UMLS:C0011849 - FACTA Search

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

Traditional contraindications to beta-blockers are peripheral vascular diseases, diabetes mellitus, chronic obstructive pulmonary disease (COPD) and asthma. Recent data seem to show that rigorous application of these rules are not completely justified and indicate that many patients would be inappropriately excluded from the beneficial effects of this therapy. Appraisal of clear guidelines for a safe use of beta-blockers is thus mandatory for the clinician. A brief review of the effects of beta-adrenergic receptor blockade is offered. The therapy is aimed at blocking beta 1-receptors. On the other hand, the block of beta 2-receptors causes the well known side effects, i.e. vasoconstriction, delayed response to hypoglycemia in diabetic patients, bronchoconstriction. From the first compound, propranolol, with uniform action on beta 1 and beta 2-receptors, further generation of beta-blockers were subsequently developed: beta 1-selective, with intrinsic sympathomimetic activity, and with associated vasodilating "ancillary" property. Some favorable reduction in collateral effects has thus been obtained with new compounds, without reaching complete safety. Examination of exclusion criteria applied in clinical trials offers no useful indications because of their imprecise definition. Examination of the literature and a more accurate understanding of the diseases, traditionally considered contraindications, may help setting up a uniform and clear path: peripheral vascular disease: beta-blockers should be avoided only in those patients with vasospastic disorders, rest pain with severe peripheral vascular disease or nonhealing lesions. In patients with mild to moderate disease, beta-blockers can be prescribed, but careful surveillance for any changes in symptoms related to intermittent claudicatio should be achieved; diabetes mellitus: previous apprehension for the lessening reaction to hypoglycemia in patients treated with insulin has been retracted. Beta-blockers are not contraindicated in these patients. Some caution should be addressed when signs of autonomic disease are present or in patients with difficult glycemic control. Patients on oral long-acting antidiabetic drugs should not be neglected. The risk of prolonged and paucisymptomatic hypoglycemia while taking beta-blocker agents is somewhat more relevant than in patients treated regularly with insulin; COPD and asthma: confusion may arise if rigorous definition of these diseases and their severity is not applied following the guidelines of the American Thoracic Society. Because bronchial hyperreactivity seems the crucial factor in determining collateral effects to beta-blocker agents, agreement can be reached on the following statements. Beta-blockers are contraindicated a) when history of asthma is present, b) when COPD is moderate to severe, i.e. with FEV1 reduction < 50% of the predicted value, c) in patients on chronic bronchodilator treatment, d) in chronic airflow limitation with evidence of > or = 20% reversibility in airway obstruction in response to inhaled salbutamol. When FEV1 is > 50% of the predicted value, beta-blockers can be given, providing adequate control of stability of ventilatory conditions.
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PMID:[True and presumed contraindications of beta blockers. Peripheral vascular disease, diabetes mellitus, chronic bronchopneumopathy]. 1099 10

The role of cytokines in the pathogenesis of diabetic retinopathy and mechanism of action of laser coagulation of the retina were investigated. A total of 110 patients with insulin-dependent diabetes mellitus without clinical signs of diabetic retinopathy and at various stages of its development (subclinical, manifest preproliferative, and proliferative) were observed. Twenty-four of them were subjected to laser coagulation of the retina and/or vitrectomy. Control group consisted of 30 healthy donors. Ten cytokines (alpha-IFN, gamma-IFN, GM-CSF, TGF-beta 1, Il-1, Il-4, Il-6, Il-6sR, TNF alpha) were measured in the serum, lacrimal fluid, and vitreous and subretinal fluid collected during operations. The data indicate that excessive or insufficient local and/or systemic production of at least seven cytokines (TNF alpha, gamma-IFN, Il-6, Il-pR, alpha-IFN, Il-8, and RGF-beta 1) can affect the retinal involvement in the pathological process and development of proliferative retinopathy in patients with insulin-dependent diabetes mellitus. The authors defined the criteria which can be used in clinical practice for predicting the manifestation of diabetic retinopathy, progress of the pathological process with formation of proliferative diabetic retinopathy, and the results of treatment by laser coagulation of the retina. The authors consider early immunorehabilitations of diabetics with the aim of preventing the development and progress of diabetic retinopathy a promising approach to treatment.
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PMID:[Comparative study of the role of cytokines in various eye diseases. 2. Diabetic retinopathy]. 1152 35

