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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence suggests that several growth factors participate in diabetic glomerular disease by mediating increased extracellular matrix accumulation and altered cell growth and turnover leading to mesangial expansion. Transforming growth factor (TGF)-beta has been demonstrated to be upregulated both in vivo and in vitro, whereas studies on the activity of the renal insulin-like growth factor (IGF) system in experimental diabetes have provided conflicting results. We investigated the effects of prolonged exposure (4 weeks) of cultured human and rat mesangial cells to high (30 mmol/l) glucose vs iso-osmolar mannitol or normal (5.5 mmol/l) glucose levels on: 1) the autocrine/paracrine activity of the IGF system (as assessed by measuring IGF-I and II, IGF-I and II receptors, and IGF binding proteins); and, in parallel, on 2) TGF-beta 1 gene expression; 3) matrix production; and 4) cell proliferation. High glucose levels progressively increased the medium content of IGF-I and the mRNA levels for IGF-I and IGF-II, increased IGF-I and IGF-II binding and IGF-I receptor gene expression, and reduced IGF binding protein production. TGF-beta 1 transcripts and matrix accumulation and gene expression were increased in parallel, whereas cell proliferation was reduced. Iso-osmolar mannitol did not affect any of the above parameters. These experiments demonstrated that high glucose levels induce enhanced mesangial IGF activity, together with enhanced TGF-beta 1 gene expression, increased matrix production, and reduced cell proliferation. It is possible that IGFs participate in mediating diabetes-induced changes in matrix turnover leading to mesangial expansion, by acting in a paracrine/autocrine fashion within the glomerulus.
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PMID:Increased activity of the insulin-like growth factor system in mesangial cells cultured in high glucose conditions. Relation to glucose-enhanced extracellular matrix production. 881 1

Oral administration of self-antigens has been proposed as a therapy to prevent and treat autoimmune diseases. Here we report that oral treatment with insulin prevents virus-induced insulin-dependent diabetes mellitus (IDDM) in a transgenic (tg) mouse model. Such mice express the viral nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter in their pancreatic beta cells and < 2% spontaneously develop diabetes. However, 2 mo after challenge with LCMV, IDDM occurs in > 95% of tg mice but not in controls. Oral treatment with 1 mg of insulin twice per week for 2 mo starting either 1 wk before or 10 d after initiating LCMV infection prevents IDDM in > 50% of the tg mice (observation time 8 mo). Thus, insulin therapy is effective in preventing progression to overt IDDM in prediabetic tg mice with ongoing islet infiltration. Oral administration of insulin does not affect the generation of LCMV-NP-specific anti-self cytotoxic T lymphocytes nor the infiltration of lymphocytes into the pancreas. However, less beta cells are destroyed in insulin-treated mice, upregulation of MHC class I and II molecules does not occur, and antiviral (self) cytotoxic T lymphocytes are not found in the islets, events present in tg mice developing IDDM. The majority of lymphocytes in the islets of insulin-treated tg mice without IDDM produces IL-4, IL-10, and TGF-beta. In contrast, lymphocytes from islets of tg mice developing IDDM mainly make gamma-IFN.
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PMID:Oral insulin treatment suppresses virus-induced antigen-specific destruction of beta cells and prevents autoimmune diabetes in transgenic mice. 882 97

We investigated the intrarenal distribution of transforming growth factor-beta 1 (TGF-beta 1) protein and the TGF-beta 1 mRNA levels in the glomeruli and renal cortex of Wistar rats with streptozotocin-induced diabetes before and after the onset of diabetic nephropathy. Monthly urinary albumin excretion, glomerular filtration rate, glomerular volume, renal histology and immunohistochemical reaction for type-I collagen were also studied. The results showed progressively higher glomerular immunohistochemical TGF-beta 1 staining in rats with a diabetes duration of 24 and 40 weeks which was correlated with albuminuria (r = 0.905, p < 0.01) and was temporally associated with the appearance of glomerular deposition of total and type-I collagen. The glomerular content of TGF-beta 1 mRNA was higher in rats diabetic for 20 weeks while lower cortical RNA-TGF-beta 1 levels were found in rats with a diabetes duration of 1-40 weeks. These data suggest that this polypeptide may be an important mediator of diabetic glomerulosclerosis.
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PMID:Transforming growth factor-beta in the development of rat diabetic nephropathy. A 10-month study with insulin-treated rats. 888 39

