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)

Fetal mesenchyme-derived factors are likely to play an important role in pancreatic islet development and growth. We have used primary cultures of human fetal pancreatic tissue to identify growth factors that have morphogenic, mitogenic, and insulinotropic activity. The formation of islet-like cell clusters (ICCs) during a 6-day culture was stimulated two- to threefold by hepatocyte growth factor/scatter factor (HGF/SF) basic fibroblast growth factor (FGF)-2, and to a lesser extent by keratinocyte growth factor (FGF-7) and insulin-like growth factor-II (IGF-II). In contrast, transforming growth factor-beta (TGF-beta) had a strong inhibitory effect. The ICCs formed during HGF/SF stimulation consisted mainly of epithelial cells, whereas FGF-2-induced ICCs were predominantly nonepithelial. Furthermore, although both FGF-2 and HGF/SF increased the total insulin content of the cultures, only HGF/SF increased the insulin content per DNA. Quantitatively, HGF/SF stimulated a 2.3-fold increase in the proportion of insulin-positive cells and a 3-fold higher number of replicating beta-cells. Blocking of the IGF-I receptor inhibited ICC formation but did not affect their insulin content. Immunoneutralizing TGF-beta resulted in increased cell growth and insulin content, indicating the presence of an endogenous inhibitory TGF-beta activity in the model system. Our results suggest that HGF/SF may be an important component of the fetal mesenchyme-derived factors responsible for pancreatic islet development. HGF/SF also may prove valuable for supporting the in vitro growth of islet cells.
Diabetes 1994 Jul
PMID:Hepatocyte growth factor/scatter factor has insulinotropic activity in human fetal pancreatic cells. 801 61

We describe early alterations in rat bladder gene expression which may relate to the development of diabetic bladder dysfunction in a streptozotocin model of inducible diabetes. Utilizing cDNA probes, the gene products sulfated glycoprotein-2 (SGP-2), transforming growth factor-beta (TGF-beta), beta-actin (beta-actin), N-ras and beta nerve growth factor (beta-NGF), were quantitated in bladders of male Sprague-Dawley rats at 1, 2, 4 and 6 weeks after induction of diabetes with streptozotocin (STZ). beta-actin and SGP-2 expression were transiently increased at 1 and 4 weeks after induction, respectively. TGF-beta was not altered over the period of the study. N-ras was reduced at all times compared with control rat bladders. Transcripts encoding beta-NGF were dramatically increased in STZ-treated rats at 4 weeks. None of these changes were seen in diuresis control group fed 5% sucrose. Our results suggest that during the early stages of diabetes, cellular hypertrophy, growth and remodeling are occurring concomitantly with cellular injury and programmed cell death. Furthermore, the transient increase in expression of beta-NGF mRNA may represent a compensatory response to the diabetic condition in an attempt to attract further innervation and revascularization.
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PMID:Early molecular changes associated with streptozotocin-induced diabetic bladder hypertrophy in the rat. 817 58

The actions of transforming growth factor-beta isoforms as potent regulators of growth and differentiation have led to the examination of their presence in the human pancreas. The cellular localization of TGF-beta 1, TGF-beta 2, and TGF-beta 3 was assessed in the normal human pancreas by using immunohistochemical and in situ hybridization techniques. Although cytoplasmic immunoreactivity for TGF-beta 1, TGF-beta 2, and TGF-beta 3 was found in islet cells, acinar cells, and ductal cells, a differential immunostaining pattern for TGF-beta isoforms was observed. In the endocrine pancreas, the islet cells demonstrated diffuse cytoplasmic immunostaining for TGF-beta 1, TGF-beta 2, and TGF-beta 3. However, only TGF-beta 2 and TGF-beta 3 exhibited an intense pattern of immunostaining in a few endocrine cells. Most of the positive islet cells coexpressed insulin. In contrast, in the exocrine pancreas, a greater number of acinar cells showed immunoreactivity for TGF-beta 1 than for TGF-beta 2 and TGF-beta 3. In the ductal cells, all three TGF-beta isoforms showed a similar intensity and pattern of immunostaining and were observed more frequently in the smaller distal ductules than in the larger pancreatic ducts. TGF-beta 1 and TGF-beta 3, but not TGF-beta 2, immunostaining was detected strongly in the smooth muscle cells and weakly in the endothelial cells of the blood vessels, whereas the fibroblasts of the interstitium were completely negative. In situ hybridization revealed that mRNA encoding all three TGF-beta isoforms colocalized with their respective proteins in islets, acinar cells, and ductal cells. In contrast, mRNA expression was absent in the smooth muscle cells and endothelium of the vessels. These results suggest that TGF-beta isoforms may act by both autocrine and paracrine mechanisms in the pancreas. The differential pattern of expression observed for each TGF-beta isoform implies unique roles for these proteins in the regulation of the endocrine and exocrine pancreas.
Diabetes 1993 May
PMID:Synthesis and expression of transforming growth factor beta-1, beta-2, and beta-3 in the endocrine and exocrine pancreas. 848 32

