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

Diabetes mellitus is commonly considered as a disease of a scant beta-cell mass that fails to respond adequately to the functional demand. Tyrosine kinases may play a role for beta-cell replication, differentiation (neoformation) and survival. Transfection of beta-cells with DNA constructs coding for tyrosine kinase receptors yields a ligand-dependent increase of DNA synthesis in beta-cells. A PCR-based technique was adopted to assess the repertoire of tyrosine kinases expressed in fetal islet-like structures, adult islets or RINm5F cells. Several tyrosine kinase receptors, such as the VEGFR-2 (vascular endothelial growth factor receptor 2) and c-Kit, were found to be present in pancreatic duct cells. Because ducts are thought to harbor beta-cell precursor cells, these receptors may play a role for the neoformation of beta-cells. The Src-like tyrosine kinase mouse Gtk (previously named Bsk/Iyk) is expressed in islet cells, and was found to inhibit cell proliferation. Furthermore, it conferred decreased viability in response to cytokine exposure. Shb is a Src homology 2 domain adaptor protein which participates in tyrosine kinase signaling. Transgenic mice overexpressing Shb in beta-cells exhibit an increase in the neonatal beta-cell mass, an improved glucose homeostasis, but also decreased survival in response to cytokines and streptozotocin. It is concluded that tyrosine kinase signaling may generate multiple responses in beta-cells, involving proliferation, survival and differentiation.
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PMID:Role of tyrosine kinase signaling for beta-cell replication and survival. 1109 2

Extensive angiogenesis and invasion of the maternal decidua by trophoblasts are essential for the development and function of the placenta. Vascular endothelial growth factors (VEGF), placenta growth factor (PlGF) and their receptors VEGFR-1/Flt-1, VEGFR-2/KDR and VEGFR-3/Flt4 have important roles in vasculogenesis and angiogenesis. We have studied the localization of these proteins by immunohistochemistry and Western blotting in the placenta and of PlGF in maternal serum, and their association with diabetes, pre-eclampsia, fetal growth restriction (FGR) and fetal alcohol syndrome (FAS). VEGFR-1 and VEGFR-3 were detected mainly in the syncytiotrophoblastic layer whereas VEGFR-2 was detected in the vascular endothelial cells of the placenta. VEGFR-1, but not the other receptors, showed increased expression in placental syncytiotrophoblasts from 50% of patients with severe pre-eclampsia and FGR when compared with normal placentas. PlGF was undetectable in 38 of 44 samples of amniotic fluid of mothers with normal and complicated pregnancies. However, maternal serum PlGF concentrations were significantly lower in pre-eclamptic patients and in those with FGR when compared to diabetic women or healthy controls. These results suggest that low maternal serum PlGF and increased placental expression of its receptor VEGFR-1 are associated with pre-eclampsia and FGR.
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PMID:Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentas from normal and complicated pregnancies. 1116 Aug 48

Recent studies provide increasing evidence that postnatal neovascularization involves bone marrow-derived circulating endothelial progenitor cells (EPCs). The regulation of EPCs in patients with coronary artery disease (CAD) is unclear at present. Therefore, we determined the number and functional activity of EPCs in 45 patients with CAD and 15 healthy volunteers. The numbers of isolated EPCs and circulating CD34/kinase insert domain receptor (KDR)-positive precursor cells were significantly reduced in patients with CAD by approximately 40% and 48%, respectively. To determine the influence of atherosclerotic risk factors, a risk factor score including age, sex, hypertension, diabetes, smoking, positive family history of CAD, and LDL cholesterol levels was used. The number of risk factors was significantly correlated with a reduction of EPC levels (R=-0.394, P=0.002) and CD34-/KDR-positive cells (R=-0.537, P<0.001). Analysis of the individual risk factors demonstrated that smokers had significantly reduced levels of EPCs (P<0.001) and CD34-/KDR-positive cells (P=0.003). Moreover, a positive family history of CAD was associated with reduced CD34-/KDR-positive cells (P=0.011). Most importantly, EPCs isolated from patients with CAD also revealed an impaired migratory response, which was inversely correlated with the number of risk factors (R=-0.484, P=0.002). By multivariate analysis, hypertension was identified as a major independent predictor for impaired EPC migration (P=0.043). The present study demonstrates that patients with CAD revealed reduced levels and functional impairment of EPCs, which correlated with risk factors for CAD. Given the important role of EPCs for neovascularization of ischemic tissue, the decrease of EPC numbers and activity may contribute to impaired vascularization in patients with CAD. The full text of this article is available at http://www.circresaha.org.
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PMID:Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. 1144 Sep 84

