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 a leading cause of end-stage renal disease in the Western world. Histologically, mesangial expansion with increased extracellular matrix protein is observed in patients with diabetic nephropathy. Because transforming growth factor (TGF)-beta promotes extracellular matrix production in response to high glucose, TGF-beta is considered to play a central role in the pathogenesis of diabetic nephropathy. We investigated the association of TGF-beta1 T29C polymorphism and the progression of diabetic nephropathy. Forty patients with type 2 diabetes mellitus were enrolled. All patients had had diabetes for more than 10 years. DNA was extracted from peripheral blood cells, and genotype was determined using real-time polymerase chain reaction method. Patients were classified into three groups according to genotype: TT, TC, and CC. Grade of diabetic nephropathy was determined using the amount of urinary excretion of albumin. Demographic characteristics of the patients with each genotype were not statistically different. No differences in the glycemic control and the mode of therapy were observed. Among patients with three genotypes, the severity of diabetic nephropathy was not statistically different. The patients with TT genotype tended to have a higher rate of progression of nephropathy; however, no statistically significant difference was observed among the three groups. Our results suggest that TGF-beta1 T29C polymorphism is not associated with the progression of diabetic nephropathy. Further studies are required to determine the exact role of this polymorphism in the progression of diabetic nephropathy.
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PMID:Association of transforming growth factor-beta1 T29C polymorphism with the progression of diabetic nephropathy. 1157 51

In recent years there has been an effort to understand possible noncalcemic roles of vitamin D, including its role in the immune system and, in particular, on T cell-medicated immunity. Vitamin D receptor is found in significant concentrations in the T lymphocyte and macrophage populations. However, its highest concentration is in the immature immune cells of the thymus and the mature CD-8 T lymphocytes. The significant role of vitamin D compounds as selective immunosuppressants is illustrated by their ability to either prevent or markedly suppress animal models of autoimmune disease. Results show that 1,25-dihydroxyvitamin D3 can either prevent or markedly suppress experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease. In almost every case, the action of the vitamin D hormone requires that the animals be maintained on a normal or high calcium diet. Possible mechanisms of suppression of these autoimmune disorders by the vitamin D hormone have been presented. The vitamin D hormone stimulates transforming growth factor TGFbeta-1 and interleukin 4 (IL-4) production, which in turn may suppress inflammatory T cell activity. In support of this, the vitamin D hormone is unable to suppress a murine model of the human disease multiple sclerosis in IL-4-deficient mice. The results suggest an important role for vitamin D in autoimmune disorders and provide a fertile and interesting area of research that may yield important new therapies.
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PMID:Vitamin D: its role and uses in immunology. 1172 33

Viral and nonviral gene therapy vectors have been successfully employed to deliver inflammatory cytokine inhibitors (anticytokines), or anti-inflammatory cytokines, such as transforming growth factor beta-1 (TGF-beta 1), which protect against experimental autoimmune diseases. These vectors carry the relevant genes into a variety of tissues, for either localised or systemic release of the encoded protein. Administration of cDNA encoding soluble IFN-gamma receptor (IFN-gamma R)/IgG-Fc fusion proteins, soluble TNF-alpha receptors, or IL-1 receptor antagonist (IL-1ra), protects against either lupus, various forms of arthritis, autoimmune diabetes, or other autoimmune diseases. These inhibitors, unlike many cytokines, have little or no toxic potential. Similarly, TGF-beta 1 gene therapy protects against numerous forms of autoimmunity, though its administration entails more risk than anticytokine therapy. We have relied on the injection of naked plasmid DNA into skeletal muscle, with or without enhancement of gene transfer by in vivo electroporation. Expression plasmids offer interesting advantages over viral vectors, since they are simple to produce, non-immunogenic and nonpathogenic. They can be repeatedly administered and after each treatment the encoded proteins are produced for relatively long periods, ranging from weeks to months. Moreover, soluble receptors which block cytokine action, encoded by gene therapy vectors, can be constructed from non-immunogenic self elements that are unlikely to be neutralised by the host immune response (unlike monoclonal antibodies [mAbs]), allowing long-term gene therapy of chronic inflammatory disorders.
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PMID:Anticytokine gene therapy of autoimmune diseases. 1172 11