Transgenic mice whose pancreata express transforming growth factor-beta (TGF-beta) directed by an insulin promoter (Ins-TGF-beta mice) were used to assess the effect of local TGF-beta1 on allograft rejection and on autoimmune diabetes occurring as a cross-reaction to viral antigens. Pancreatic TGF-beta1 did not delay allograft rejection, nor did it inhibit autoimmune diabetes after lymphocytic choriomeningitis infection of double transgenic mice (LCMV/TGF-beta1 mice). These results suggest that local TGF-beta1 does not serve as an immunosuppressive agent for allograft rejection or virus-mediated autoimmune diabetes.
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PMID:Transforming growth factor-beta fails to inhibit allograft rejection or virus-induced autoimmune diabetes in transgenic mice. 862 95

We previously reported the generation and characterization of a panel of CD4(+) autoreactive T cell clones that suppress development of autoimmune diabetes in non-obese diabetic (NOD) mice. We showed that the protective capacity of the T cell clones correlated with secretion of an activity that potently inhibits allogeneic mixed lymphocyte reaction (allo-MLR). In this report, we describe the biological characteristics of the allo-MLR inhibitory activity (MLR-IA, short for mixed lymphocyte reaction inhibitory activity) secreted by the protective T cell clone, NOD-5. MLR-IA has little effect on initiation of proliferation in an allo-MLR, but it potently inhibits the maintenance and amplification of the proliferative response. MLR-IA is also capable of inhibiting concanavalin A (Con A) stimulated splenic responder T cell proliferation. MLR-IA is reversible in vitro and is not restricted by MHC class I or II proteins. MLR-IA does not affect IL-2 receptor expression of responding T cells and has no effect on IL-2-dependent proliferation of CTLL-20 T cells. Partially purified MLR-IA inhibits IL-2 production in a primary allo-MLR, and decreases IFN-gamma production during secondary allo-MLR and Con A activation, whereas it enhances IL-4 production in both primary and secondary Con A activation. MLR-IA is not neutralized by combination of antibodies specific for transforming growth factor-beta, IL-10, tumor necrosis factor-alpha/beta or IFN-gamma, suggestive of a novel activity. MLR-IA is ammonium sulfate precipitable, sensitive to protease digestion and is destroyed by boiling, indicating that a protein moiety is part of its active structure. Our work suggests that a potentially novel immunoregulatory activity, capable of inhibiting T lymphocyte proliferation and IFN-gamma production, and stimulating IL-4 production, may regulate development of autoimmune diabetes in NOD mice.
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PMID:Biological characteristics of an immunoregulatory activity secreted by an autoreactive CD4+ T cell clone that suppresses autoimmune diabetes in non-obese diabetic mice. 867 56

