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)

Most autoimmune diseases are HLA-associated which supports the notion that they are dependent upon specific immune activation of a limited set of T cell clones. Findings which imply that induction of autoimmune reactivity probably does not differ from normal immune responses are discussed. The possibility of transferring autoimmune disease using T cell clones indicates that target structures for auto-immune attack are also present in healthy individuals. In the present article, it is argued that autoimmune reactions and immunity against nominal conventional antigens in principle are effected and regulated by similar mechanisms. It is assumed that persistent tissue damage occurs if immune attack is directed against tissues that cannot be regenerated, such as in diabetes, or are only slowly reconstituted, such as in rheumatoid arthritis. Normal immune responses are regulated by various inflammatory mediators and cytokines/interleukins. The joint of patients with rheumatoid arthritis is discussed as a model for propagation of immune reactions and tissue destruction in autoimmune disease. Of the different cytokines which are present in the synovial fluid or produced by cells in the synovial tissue, most are presumed to have originated in macrophages/monocytes such as IL-1, IL-6, IL-8, TNF-alpha and TGF-beta. Even so, T cells are believed to have an important role for the continued reactivity associated with autoimmune disease. This discrepancy can be explained in different ways. T cell products might escape detection because they are short-lived, they are immediately consumed or they are produced only during short time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific and non-specific autoreactive immunity. 150 34

To understand mechanisms at the cellular level that may lead to the selective organomegaly seen in fetuses of diabetic mothers, we examined the role of insulin and autocrine-paracrine growth factors in the regulation of hepatic growth in the fetal rat. Analyses of fetal liver from the last one-third of gestation demonstrated the presence of specific mRNAs for the transforming growth factors (TGFs) TGF-alpha and TGF-beta. TGF-alpha, a homologue of epidermal growth factor (EGF), acts through EGF receptors. Levels of mRNA for TGF-alpha increased dramatically postnatally, whereas EGF receptor number increased just before term. In contrast, levels of mRNA for TGF-beta, an inhibitor of epithelial cell growth, were greater in fetal liver than in adult liver, as was TGF-beta-receptor binding. Other analyses demonstrated increases in tyrosine kinase activities of the insulin receptor, EGF receptor, and insulinlike growth factor I receptor as term approached. Proliferation of fetal rat hepatocytes in primary culture did not require mitogens or serum, consistent with production and activity of autocrine-paracrine growth factors. TGF-beta was a potent inhibitor of fetal hepatocyte proliferation in culture, whereas insulin potentiated fetal hepatocyte growth above "mitogen-independent" levels. The regulatory mechanisms controlling fetal hepatic growth involve a complex interaction between stimulatory and inhibitory factors. Growth factor expression, receptor expression, receptor tyrosine kinase activity, and postreceptor signal transmission represent potential loci for insulin action that might be involved in the pathogenesis of fetal macrosomia seen in diabetic pregnancies.
Diabetes 1991 Dec
PMID:Fetal growth factors as determinants of intrauterine hepatic growth. 166 Aug 27

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

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

Dietary protein restriction has been shown to slow the rate of loss of kidney function in humans with progressive glomerulosclerosis due to glomerulonephritis or diabetes mellitus. A central feature of glomerulosclerosis is the pathological accumulation of extracellular matrix within the diseased glomeruli. Transforming growth factor beta 1 (TGF-beta 1) is known to have widespread regulatory effects on extracellular matrix and has been implicated as a major cause of increased extracellular matrix synthesis and buildup of pathological matrix within glomeruli in experimental glomerulonephritis. In the present study, it is shown that administration of a low protein diet to rats rapidly reduces the elevated expression of TGF-beta 1 mRNA and TGF-beta 1 protein that is known to occur within glomeruli after induction of glomerulonephritis. Compared to a normal protein diet, glomerulonephritic rats receiving the low protein diet did not develop an increase in glomerular extracellular matrix and showed significantly less proteinuria. Glomeruli isolated from glomerulonephritic rats fed the normal protein diet showed a marked increase in proteoglycan synthesis on day 7 of disease and were demonstrated to be secreting increased amounts of TGF-beta 1 into the medium, whereas glomeruli at the same point in time isolated from rats on a low protein diet showed no increase in proteoglycan production or TGF-beta 1 secretion. These results suggest that a mechanism of the rapid therapeutic effect of a low protein diet on experimental glomerulonephritis is through suppression of TGF-beta 1 expression and prevention of the induction of extracellular matrix synthesis within the injured glomeruli.
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PMID:Dietary protein restriction rapidly reduces transforming growth factor beta 1 expression in experimental glomerulonephritis. 194 1

