound site improved the wound-breaking strength (WBS) of fascial wounds. The improvement in WBS was associated with an immediate and significant increase in collagen levels (types I-V) in the wound bed. In addition, treatment with BMSCs increased the expression of growth factors critical to proper repair and regeneration of the damaged tissue moderately (TGF-beta, KGF) to markedly (EGF, VEGF, PDGF-BB). These data suggest that cell therapy with BMSCs has the potential to augment healing of the diabetic wounds.
 ...
PMID:Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats. 1859 94

This study compares the efficacy of 0.01% rh-PDGF-BB with standard wound care in 20 patients with diabetes mellitus with neuropathic large plantar ulcers off-loaded with modified total contact cast. The incidence, duration and rate of healing were compared. An accelerated rate of healing in rhPDGF group was observed.
Diabetes Res Clin Pract 2009 Jan
PMID:Which is the better option: recombinant human PDGF-BB 0.01% gel or standard wound care, in diabetic neuropathic large plantar ulcers off-loaded by a customized contact cast? 1908 Nov 56

Homo- and heterodimers of platelet-derived growth factor-A (PDGF-A) and PDGF-B chains are involved through PDGF alpha- and beta-receptors in the growth regulation of multiple normal and tumoural cell types as well as in tumour neovascularization. Since little information is available on the impact of PDGF/PDGF receptors in normal and adenomatous pituitary, we studied the expression and action of this growth factor system in a variety of pituitary tumour cell lines and in rat anterior pituitary cell cultures. By RT-PCR, mRNA expression of PDGF-A and -B chains and of both receptors was found in rat pituitary and mouse folliculostellate TtT/GF pituitary tumour cells. Rat somatotroph MtT-S and mouse corticotroph AtT20 tumor cells expressed only a part of the PDGF/PDGF receptor components whereas mouse gonadotroph alphaT3-1 and rat lactosomatotroph GH3 pituitary tumour cells contained neither PDGF nor PDGF receptors. To further characterize the role of PDGF in TtT/GF cells, the effect of PDGF-AB and -BB on growth and vascular endothelial growth factor-A (VEGF-A) release was studied. Proliferation of TtT/GF cells was weakly but significantly stimulated by PDGF. Both in rat pituitary cell cultures and in TtT/GF cells, PDGF-AB and -BB strongly enhanced VEGF-A secretion. The PI3 kinase inhibitor LY 294002 blocked the increase in VEGF-A. Western immunoblotting confirmed the participation of key components of the PI3 kinase/Akt signal pathway (PDK1, Akt-Ser476) in PDGF-stimulated VEGF production. Thus the PDGF/PDGF receptor system is expressed in folliculostellate cells and is involved in VEGF regulation. Its role in endocrine pituitary tumour cell lines and pituitary adenomas need to be clarified in future studies.
Exp Clin Endocrinol Diabetes 2010 Feb
PMID:Platelet-derived growth factor (PDGF) and PDGF receptor expression and function in folliculostellate pituitary cells. 1937 54


<< Previous 1 2 3 4 5 6 7 8 9 Next >>