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)

AGEs are nonenzymatically glycosylated adducts of proteins that accumulate in vascular tissues with aging and at an accelerated rate in people with diabetes; AGEs are closely linked to tissue damage due to their high reactivity in protein cross-linking. A macrophage-monocyte receptor system for AGE moieties is shown to mediate the uptake of AGE-modified proteins by a process that also induces cachectin-TNF, IL-1, IGF-I, and PDGF secretion. Thus, in addition to removing senescent glucose-modified proteins and cells, AGE-mediated release of growth-promoting factors may represent a mechanism by which macrophages signal mesenchymal cells the need for replacement of senescent proteins. The age of the macrophage correlates inversely with the binding and removal capacity of the AGE receptor, possibly preventing the clearance of cross-linked proteins and the compounding aging-related tissue damage. In addition to monocyte and macrophages, other cells express similar receptors for AGE-proteins, including endothelial cells, fibroblasts, and mesangial cells. Endothelial cell AGE-receptors mediate transcytosis of AGEs to the subendothelium, induce increased permeability, and enhance endothelium-dependent procoagulant activity. Renal mesangial AGE receptors mediate PDGF-dependent extracellular matrix protein production. Fibroblast AGE receptors may influence cellular proliferation by EGF and EGF-receptor regulation. These findings, in connection with the known abundance of AGEs in aged and diabetic tissues, indicate that AGE-ligand-receptor interactions are crucial for the development of age- and diabetes-related vascular tissue and renal pathology.
Diabetes 1992 Oct
PMID:Receptor-mediated interactions of advanced glycosylation end products with cellular components within diabetic tissues. 132 53

In this series of studies, we have presented evidence for a novel, pancreatic islet-specific growth factor, which we call ilotropin. Ilotropin is acid stable, heat stable, ethanol-precipitable, and sensitive to trypsin digestion. It appears to have a molecular weight between 29 - 44,000, and preliminary data not presented here suggests that it has a relatively basic pI. Unlike many other growth factors, ilotropin does not bind to heparin. Ilotropin is distinguishable from most of the known growth factors on the basis of at least one of the characteristics established in these studies. The apparent molecular weight of 29 - 44,000 eliminates all but the larger growth factors such as PDGF and hepatic growth factor. The fact that ilotropin is acid stable rules out identity with hepatic growth factor, and its lack of binding to heparin and apparent basic pI rules out identity with PDGF. Thus, the combination of characteristics described in these studies eliminates most of the known growth factors as candidates for the role of ilotropin. Certain growth factor precursor molecules (e.g. TGF-a) and several interleukins and cytokines (e.g. pro-IL-1 and melanocyte growth factor) also fall into this molecular weight range. Whether these proteins might be related to ilotropin or play a role in its biological activity remains to be determined. Current studies of ilotropin include further purification to homogeneity, determination of the peptide sequence of ilotropin, and development of an in vitro bioassay using trophic responses of primary cultures of pancreatic duct cells as an indicator of ilotropin activity. With purified material we ought to be able to identify the cells of origin and the target cells for the action of ilotropin, and establish assays to determine the relationship to failure of beta-cell regeneration that accompanies diabetes. Ultimately we hope that ilotropin may lead to new ways of approaching aspects of the problems presented in pancreatic beta-cell failure.
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PMID:The partial isolation and characterization of ilotropin, a novel islet-specific growth factor. 144 77