Renal cells are a rich source of transforming growth factor (TGF)-beta, and they serve as targets for its actions. Our hypothesis that activation of the TGF-beta system in the kidney is implicated in the development of diabetic renal disease stems from the close similarity of actions of TGF-beta and high ambient glucose on renal cell growth and extracellular matrix metabolism. Proximal tubule cells and glomerular mesangial cells cultured in high glucose concentration express increased TGF-beta 1 mRNA and protein levels, and treatment with anti-TGF-beta antibodies results in prevention of the effects of high glucose to induce cellular hypertrophy and stimulate collagen biosynthesis. Several in vivo studies by different groups of investigators have reported overexpression of TGF-beta in the glomeruli in human and experimental diabetes. We have also observed that the development of renal hypertrophy in the insulin-dependent diabetic BB rat and NOD mouse is associated with increased expression of TGF-beta 1 in the kidney and that short-term administration of antibodies capable of neutralizing the activity of TGF-beta in the streptozotocin mouse model of diabetes results in attenuation of whole kidney and glomerular hypertrophy and overexpression of mRNAs encoding matrix components. Together, these findings are consistent with the hypothesis that the diabetic state stimulates TGF-beta expression in the kidney and that in turn this growth factor may mediate, in an autocrine/paracrine manner, some of the principal early manifestations of diabetic renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Oct
PMID:Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator. 755 48

We have previously reported that the mRNA levels of extracellular matrix (ECM) components including alpha 1(I), alpha 1(III), and alpha 1(IV) collagen chains, laminin B1 and B2 chains, and growth factors including tumor necrosis factor (TNF)-alpha, platelet-derived growth factor (PDGF)-B chain, transforming growth factor (TGF)-beta, and basic fibroblast growth factor (FGF) all increase with age in diabetic glomeruli. The present study was designed to assess whether glomerular expression of these mRNAs in rat diabetic glomeruli is affected by a specific endothelin receptor A antagonist, FR139317. Diabetes was produced by streptozotocin injection, and animals were divided into four groups: untreated diabetic rats, FR139317-treated diabetic rats, control nondiabetic rats, and FR139317-treated control rats. FR139317 treatment was continued for 24 weeks. FR139317 attenuated the rise in creatinine clearance (P < 0.01) and reduced urinary protein excretion (P < 0.01) in diabetic rats, but did not affect blood pressure. FR139317 attenuated the increases in glomerular mRNA levels of alpha 1(I) (P < 0.01), alpha 1(III) (P < 0.01), and alpha 1(IV) (P < 0.01) collagen chains, laminin B1 (P < 0.01) and B2 (P < 0.01) chains, TNF-alpha (P < 0.01), PDGF-B (P < 0.01), TGF-beta (P < 0.001) and basic FGF (P < 0.01) in diabetic rats. However, FR139317 did not affect these mRNA levels in glomeruli of control rats. These findings suggest that FR139317 may be useful in the treatment of diabetic glomerulopathy by reducing mRNA levels of ECM components and growth factors.
Diabetes 1995 Aug
PMID:Effect of a specific endothelin receptor A antagonist on mRNA levels for extracellular matrix components and growth factors in diabetic glomeruli. 762 93