Recently a series of non-cyclooxygenase-derived prostanoids were identified in vivo in humans and in animal models of free radical injury as products of free radical-catalyzed peroxidation of arachidonic acid. One of these, an F2-isoprostane, 8-epiprostaglandin F2 alpha (8-epi-PGF 2 alpha), is a potent renal vasoconstrictor and can increase vascular smooth muscle cell (VSMC) DNA synthesis. In the present study we have evaluated whether F2-isoprostanes play a role in diabetic vascular dysfunction by studying the formation of 8-epi-PGF2 alpha in porcine VSMC (PVSMC) cultured under hyperglycemic conditions. 8-Epi-PGF2 alpha levels were quantitated by a specific enzyme immunoassay. We also examined whether certain VSMC growth factors, such as angiotensin II, platelet-derived growth factor, and transforming growth factor-beta, could also regulate the formation of 8-epi-PGF2 alpha. We observed that PVSMC cultured under high glucose (HG) conditions produced significantly higher amounts of 8-epi-PGF2 alpha compared with normal glucose (NG) conditions (3.7 +/- 0.13 ng/10(6) cells in HG vs. 2.9 +/- 0.2 ng/10(6) cells in NG, P < 0.05). Furthermore, all three growth factors tested evoked significant dose-dependent formation of 8-epi-PGF2 alpha (ranging from 125 to 220% of control). These results suggest that 8-epi-PGF2 alpha formation, as a result of hyperglycemia or due to growth factor action, may lead to increased VSMC growth and contribute to the complications of diabetes and cardiovascular disease.
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PMID:Formation of an F2-isoprostane in vascular smooth muscle cells by elevated glucose and growth factors. 876 Jan 71

Endothelial cells are known to secrete various antiproliferative and vasodilating factors. Although injury of endothelial cells has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes, the mechanisms of endothelial injury in diabetes are not yet clarified. Therefore, it is important to know the effects of high glucose on the factors that may influence endothelial cell growth. A novel member of endothelium-specific growth factors, hepatocyte growth factor (HGF), is produced in vascular cells. To investigate the effects of high glucose on vascular cells, we examined 1) the effects of high glucose on endothelial cell and vascular smooth muscle cell (VSMC) growth and 2) the effects of high glucose on local HGF production in endothelial cell and VSMC. Treatment of human aortic endothelial cell with a high concentration of D-glucose, but not mannitol and L-glucose, resulted in a significant decrease in cell number. Interestingly, addition of recombinant HGF attenuated high D-glucose-induced endothelial cell death. Therefore, we measured local HGF secretion of endothelial cell. Importantly, local HGF production was significantly decreased by high D-glucose treatment. In contrast, high D-glucose treatment resulted in a significant increase in the number of human aortic VSMCs, whereas local HGF production was significantly decreased in accordance with increase in D-glucose concentration. No significant changes in numbers were observed in VSMC treated with high mannitol and L-glucose. We also studied the mechanisms of local HGF suppression by high D-glucose. High D-glucose treatment stimulated transforming growth factor-beta (TGF-beta) concentration in endothelial cell and VSMC. Decreased local vascular HGF production was abolished by addition of anti-TGF-beta antibody. As TGF-beta inhibited local HGF production in endothelial cell and VSMC, increased TGF-beta induced by high D-glucose may suppress local HGF production. This study demonstrated that high D-glucose induced endothelial cell death, stimulated VSMC growth, and decreased local HGF production through the stimulation of TGF-beta production both in endothelial cell and VSMC. Overall, decrease in a local endothelial stimulant, HGF, by high D-glucose may be a trigger of endothelial injury in diabetes, potentially resulting in the progression of atherosclerosis.
Diabetes 1997 Jan
PMID:Potential role of an endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes. 897 Oct 94