Neovascularisation is the biological process of forming new blood vessels. Many conditions can initiate neovascularisation including trauma or chronic ischaemia produced by diseases such as diabetes. Neovascularisation proceeds through a series of steps beginning with destruction of the basement membrane surrounding the microvascular endothelial cells, which allows endothelial cells to extend cytoplasmic buds in the direction of chemotactic factors. Migrating endothelial cells elongate, divide and eventually form tube structures which join to form mature new capillaries. Results of in vitro experiments, in vivo experiments, and clinical studies suggest that peptide growth factors can play key regulatory roles in each step of neovascularisation through both direct and indirect actions. At sites of vascular injuries, degranulating platelets release PDGF, IGF-I, EGF, and TGF-beta. Macrophages and neutrophiles drawn into the ischaemic or injured areas synthesise and release TGF-alpha, TGF-beta, and PDGF, and wounded endothelial cells secrete FGF. These peptide growth factors can stimulate migration, mitosis and differentiation of endothelial cells in culture and can induce neovascularisation in animal models. Clinical correlations suggest that peptide growth factors in the vitreous such as IGF-I and bFGF may promote diabetic retinopathy. As the biological mechanisms of neovascular growth factors become better understood, it may be possible to develop therapeutic approaches to selectively inhibit the peptide growth factors which regulate neovascular diseases.
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PMID:Neovascular growth factors. 171 36

Essential hypertension and non-insulin-dependent diabetes mellitus are both associated with hyperinsulinemia and it has been proposed that this might contribute to increased atherogenesis in these conditions. In hypertension, hyperinsulinemia probably reflects reduced insulin-stimulated glucose uptake, but the reason for this, and the contribution of hyperinsulinemia (or of resistance to insulin) to the development of hypertension and atheroma, remains unclear. As well as glucose uptake, insulin has important effects on other aspects of cell function; for example, the hormone is an important regulator of the expression and function of the major inhibitory guanine nucleotide binding protein Gi. In insulin deficiency, Gi levels and function are greatly reduced and are restored by insulin treatment. We have examined whether in human hypertension or in animal models of hypertension there is evidence of abnormal regulation of this protein. Platelet membranes from humans and rat membranes from a range of tissues, including myocardium and vasculature, were studied. No alteration in Gi levels or function was found in these studies, and there is no evidence that this aspect of insulin action on cell function is abnormal. Insulin is also involved in the regulation of cell growth, and in vascular smooth muscle cells there is evidence that this effect involves action of other growth factors, such as PDGF. If the growth regulatory actions of insulin are also unimpaired despite limitation of insulin-stimulated glucose uptake, chronic hyperinsulinemia could lead to increased vascular smooth muscle cell growth and contribute to development of atheroma.
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PMID:Hypertension, insulin, and atherogenesis. 172 42

Sixty thousand to 118,000 lower extremity amputations are performed each year in the United States. The combination of peripheral vascular disease and diabetes mellitus accounts for most cases, with diabetic patients representing 45% to 70% of all nontraumatic, lower extremity amputations. The 3-year survival rate after amputation is only 50%. As podiatric physicians, we are directly involved in limb preservation. Progress has occurred in both the diagnosis and treatment of lower extremity, chronic, nonhealing ulcers. An aggressive, comprehensive amputation intervention program is critical to those patients with refractory wounds to prevent the emotional, functional, and economic costs of limb loss. Recent developments in recombinant growth factors are making it possible to decrease the morbidity and mortality associated with defective angiogenesis, fibroblastic proliferation, collagen remodeling, and epithelial regeneration. Widespread use of growth factors will first occur in topical applications. Absorbable sutures, as well as impregnated bandages, are a likely method of delivering the growth factors to the wound site. Biotechnology companies are developing a stable formulation for bFGF topical application. Clinical trials have begun at various teaching hospitals across the United States for treatment of venous stasis ulcers. U.S. and European firms are collaborating to conduct the clinical studies required to obtain regulatory approvals leading to the sale of topical recombinant bFGF. Although U.S. approval is pending, European use of EFG in the healing of corneal incisions began several years ago. In the future, use of recombinant EGF topically with burn patients may permit earlier reharvesting of healed donor sites as well as coverage of larger graft areas. As some growth factors affect specific processes of healing and cell types, it may be necessary to combine growth factors for complex wounds. PDGF application in combination with other growth factors to incisional wounds may decrease postoperative complications with wound dehiscence while mediating inflammation and repair. In vivo experimental findings suggest that combinations of PDGF and insulin applied topically to wounds may increase the rate of wound repair in diabetics. It is also possible that even the normal healing process may be accelerated, thereby shortening postsurgical convalescence. Approval for internal administration of growth factors will require additional research and thorough clinical trials. The ability of TGF-beta to promote collagen formation may also relate to a metabolic condition such as osteoporosis, in which inadequate formation of collagen or other components of the bone matrix may contribute to pathogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Growth factor impact on wound healing. 193 39