Neovascularization in the retina and iris of diabetic patients is a major cause of severe visual loss. However, study of these lesions is compromised by the lack of a comparable diabetic rodent model. Because the vasoactive and angiogenic agent, angiotensin II, is involved in diabetic microvascular disease, we aimed to determine whether endothelial cell proliferation could be induced in the retinae and irides of hypertensive transgenic (mRen-2)27 rats that display an enhanced extra-renal renin-angiotensin system (RAS), including the eye. Six-week-old Ren-2, spontaneously hypertensive, and Sprague-Dawley rats received either streptozotocin or control vehicle and were studied for 36 weeks. Additional nondiabetic and diabetic Ren-2 rats were treated throughout with the angiotensin-converting enzyme inhibitor lisinopril (LIS) (10 mg/kg/day in drinking water). Endothelial cell proliferation was only observed in retinae and irides of diabetic Ren-2 rats and was reduced with LIS. In diabetic Ren-2, vascular endothelial growth factor (VEGF) and VEGFR-2 mRNA were increased in retinae and irides and reduced with LIS. Diabetes activated ocular renin in Ren-2 but not Sprague-Dawley rats. The diabetic Ren-2 rat is a model of intraocular endothelial cell proliferation that can be attenuated by RAS blockade via VEGF-dependent pathways. RAS blockade is a potential treatment for vision-threatening diabetic microvascular complications.
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PMID:The renin-angiotensin system influences ocular endothelial cell proliferation in diabetes: transgenic and interventional studies. 1250 98

Angiogenesis is deeply involved in the progression of major diseases such as cancer, diabetes, and rheumatoid arthritis. Molecular mechanism on angiogenesis was extensively studied, and several signaling systems including VEGF (VEGF-A), angiopoietin, PDGF, and ephrin were shown to be crucial for physiological angiogenesis. Interestingly, among these factors, VEGF appears to play key roles in most of the pathological angiogenesis, and other factors are considered to have additional effects on its development depending on the situation. VEGF binds and activates two tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and stimulates endothelial cell growth, survival, and vascular permeability. VEGF induces not only tumor angiogenesis but also blood-vessel-dependent metastasis. Based on the importance of VEGF in diseases, many companies and institutes are now trying to generate appropriate small molecules as well as proteins that strongly antagonize the VEGF-VEGFR system. Several molecules quite effective for suppression of tumorigenesis and pathological angiogenesis in animal models are under clinical trials.
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PMID:VEGF-receptor inhibitors for anti-angiogenesis. 1463 4

Pancreatic islet transplantation is an emerging therapy for type 1 diabetes. To survive and function, transplanted islets must revascularize because islet isolation severs arterial and venous connections; the current paradigm is that islet revascularization originates from the transplant recipient. Because isolated islets retain intraislet endothelial cells, we determined whether these endothelial cells contribute to the revascularization using a murine model with tagged endothelial cells (lacZ knock-in to Flk-1/VEGFR2 gene) and using transplanted human islets. At 3-5 weeks after transplantation beneath the renal capsule, we found that islets were revascularized and that the transplant recipient vasculature indeed contributed to the revascularization process. Using the lacZ-tagged endothelial cell model, we found that intraislet endothelial cells not only survived after transplantation but became a functional part of revascularized islet graft. A similar contribution of intraislet endothelial cells was also seen with human islets transplanted into an immunodeficient mouse model. In the murine model, individual blood vessels within the islet graft consisted of donor or recipient endothelial cells or were a chimera of donor and recipient endothelial cells, indicating that both sources of endothelial cells contribute to the new vasculature. These observations suggest that interventions to activate, amplify, or sustain intraislet endothelial cells before and after transplantation may facilitate islet revascularization, enhance islet survival, and improve islet transplantation.
Diabetes 2004 May
PMID:Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. 1511 2

Placenta growth factor (PlGF) has been implicated in both physiological and pathological angiogenesis; however, little is known about what regulates its expression. In this study, retinal microvascular endothelial cells and pericytes were exposed to varying concentrations of VEGF and glucose and PlGF expression measured by RT-PCR and Western blotting. Both PlGF mRNA and protein were observed in unstimulated microvascular endothelial cells with only weak expression in pericytes. In endothelial cells, VEGF (100 ng/ml) and glucose (15 mM) induced an increase in expression of PlGF at both the mRNA and protein level while no effect was observed for pericytes. The increase in PlGF expression could be totally abolished by blocking VEGFR-2, and in the case of glucose by neutralising VEGF. VEGF-stimulated PlGF expression was largely inhibited by PD 98059, an inhibitor of mitogen-activated protein kinase (MAPK) and partially by GF 109203X, an inhibitor of protein kinase C (PKC), indicating that VEGF up-regulates PlGF expression via the MAPK signalling pathway and partially through PKC. Taken together, our findings suggest that VEGF orchestrates the contribution of PlGF in angiogenesis via more than one intracellular pathway and that hyperglycaemia, as occurs in diabetes, is an important regulator of PlGF expression via VEGF up-regulation.
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PMID:Expression of placenta growth factor is regulated by both VEGF and hyperglycaemia via VEGFR-2. 1550 Dec 43