Several systemic or intrarenal networks of cytokines and growth factors can be modulated by the diabetic state. We summarize the status of the renin-angiotensin system in diabetes mellitus and review the evidence of its involvement in the pathogenesis of diabetic nephropathy. Particular emphasis is placed on the nonhemodynamic properties of this vasoactive agent as both a renal growth factor and a profibrogenic peptide. Antagonizing the effects of angiotensin II with converting enzyme inhibitors is an established protective strategy in the management of diabetic nephropathy even in the absence of systemic hypertension. This and other indirect evidence from experimental animal studies suggest that the intrarenal concentration of angiotensin II may be increased as a result of increased synthesis and despite enhanced breakdown, that this peptide participates in the progression of diabetic nephropathy. However, down-regulation of angiotensin type 1 (AT1)-receptors is one of the abnormalities of both tubules and glomeruli in diabetic renal disease. A heightened bioactivation of the intrarenal angiotensin II system is therefore likely but not certain. Studies in cultured proximal tubular and glomerular mesangial cells have disclosed striking similarities between the effects of high glucose-containing medium and of treatment with angiotensin II on the growth properties and the induction of cytokines in these cells. There may also exist additive effects of angiotensin II and high glucose on signal-transduction pathways, such as activation of protein kinase C, although the contractile response to angiotensin II may be blunted by high glucose in mesangial cells. An important downstream mediator of the effects of both angiotensin II and high glucose is the activation of transforming growth factor-beta that can mediate at least some of the hypertrophic and profibrotic effects of either angiotensin II or high glucose in the diabetic kidney.
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PMID:The role of angiotensin II in diabetic nephropathy: emphasis on nonhemodynamic mechanisms. 900 45

Long-term incubation of proteins with glucose leads to advanced glycation end products (AGEs) with fluorescence and a brown color. We recently demonstrated immunologically the intracellular AGE accumulation in smooth muscle cell (SMC)-derived foam cells in advanced atherosclerotic lesions. To understand the mechanism of AGE accumulation in these foam cells, we have now characterized the interaction of AGE proteins with rabbit-cultured arterial SMCs. In experiments at 4 degrees C, 125I-labeled AGE-bovine serum albumin (AGE-BSA) showed a dose-dependent saturable binding to SMCs with an apparent dissociation constant (Kd) of 4.0 microg/ml. In experiments at 37 degrees C, AGE-BSA underwent receptor-mediated endocytosis and subsequent lysosomal degradation. The endocytic uptake of 125I-AGE-BSA was effectively inhibited by unlabeled AGE proteins such as AGE-BSA and AGE-hemoglobin, but not by acetylated LDL and oxidized LDL, well-known ligands for the macrophage scavenger receptor (MSR). Moreover, the binding of 125I-AGE-BSA to SMCs was affected neither by amphoterin, a ligand for one type of the AGE receptor, named RAGE, nor by 2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole-hexanoic acid-BSA, a ligand for the other AGE receptors, p60 and p90. This indicates that the endocytic uptake of AGE proteins by SMCs is mediated by an AGE receptor distinct from MSR, RAGE, p60, and p90. To examine the functional role of this AGE receptor, the migratory effects of AGE-BSA on these SMCs were tested. Incubation with 1-50 microg/ml of AGE-BSA for 14 h resulted in significant dose-dependent cell migration. The AGE-BSA-induced SMC migration was chemotactic in nature and was significantly inhibited (approximately 80%) by an antibody against transforming growth factor-beta (TGF-beta), and the amount of TGF-beta secreted into the culture medium from SMC by AGE-BSA was sevenfold higher than that of control, indicating that TGF-beta is involved in the AGE-induced SMC chemotaxis. These data suggest that AGE may play a role in SMC migration in advanced atherosclerotic lesions.
Diabetes 1997 Mar
PMID:The receptor for advanced glycation end products mediates the chemotaxis of rabbit smooth muscle cells. 903 4

Orally administered autoantigens suppress autoimmunity in animal models, including experimental allergic encephalomyelitis, collagen and adjuvant-induced arthritis, uveitis, and diabetes in the non-obese diabetic mouse. Low doses of oral antigen induce antigen-specific regulatory T-cells in the gut, which act by releasing inhibitory cytokines such as transforming growth factor-beta, interleukin-4, and interleukin-10 at the target organ. Thus, one can suppress inflammation at a target organ by orally administering an antigen derived from the site of inflammation, even if it is not the target of the autoimmune response. Initial human trials of orally administered antigen have shown positive findings in patients with multiple sclerosis and rheumatoid arthritis. A double-blind, placebo-controlled, phase III multi-center trial of oral myelin in 515 relapsing-remitting multiple sclerosis patients is in progress, as are phase II clinical trials investigating the oral administration of type II collagen in rheumatoid arthritis, S-antigen in uveitis, and insulin in type I diabetes.
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PMID:Oral tolerance for the treatment of autoimmune diseases. 904 67


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