Although lipids have received most attention in relation to atherosclerosis, vessel injury also has a role in the development of atherosclerotic lesions. Thrombi that form at sites of injury can be incorporated into the wall, causing thickening, and platelets that adhere to damaged vessel walls release a growth factor (PDGF) that stimulates smooth muscle cell proliferation. The early lesions of atherosclerosis are focal and develop around vessel orifices and branches in relation to the patterns of blood flow and areas of increased permeability and endothelial cell damage. Platelets also contribute to the complications of advanced atherosclerosis caused by occlusive thrombi, thromboembolism, and spasm. The causes of vessel wall injury are not established, although there is evidence pointing to disturbed blood flow, hypertension, antigen--antibody complexes, complement, materials originating from platelets and white blood cells, bacteria, endotoxin, viruses, smoking, dietary lipids, homocystinemia, diabetes, other metabolic disorders, and stress. Platelets do not adhere to intact endothelium, but they adhere to the constituents of the subendothelium, release the contents of their granules (including PDGF), and form thromboxanes. If blood flow is disturbed, platelet--fibrin thrombi can form at sites of injury. Platelet adherence to a damaged wall does not require von Willebrand factor except under conditions of high wall shear. Repeated injury of a vessel wall leads to the development of lipid-rich atherosclerotic lesions, even in normocholesterolemic animals, but these lesions do not form if the experimental animals are made thrombocytopenic before injury is induced. Measurable changes in platelets that are associated with the clinical complications of atherosclerosis include shortened survival, release of granule contents (platelet factor 4, beta-thromboglobulin, thrombospondin), formation of thromboxanes, and decreased buoyant density. "Antiplatelet drugs" such as aspirin are proving to be beneficial in selected groups of patients, such as those with unstable angina. Thromboxane synthetase inhibitors and agents that block the thromboxane receptor on platelets are under investigation. Long term administration of "antiplatelet drugs" to affect the rate of development of atherosclerosis seems neither feasible nor desirable. Modification of dietary and smoking habits and control of hypertension are more likely to be beneficial for most individuals.
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PMID:The role of platelets in the development and complications of atherosclerosis. 351 36

Despite the availability of various topical agents and of new technics for surgical correction, venous stasis ulcers are still characterized by high recurrent rates. Experimental data from wound healing studies demonstrate stimulation of wound healing after topical application of various growth factors (TGF beta, PDGF, EGF). The results of clinical studies suggest that topical use of an autologous platelet releasate (PDWHF) containing various growth factors accelerates healing. In this prospective study the stimulating effect of autologous PDWHF on epithelialization of small ulcers (group A, < 5000 mm2) and granulation of large ulcers before mesh grafting (> 5000 mm2) will be demonstrated. Inclusion criteria were the venous aetiology of the ulcer and the failure of conventional therapy for 6 month. Exclusion criteria were arterial occlusive disease, diabetes mellitus, acute wound infection, thrombocytopenia and pregnancy. There were 24 patients with 36 ulcers, caused by postthrombotic syndrome in one-third of cases and in two-thirds by severe insufficiency of the perforating veins. The ulcer had been present for more than in 10 years in 38% of cases, while there were 6 circumferential ulcers. The overall ulcer healing rate was 77% after a mean of 14 weeks. In group A 78% of the patients were healed after a mean of 16 weeks. In group B the mesh graft procedure was successful in 90% of the patients after a mean of 13 weeks. Compared with other conventional therapy studies, we achieved a higher healing rate. PDWHF seems to create ideal granulation tissue for mesh graft, indicated by a high uptake of the skin grafts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Ulcus cruris venosum: surgical debridement, antibiotic therapy and stimulation with thrombocytic growth factors]. 776 Jun 47