Podocyte-derived vascular endothelial growth factor (VEGF) is upregulated in diabetes and may contribute to albuminuria. Although believed to act upon the glomerular endothelium, VEGF may have pronounced effects on the podocyte itself. The functionality of this VEGF autocrine loop was investigated in conditionally immortalized mouse podocytes. Exogenous VEGF(164) increased the production of alpha3(IV) collagen, an integral component of the glomerular basement membrane (GBM); this effect was completely prevented by SU5416, a pan-VEGF receptor inhibitor. The VEGF inhibitor also partially prevented the stimulation of alpha3(IV) collagen by transforming growth factor (TGF)-beta1, establishing a novel role for endogenous VEGF. However, VEGF did not influence the production of another novel chain of collagen IV, alpha5(IV) collagen, and SU5416 failed to reverse the known inhibitory effect of TGF-beta1 on alpha5(IV) collagen production. Cultured mouse podocytes possess at least the VEGFR-1 receptor, confirmed by RT-PCR, immunoblotting, and immunocytochemistry. By these techniques, however, VEGFR-2 is absent. VEGF signaling proceeds via autophosphorylation of VEGFR-1 and activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Thus, podocyte-derived VEGF operates in an autocrine loop, likely through VEGFR-1 and PI3K, to stimulate alpha3(IV) collagen production. The TGF-beta1-stimulated endogenous VEGF may have significant implications for podocyte dysfunction in diabetic glomerulopathy, manifesting as GBM thickening and altered macromolecular permeability.
Diabetes 2004 Nov
PMID:Podocyte-derived vascular endothelial growth factor mediates the stimulation of alpha3(IV) collagen production by transforming growth factor-beta1 in mouse podocytes. 1550 75

Placental bed vascular function is compromised in pregnancies complicated by preeclampsia (PE), intrauterine growth retardation (IUGR), and maternal diabetes mellitus (DM). We performed an immunohistochemical analysis of vascular endothelial growth factor (VEGF), its receptors (VEGFR) -1 and -2, and the Tie-1 and -2 receptors in cryostat tissue sections of the placental bed from healthy women (n = 5) and women with PE (n = 5), IUGR (n = 5), and DM (n = 5). VEGF immunoreactivity was stable between the study groups. VEGFR-1 immunoreactivity in the myometrial vascular smooth muscle cells was strongest in the controls. In the myometrial cells, the strongest VEGFR-2 immunoreactivity was seen in women with IUGR. In the decidual vascular endothelial cells, the strongest Tie-1 immunoreactivity was observed in healthy women and in those with DM. Alterations in the placental bed expression of VEGFR-1, VEGFR -2, and Tie-1, but not of VEGF and Tie-2, may be associated with PE, IUGR, or DM.
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PMID:Vascular endothelial growth factor, its receptors, and the tie receptors in the placental bed of women with preeclampsia, diabetes, and intrauterine growth retardation. 1662 96

Diabetes alters microvascular structure and function and is a major risk factor for cardiovascular diseases. In diabetic skeletal muscle, impaired angiogenesis and reduced VEGF-A expression have been observed, whereas in healthy muscle exercise is known to have opposite effects. We studied the effects of type 1 diabetes and combined exercise training on angiogenic mRNA expression and capillarization in mouse skeletal muscle. Microarray and real-time PCR analyses showed that diabetes altered the expression of several genes involved in angiogenesis. For example, levels of proangiogenic VEGF-A, VEGF-B, neuropilin-1, VEGFR-1, and VEGFR-2 were reduced and the levels of antiangiogenic thrombospondin-1 and retinoblastoma like-2 were increased. Exercise training alleviated some of these changes, but could not completely restore them. VEGF-A protein content was also reduced in diabetic muscles. In line with the reduced levels of VEGF-A and other angiogenic factors, and increased levels of angiogenesis inhibitors, capillary-to-muscle fiber ratio was lower in diabetic mice compared to healthy controls. Exercise training could not restore capillarization in diabetic mice. In conclusion, these data illustrate that type 1 diabetes is associated with reduced skeletal muscle capillarization and the dysregulation of complex angiogenesis pathways.
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PMID:Effects of experimental type 1 diabetes and exercise training on angiogenic gene expression and capillarization in skeletal muscle. 1681 23


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