The small and large vessel disease associated with diabetes mellitus is responsible for its morbidity and mortality. Although much of the pathogenesis remains to be clarified, the role of hyperinsulinemia and hyperglycemia per se in the progression of vascular disease is beginning to emerge. Hyperinsulinemia increases the release of very low density lipoprotein (VLDL) and may also be responsible for the low HDL cholesterol levels in patients with diabetes. Hyperinsulinemia also contributes to increased blood pressure, which independently promotes vascular disease. High glucose concentrations have direct influence on intracellular signal transduction, including effects on sorbitol pathway and associated changes of pyridine nucleotides, the de novo synthesis of diacylglycerol with subsequent stimulation of protein kinase C, and possibly changes in the cellular generation of myoinositol. Hyperglycemia also exerts long-lasting changes in cellular function, which result from non-enzymatic glycosylation of matrix and membrane proteins with subsequent binding of these proteins to specific receptors. These receptors are termed the advanced glycosylation end-products (AGE) receptors. Their activation leads to an increased release of cytokines and growth factors including PDGF, interleukins, TNF-alpha, and TGF-beta, all of which may act concomitantly in the disease process.
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PMID:The role of hyperglycemia and hyperinsulinemia in the pathogenesis of diabetic angiopathy. 890 9

The unstimulated and stimulated thyrocyte is able to produce more different cytokines in vitro than any other endocrine cell. Cytokines produced by thyrocytes may play a role in the local stimulation and maintenance of immune responses against autoantigens in the thyroid, in the modulation of goiter size in response to TSH, and in the clinical course of patients with thyroid tumors. This paper tries to summarize the results of relevant studies investigating cytokine production by thyrocytes. Although there is an agreement in published work that thyrocytes secrete a number of cytokines such as II-1, II-6, II-8 and TGF-beta in vitro it is unclear whether these factors are produced also by thyrocytes in vivo. By the example of GM-CSF in vitro secretion by stimulated anaplastic thyroid carcinoma cell lines and stimulated thyrocytes, the relevance of these findings during the clinical course of patients with anaplastic thyroid tumours is discussed.
Exp Clin Endocrinol Diabetes 1996
PMID:Expression of cytokines in the thyroid: thyrocytes as potential cytokine producers. 898 Oct 5

Hyperglycemia is a principal characteristic of diabetes, and has an influence on many cellular functions. In order to investigate whether the intracellular signaling pathways inducing proliferation, hypertrophy and matrix synthesis of mesangial cells are altered in a diabetic environment, we evaluated the effects of a high concentration of extracellular glucose(25 mM; 450 mg/dl) on [3H]thymidine uptake, hypertrophy, and [3H]proline incorporation into a collagenase-sensitive protein, induced by angiotensin II(Ang II) or transforming growth factor(TGF)-beta, in cultured rat mesangial cells. The exposure to a high glucose concentration for 7 days significantly inhibited Ang II(10(-6) M)-induced [3H]thymidine uptake, compared to normal glucose concentration (5 mM)(M +/- SD., 1050 +/- 100 cpm/well vs 550 +/- 97, p < 0.05), and markedly prevented the inhibition of [3H]thymidine uptake by TGF-beta(1 ng/ml)(132 +/- 10 vs 340 +/- 67, p < 0.05). The administration of H-7(50 microM), a protein kinase C(PKC) inhibitor, did not reverse these effects of high glucose on [3H]thymidine uptake. On flow cytometric analysis of cell size, the mean cell size was significantly greater for the cells exposed to high glucose or treated with Ang II or TGF-beta, compared to that for the untreated cells. But the addition of Ang II or TGF-beta to the cells exposed to high glucose did not show further enlargement in size. The exposure to high glucose and the treatment with Ang II or TGF-beta significantly increased collagen synthesis, measured by [3H]proline incorporation. The Ang II -or TGF-beta-induced increase of [3H]proline incorporation did not show changes under high glucose culture condition, compared to normal glucose concentration(Ang II, 27880 +/- 3560 cpm vs 26978 +/- 2284, TGF-beta, 26559 +/- 3700 vs 25800 +/- 1660, p > 0.05). In conclusion, although the signaling pathway for DNA synthesis by Ang II or TGF-beta are influenced, possibly mediated by PKC-independent mechanism(s), the pathway inducing hypertrophy or collagen synthesis by both agents appears to be unchanged under the high extracellular glucose concentration in cultured rat mesangial cells.
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PMID:The effects of high glucose concentration on angiotensin II- or transforming growth factor-beta-induced DNA synthesis, hypertrophy and collagen synthesis in cultured rat mesangial cells. 899 62