Evaluations of glomerular mRNA levels encoding for PCNA, TNF-alpha, PDGF-A and -B chains, TGF-beta, IGF-I, bFGF, and EGF were made at 4, 12, and 24 wk after injection of STZ in Sprague-Dawley rats. The mRNA levels for PCNA, TNF-alpha, PDGF-B chain, TGF-beta, and bFGF increased with age in STZ-induced diabetic rats. At 24 wk after STZ injection, mRNA levels for PCNA, TNF-alpha, PDGF-B chain, TGF-beta, and bFGF were increased 3.8-fold, (P < 0.01), 4.2-fold (P < 0.01), 4.0-fold (P < 0.01), 5.2-fold (P < 0.001), and 3.6-fold (P < 0.01), respectively, in the glomeruli of diabetic rats when compared with control rats. In contrast, mRNA levels for IGF-I, PDGF-A chain, and EGF were not altered in glomeruli from diabetic and control rats throughout the experimental period. Insulin treatment partially ameliorated the increase in mRNA levels for PCNA, TNF-alpha, PDGF-B chain, TGF-beta, and bFGF in the glomeruli of diabetic rats. These data indicate that alterations in growth factor mRNA levels in glomeruli may be a manifestation of diabetic nephropathy, and that hyperglycemia or insulin deficiency may play a role in abnormal growth factor gene regulation.
Diabetes 1993 Mar
PMID:mRNA expression of growth factors in glomeruli from diabetic rats. 809 59

Our single channel work has characterized two ion channels capable of depolarizing mesangial cells and activating classic, voltage-activated Ca2+ channels in response to growth-stimulatory peptides (such as Ang II, ET and insulin): (1) Ca(2+)-dependent, 4 pS Cl- channel promoting Cl- efflux; and (2) Ca(2+)-dependent, 27 pS nonselective cation channels promoting cation influx. We have also characterized a third channel which provides an alternative, receptor-operated pathway for Ca2+ entry in response to the growth factor, PDGF: (3) Ca(2+)-permeable, 1 pS cation channel. Consistent with our model of mesangial cell signal transduction (Fig. 1), these three mesangial cell ion channels are activated by binding of growth factors to membrane receptors (Fig. 8). Defective channel regulation, such as occurs in early diabetes mellitus, would promote mesangial cell relaxation and pathogenic glomerular hyperfiltration. Glomerular hyperfiltration and hypertension have been proposed to be major pathogenic factors in renal disease progression [4, 29, 38, 39]. Compensatory renal growth factor responses initially provide adaptive changes in glomerular hemodynamics after loss of functional renal mass. However, chronic stimulation of these mesangial cell ion channels by renal growth factors would promote sustained extracellular Ca2+ entry, resulting in mesangial cell contraction and growth, and progressive decreases in Kf and GFR. Eventually, this process leads to irreversible renal damage due to the development of glomerulosclerosis and interstitial fibrosis.
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PMID:Role of growth factors in mesangial cell ion channel regulation. 856 77

The molecular basis for the clinical association between diabetes mellitus and pancreatic cancer was investigated, using Mia PaCa-2 human pancreatic cancer cells in culture. Advanced glycation endproducts (AGE) prepared with bovine serum albumin and glucose were found to stimulate Mia PaCa-2 cell synthesis of DNA in a dose-dependent manner and also to significantly increase the number of viable cells. Evidence that platelet-derived growth factor-B (PDGF-B) mediates this growth promotion was obtained; AGE upregulated the level of PDGF-B mRNA, and antibodies against PDGF-BB completely neutralized the AGE-induced DNA synthesis. Antisense oligodeoxyribonucleotides complementary to mRNA encoding a receptor for AGE were found to reverse both the PDGF-B upregulation and the AGE-induced DNA synthesis. These results thus indicate that AGE ligand-receptor interactions could play an active part in the progression of pancreatic cancer through the induction of autocrine PDGF-B.
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PMID:Advanced glycation endproducts-receptor interactions stimulate the growth of human pancreatic cancer cells through the induction of platelet-derived growth factor-B. 865 8


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