Studies of ocular immunity showed that incubation of peritoneal exudate cells with antigen in the presence of aqueous humor containing TGF-beta, conferred upon them the ability to systemically inhibit antigen-specific cellular immunity when injected into naive recipients. Since cell mediated immunity has been implicated in the destruction of the islets of Langerhans in diabetes, it was theorized that injection of naive diabetes prone BB/W or rats with peritoneal exudate cells pre-cultured in the presence of islet antigen and TGF-beta might similarly inhibit their anti-islet immune reactions and prevent their development of diabetes. 34.2% (13 of 38) of experimental recipient diabetes prone rats developed diabetes while 78.4% (29 of 37; p < 0.0005 compared to experimentals), 72.2% (13 of 18; p < 0.03 compared to experimentals), 68.8% (11 of 16; p < 0.09 compared to experimentals), and 77.7% (7 of 9; p < 0.08 compared to experimentals) of controls receiving peritoneal exudate cells pre-cultured alone, with TGF-beta, with TGF-beta and pheochromocytoma (PC12) cells, or with islets + TGF-beta + anti-TGF-beta antibody, respectively, became diabetic. Experimental treatment did not markedly alter recipient spleen cell subsets, and spleen cells from protected rats did not confer disease protection when transferred into naive recipients. These data demonstrate that the above approach is efficacious and represents a unique strategy for preventing the development of autoimmune type I diabetes in an animal model.
Diabetes Res 1994
PMID:Prevention of diabetes in BB/Wor rats by injection of peritoneal exudate cells cultured in the presence of transforming growth factor beta (TGF-beta) and islet cells. 764 92

Renal hypertrophy is an early feature of diabetes, and it may predispose the kidney to the eventual development of parenchymal dysfunction. Since we have previously demonstrated that short-term culture in high glucose concentration stimulates production of transforming growth factor-beta 1 (TGF-beta 1) in proximal tubular and glomerular mesangial cells, we postulated that this cytokine, which has potent regulatory effects on cellular growth and extracellular matrix production, is important in mediating diabetic renal disease. In this study we evaluated the gene and protein expression of TGF-beta 1 in the kidney of two rodent models of spontaneous insulin-dependent diabetes mellitus [the biobreeding (BB) rat and the nonobese diabetic (NOD) mouse]. In association with the appearance in both models of significant renal hypertrophy, TGF-beta 1 mRNA levels were increased threefold in the kidney of the diabetic BB rat after 3 days of diabetes and also threefold after 7-9 days in the NOD mouse. There was no increase in TGF-beta 1 transcripts in the livers of the diabetic animals, suggesting that this response is tissue specific. Immunohistochemical studies revealed that TGF-beta 1 protein is concordantly elevated in the cortical tubular cells of the diabetic kidney in both models. These results suggest that the stimulated expression of renal TGF-beta is an early manifestation of the involvement of the kidney by diabetes. Whether increased TGF-beta production in the diabetic kidney is a key promoter of diabetic renal manifestations (e.g., hypertrophy) deserves additional studies.
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PMID:Renal hypertrophy is associated with upregulation of TGF-beta 1 gene expression in diabetic BB rat and NOD mouse. 781 Jun 96

The cellular redox state is altered in a number of pathological conditions, including various forms of glomerular injury and diabetes. For example, glucose, via the pentose phosphate pathway generates NADPH, which maintains glutathione (GSH) (part of a major intracellular reducing system) in its reduced state. GSH in turn influences the activity of transcription factors on gene expression. We therefore examined whether changes in cellular GSH influence total collagen synthesis and mRNA levels for collagen I, collagen IV and TGF-beta in SV-40 transformed mouse mesangial cells (MC) maintained in either 5 or 25 mM glucose media. Total intracellular GSH was increased by N-acetylcysteine (NAC; 10 mM) or decreased with the GSH synthesis inhibitor buthionine sulfoximine (BSO; 0.2 mM) in MC. NAC increased 3H-proline incorporation into collagenase-sensitive protein while BSO decreased it under both glucose conditions. The presence of BSO did not reverse the increased collagen synthesis seen in the NAC stimulated cells. Northern blot analysis showed increased mRNA levels for collagen I, collagen IV and TGF-beta in cells grown in high glucose (25 mM). NAC increased the mRNA for all three compounds while BSO alone had no effect on these mRNA levels. However, BSO reversed the increased mRNA levels for collagen I, IV and TGF-beta seen in the presence of NAC. These findings suggest that the cellular redox state may influence gene transcription in MC, and may have implications in explaining injury-associated alterations of mesangial matrix generation.
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PMID:Intracellular glutathione influences collagen generation by mesangial cells. 796 50


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