Increased expression of transforming growth factor beta-1 (TGF-beta 1) and glucose transporter (GLUT1) has been implicated in the genesis of diabetic nephropathy. The aim of this study was to evaluate GLUT1 protein levels in the renal cortex of a rat model of diabetes as well as its relationship to urinary albumin and TGF-beta1. Streptozotocin-injected rats (n = 13) and controls (n = 13) were compared for their urinary albumin, and TGF-beta 1 and for renal cortical and medullar GLUT1 protein abundance. GLUT1 protein content was determined by optical densitometry after Western blotting using an anti-GLUT1 antibody; urinary albumin was measured using electroimmunoassay, urinary TGF-beta 1 using ELISA. Forty-five days of diabetes resulted in increased albuminuria (p < 0.05), urinary TGF-beta 1 (p < 0.05) and GLUT1 protein abundance (p < 0.05). There was a positive correlation between urinary TGF-beta 1 and plasma glucose levels (r = 0.65, p < 0.05) and albuminuria (r = 0.72, p < 0.05). We concluded that 45 days of diabetes result in incipient diabetic nephropathy and increased cortical GLUT1 protein abundance. We speculate that the higher cortical GLUT1 protein levels in diabetes may amplify the effects of hyperglycemia in determining higher intracellular glucose in mesangial cells, thereby contributing to diabetes-related kidney damage.
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PMID:Increased renal GLUT1 abundance and urinary TGF-beta 1 in streptozotocin-induced diabetic rats: implications for the development of nephropathy complicating diabetes. 1173 69

To examine humoral and mucosal immune responses to food antigens and their relation to the pathophysiology of type 1 diabetes mellitus, IgA and IgG antibodies to cow's milk antigens (bovine serum albumin (BSA) and beta-lactoglobulin (BLG)) and another food antigen (ovalbumin, (OVA)) in human serum were assessed by enzyme-linked immunosorbent assay (ELISA). If anti-idiotype antibodies to the antibodies were present in serum, they might interfere with the ELISA assay, so suitable microtiter plates were employed to minimize such interference. The levels of IgA and IgG antibodies to the above antigens (P<0.001-P<0.01) and the prevalence of positive sera (P<0.001-P<0.05) in the patient group (n=52, aged 14.5+/-4.1 (S.D.) years) were significantly higher than those in the control group (n=41, aged 13.3+/-6.8 (S.D.) years). Interestingly, the levels of IgA antibodies to all the food antigens examined were elevated in 26 (50%) patients, while the elevation was seen in 3 (7%) healthy controls. The elevation of IgA antibodies in the patients was well correlated with increased concentrations of IgA and transforming growth factor (TGF)-beta, which induces IgA-producing B-cells, in serum. Although the cytokine TGF-beta is secreted from regulatory T-cells (Th3), and is related to oral tolerance, the interleukin-2 (IL-2, Th1)/IL-4 (Th2) ratio in the patient group was significantly elevated (P<0.001), which might indicate that the oral tolerance is impaired in patients. Thus, we demonstrated that both IgA and IgG antibodies to several food antigens are elevated in patients. We suggest that impairment of oral tolerance might be related to the pathogenesis of type 1 diabetes mellitus.
Diabetes Res Clin Pract 2002 Jan
PMID:Antibodies to food antigens in Japanese patients with type 1 diabetes mellitus. 1175 73