The earliest manifestations of type I diabetic nephropathy include mesangial matrix expansion, basement membrane thickening, and renal hypertrophy. Transforming growth factor (TGF)-beta, a potent inducer of matrix protein synthesis, is a prime candidate to mediate the glomerular changes observed in diabetes. However, the temporal expression of TGF-beta and matrix proteins during the early stage of diabetic nephropathy has not been clearly defined. Using in situ hybridization and immunohistochemistry, we determined the expression of TGF-beta and type IV collagen mRNAs and proteins in glomeruli and interstitium of diabetic rats 3, 7, and 14 days after streptozotocin (STZ) administration. There was a marked increase in the expression of TGF-beta and alpha1(IV) procollagen mRNAs in glomerular and tubulointerstitial cells as early as 3 days after induction of diabetes, an effect that persisted for 14 days. A concomitant increase in TGF-beta and type IV collagen proteins was also observed at each time point. Insulin treatment substantially inhibited the increased expression of TGF-beta and collagen type IV mRNAs and proteins. We conclude that TGF-beta is increased in glomeruli during the early phase of rapid renal growth in diabetes. These findings suggest that TGF-beta may be a key factor involved in the pathogenesis of basement membrane thickening and extracellular matrix accumulation. Inhibition of TGF-beta and type IV collagen expression by insulin treatment suggests that they may be useful structural markers for determining the efficacy of therapeutic intervention during early diabetic nephropathy.
Diabetes 1997 Mar
PMID:Expression of transforming growth factor-beta and type IV collagen in early streptozotocin-induced diabetes. 903 5

Hypertension, diabetes mellitus and chronic glomerular diseases reportedly cause in excess of 80% of the incident cases of end-stage renal disease (ESRD) in the U.S. The factors that initiate progressive renal failure in patients with these disorders remain unknown. Several investigators have reported enhanced synthesis and activity of cytokines in the kidneys of patients with renal failure. The ensuing inflammation and fibrosis have been postulated to contribute to the development of progressive renal failure. There is also abundant evidence supporting the contribution of genetic factors in ESRD susceptibility based upon the strong familial clustering of ESRD, particularly in African Americans. Therefore, genetic linkage analysis may be useful to evaluate the role of candidate genes in several cytokine cascades that could contribute to the pathogenesis of chronic renal failure. We tested for genetic linkage between eight cytokine candidate genes and chronic renal failure in a collection of African American sibling pairs concordant for ESRD. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta 1, TGF-beta 2 and TGF-beta 3, and tumor necrosis factor (TNF)-alpha and TNF-beta candidate genes were selected for analysis due to their putative roles in diabetic renal disease and chronic glomerulonephritis. The interleukin-1 receptor antagonist gene (IL1RN) was also genotyped due to its reported association with diabetic nephropathy. Non-parametric (genetic model independent) affected sib pair linkage analysis was used to evaluate evidence for linkage. In order to genotype TGF-beta 3, we identified four closely linked, previously unidentified, highly polymorphic microsatellite loci near the TGF-beta 3 gene. Linkage of ESRD and transforming growth factor beta 2 polymorphisms on human chromosome 1 approached significance for non-diabetic nephropathy (predominantly chronic glomerular disease, hypertensive nephrosclerosis and unknown etiology) (P = 0.08), but showed no linkage to diabetic nephropathy. The other candidate loci did not demonstrate linkage to ESRD in the total population or in the subgroups with diabetic or non-diabetic etiologies of ESRD. The IL1RN gene did not show significant evidence for linkage to ESRD; however, we did confirm an association between allele 2 of IL1RN and ESRD (as reported in diabetic nephropathy). Overall, these results suggest that these growth factor loci do not make major contributions to the pathogenesis of ESRD in African Americans.
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PMID:Genetic linkage analysis of growth factor loci and end-stage renal disease in African Americans. 906 16