Prepubertal years of diabetes mellitus are relatively protected from clinical manifestations of nephropathy. Transforming growth factor-beta1 (TGF-beta1) is a major mediator of diabetic kidney disease. Its renal expression, translation, and activation change with sexual maturation in the normal rat. The role of TGF-beta1 in postpubertal susceptibility to diabetic renal hypertrophy was addressed in the present study. Male Sprague- Dawley rats were given streptozocin at 4 weeks of age (weanling) or 14 weeks of age (mature) and treated with insulin to maintain blood glucose levels between 300 and 500 mg/dl. Nondiabetic controls received saline. After 6 weeks with ad libitum food and water, kidneys were snap-frozen for measurement of TGF-beta1 protein and mRNA. As in previous studies, diabetic renal hypertrophy was blunted in weanling animals compared with mature rats. Message for TGF-beta1 was not significantly increased in weanling animals [102 (9)% [mean (SEM)] in nondiabetic controls versus 117 (10)% in diabetic rats; P=0.91], while it was significantly increased in mature diabetic animals [100 (7)% vs. 146 (11)%; P=0.01]. Immunohistochemistry revealed focal increases in glomerular staining in mature but not weanling diabetic rats. Differences in the control of the renal TGF-beta system may explain the permissive role of puberty in the manifestations of diabetic kidney disease.
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PMID:Puberty permits increased expression of renal transforming growth factor-beta1 in experimental diabetes. 1179 95

Adequate glycemic control protects most patients with diabetes from nephropathy, but a substantial fraction of patients develop progressive disease despite lowering glycemia. We isolated mesangial cells (MC) from the glomeruli of mouse strains that model these two outcomes in patients with diabetes, namely those that have the propensity (ROP) or resistance (B6) to develop progressive diabetic nephropathy. We determined the nature and reversibility of changes in selected extracellular matrix-related molecules after chronic exposure to elevated glucose concentration. MC were exposed to 25 mmol/l glucose for 5 weeks followed by 6 mmol/l glucose and 19 mmol/l mannitol for an additional 5 weeks. Matrix metalloproteinase-2 (MMP-2) and transforming growth factor-beta(1) (TGF-beta(1)) levels increased in B6 MC exposed to 25 mmol/l glucose but returned to baseline levels when the glucose concentration was reduced to 6 mmol/l. MMP-2 and TGF-beta(1) were higher in ROP MC at baseline and increased in response to 25 mmol/l glucose, but remained elevated when glucose concentration was reduced. Type I collagen expression and accumulation increased in a reversible manner in B6 MC exposed to 25 mmol/l glucose. However, type I collagen expression was higher in ROP MC at baseline and remained unaffected by changes in glucose concentration. Thus, 25 mmol/l glucose induced reversible changes in MMP-2, TGF-beta(1), and type I collagen in MC of sclerosis-resistant mice but not in MC from sclerosis-prone mice. Therefore, progressive diabetic nephropathy may be secondary to stable alterations in the phenotype of MC as a result of the interplay between the genetic background and elevated glucose concentrations.
Diabetes 2002 Feb
PMID:Reversibility of glucose-induced changes in mesangial cell extracellular matrix depends on the genetic background. 1181 61

To date much of the recent work on pathological angiogenesis has focused on inflammatory diseases, diabetes and cancer in particular. Hereditary hemorrhagic telangiectasia or Rendu-Osler-Weber disease provides an example of the genetic disorder of angiogenesis in which a multisystemic angiodysplasia is responsible for severe hemorrhage. The disease pathogenesis is partially explained by a defect in the TGF-beta signaling system, although in more recent works a possible role of other vascular growth factors has been proposed. This paper provides a model of an aberrant angiogenesis in which multiple vascular growth factors could be involved in a diffuse angiodysplasia.
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PMID:Angiogenesis and hereditary hemorrhagic telangiectasia. Rendu-Osler-Weber disease. 1181 19