Culture of mesangial cells (MCs) in 5.6 vs. 30.0 mmol/l glucose for 3 weeks induced a sustained increase in protein kinase C (PKC) activity, transforming growth factor (TGF)-beta1 mRNA, bioactive TGF-beta, and collagen synthesis. Nitric oxide (NO), generated exogenously by the NO donor S-nitroso-N-acetyl, D,L-penicillamine (SNAP) or endogenously after the exposure of MC to interleukin-1beta (IL-1beta), suppressed bioactive TGF-beta in MCs cultured in 5.6 or 30.0 mmol/l glucose and suppressed or abolished increases in TGF-beta1 mRNA and collagen synthesis induced by high concentrations of glucose or phorbol 12,13-dibutyrate without altering values obtained with normal glucose concentrations. SNAP had a transient suppressive effect on PKC activity, which may explain at least in part some of the actions of SNAP. The selective inhibitor of PKC, bisindolylmaleimide (GFX), mimicked NO action. The ability of SNAP and IL-1beta to suppress TGF-beta and collagen synthesis was not mediated by cGMP, since the cGMP analog, 8-Br-PET-cGMP, did not mimic NO action and an antagonist of cGMP-dependent protein kinase, Rp-8-pCPT-cGMPs, did not prevent the inhibitory actions of SNAP. N-omega-L-arginine methyl ester (NMMA) increased TGF-beta in glomerular capillary endothelial cells (GCECs) and stimulated collagen synthesis by MC in a co-culture with GCECs. Captopril inhibited TGF-beta and collagen synthesis and increased cGMP in co-cultures of GCECs and MCs. These effects of captopril were abolished by NMMA, implying mediation by NO. Thus, endogenous NO produced by GCECs may modulate TGF-beta production by both GCECs and MCs and act to suppress matrix protein synthesis by MCs.
Diabetes 1997 Apr
PMID:Nitric oxide inhibition of transforming growth factor-beta and collagen synthesis in mesangial cells. 907 10

Accumulation of matrix proteins is a prominent feature of diabetic nephropathy. Glomerular visceral epithelial cells (GVECs) are important contributors to extracellular matrix (ECM) production in the glomerulus. Factors involved with increased accumulation of ECM proteins are high glucose, angiotensin II (ANG II), and transforming growth factor (TGF)-beta. Therefore, we investigated the effects of high glucose and ANG II on fibronectin and TGF-beta production by human GVECs in vitro. We found that ANG II had no effect on the production of fibronectin and TGF-beta by GVECs. Using reverse transcriptase-polymerase chain reaction analysis, no ANG II receptor could be detected on these cells. However, high glucose induced a twofold increase in fibronectin (P < 0.01) and a three- to sixfold increase in TGF-beta (P < 0.001) production. Similar results were obtained by analyzing the mRNA levels of fibronectin (increased 2.7-fold) and TGF-beta (increased 3.5-fold). Addition of increasing concentrations of rTGF-beta to control cells resulted in increased fibronectin production. Neutralizing antibodies against TGF-beta significantly reversed the increase in fibronectin protein and mRNA caused by high glucose back to control levels. We conclude that high glucose concentrations stimulate the synthesis of fibronectin and that this effect is mediated by induction of TGF-beta. These results suggest that in diabetic nephropathy, high glucose levels play a role in changing the matrix composition of the glomerular basement membrane through induction of TGF-beta. Our results indicate that a contribution to this process by an effect of ANG II on GVECs seems unlikely.
Diabetes 1997 May
PMID:Regulation of glomerular epithelial cell production of fibronectin and transforming growth factor-beta by high glucose, not by angiotensin II. 913 52


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