Overproduction of transforming growth factor (TGF)-beta 1 messenger RNA is of fundamental importance in the pathogenesis of diabetic nephropathy. In vitro studies have recently shown that the serine protease trypsin diminishes the enhanced TGF-beta 1-expression induced by advanced glycation end products. Moreover, proteolytic enzymes may accelerate the removal of TGF-beta 1 from renal tissue via a protease-induced activation of alpha 2-macroglobulin (alpha 2M). This activation results in the binding of numerous cytokines, including TGF-beta 1 and is followed by enhanced plasma clearance of the protease alpha 2M-cytokine complex. In the present study in streptozotocin-diabetic rats we investigated whether the administration of Phlogenzym, a fixed combination of the proteases trypsin and bromelain combined with the antioxidant rutosid, modulates renal hypertrophy and the formation of TGF-beta 1 in isolated glomeruli. Three weeks after induction of diabetes, renal hypertrophy developed with an enhanced kidney/body weight ratio. When compared with normal rats, an elevated content of intraglomerular TGF-beta 1 (44.25 +/- 21.9 vs. 71.1 +/- 23.4 ng/microgram DNA, p < 0.05) as well as fibronectin (2.62 +/- 0.49 vs. 3.42 +/- 0.62 ng/microgram DNA, p < 0.05) was observed. In the diabetic rats, treatment with intraperitoneal proteases prevented the rise of intraglomerular TGF-beta 1 content (34.9 +/- 22.2 ng/microgram DNA, p < 0.01) and attenuated the rise of fibronectin (3.03 +/- 1.12 ng/microgram DNA NS). Furthermore, a decrease in the kidney/body weight ratio (p < 0.01) was achieved. Protease administration did not affect blood glucose concentration and was without visible adverse effects.
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PMID:Protease administration decreases enhanced transforming growth factor-beta 1 content in isolated glomeruli of diabetic rats. 1182 24

The roles of transforming growth factor (TGF)-beta 1 in vascular proliferation, atherosclerosis, and plaque still remain controversial. TGF-beta 1 has been previously reported to inhibit the proliferation and migration of vascular smooth muscle cells and endothelial cells, in vitro. On the other hand, administration or transgenic overexpression of TGF-beta 1 enhances extracellular matrix synthesis and cellular hyperplasia of the intima and media in the normal artery and injured artery in vivo. We evaluated the correlation of arterial proliferation with plasma levels of TGF-beta 1 and TGF-beta receptor type II, respectively, in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new strain of spontaneous non-insulin-dependent diabetes mellitus (NIDDM) models. OLETF rats (n=30) were divided into three groups aged 5,15, and 30 weeks. Long-Evans Tokushima Otsuka (LETO) rats (n=30) were used as age-matched non-diabetic controls. Plasma TGF-beta1 and insulin were determined by enzyme-linked immunosorbent assay. Immunoreactive TGF-beta receptor type II antigen was detected by immunohistochemistry on the thoracic artery. Arterial media area was measured microscopically. Oral glucose tolerance test was performed to examine the stage of diabetes mellitus. The thoracic aorta wall section area increased significantly from the age of 15 weeks in OLETF rats, versus LETO rats. In both OLETF and LETO rats, plasma TGF-beta 1 increased significantly from the age of 15 weeks. In OLETF rats, plasma TGF-beta 1 increased significantly over that in LETO rats (P<0.001). Furthermore, TGF-beta receptor type II was detected on aortic wall as strong signals in OLETF rats, but only weakly in LETO rats. OLETF rats showed hyperinsulinemia and insulin resistance from the age of 15 weeks. With oral glucose tolerance test, from the age of 15 weeks, the high glucose level in OLETF rats was prolonged to 2 h after loading, and the insulin levels at both fasting and after loading were significantly higher than those of LETO rats (P<0.001). There are significant linear relations between plasma TGF-beta 1 antigen and aorta wall section area, and plasma TGF-beta 1 antigen and fasting insulin level (P<0.001, respectively). We found that plasma TGF-beta 1 and vascular TGF-beta type II receptors existed to a greater extent in pre- and early stages of diabetes mellitus (DM) in OLETF rats compared with LETO rats. The greater extent of each in OLETF rats was associated with hyperinsulinemia and/or vascular thickening.
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PMID:Vascular proliferation and transforming growth factor-beta expression in pre- and early stage of diabetes mellitus in Otsuka Long-Evans Tokushima fatty rats. 1194 99


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