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

Recently, a newly identified human HERV-K18 like endogenous retrovirus (IDDMK(1,2)22) has been associated to the etiology of type I diabetes (IDDM). Although the exact mechanism remains unclear, it was postulated that the 3' end ORF product of the env gene of IDDMK(1,2)22 would trigger a V beta 7-specific human T cell expansion leading to their infiltration in the pancreas of afflicted patients and to the autoimmune destruction of the insulin-producing beta cells. Since then, such superantigen (SAg)-like activity as well as the association between the IDDMK(1,2)22 virus and IDDM pathogenesis have been challenged. To further characterize functionally the putative IDDMK(1,2)22-encoded SAg, we have cloned from human DNA the identical 462bp ORF sequence originally described. The IDDMK(1,2)22 ORF fragment was transfected in the same human B cell line (Raji) originally used as APC to demonstrate the V beta 7 specificity. The immunostimulatory potential of IDDM ORF was tested on murine T cell hybridomas and compared to the well-characterized mouse mammary tumor virus Mtv7 SAg transfected in the same conditions. A panel of 16 T cell hybridomas encompassing 14 different V betas was analyzed. We have failed to detect IDDMK(1,2)22-induced IL-2 production from any of these hybridomas, even those bearing the murine V beta 1 mV beta 1, V beta 4 or V beta 10 TcR beta chains which are most closely related to the human V beta 7 (hV beta 7). Our results suggest that IDDMK(1,2)22 ORF is devoid of superantigenic activity as defined by classical criteria.
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PMID:Human endogenous retrovirus IDDMK(1,2)22 and mouse mammary tumor virus superantigens differ in their ability to stimulate murine T cell hybridomas. 1184 50

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

Inhibitors of angiotensin-converting enzyme (ACE) or beta isoforms of protein kinase C (PKC) are nephroprotective in diabetes mellitus. We investigated the influence of streptozotocin (STZ)-induced diabetes mellitus and of treatment with the ACE inhibitor lisinopril (4 mg/kg p.o. twice daily for 4 weeks) on the expression of PKC beta 1 and PKC beta 2 in the renal cortex of female Sprague-Dawley rats. Immunohistochemistry indicated an enhanced renocortical accumulation of macrophages expressing both MHC II, a marker for antigen-presenting cells, as well as PKC beta 2 in STZ diabetes which was confirmed by Western blotting demonstrating an enhanced renocortical expression of MHC II (1.8-fold) as well as of membrane-associated PKC beta 2 (1.9-fold). Whereas immunohistochemistry could not detect unequivocal alterations, Western blotting showed a rise in the renocortical expression of membrane-associated PKC beta 1 (1.7-fold) in STZ diabetes. Lisinopril lowered renocortical albumin content and proteinuria in STZ diabetes and attenuated the enhanced accumulation of macrophages expressing PKC beta 2 as well as the increase of membrane-associated expression of PKC beta 1 and PKC beta 2 in the renal cortex. The data suggest that the nephroprotective actions of the ACE inhibitor lisinopril in experimental diabetes mellitus were associated with and thus could be mediated in part by inhibition of diabetes-induced activation of PKC beta isoenzymes in the renal cortex.
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PMID:Protein kinase C beta isoenzymes in diabetic kidneys and their relation to nephroprotective actions of the ACE inhibitor lisinopril. 1243 80

Type 2 diabetes mellitus is a social and civilization-related disease that leads to various micro- and macroangiopathic complications, including diabetic nephropathy. At present, the most sensitive and non-invasive indicator of the progression of diabetic nephropathy is microalbuminuria. Morphological features such as accumulation of extracellular matrix proteins, thickening of glomerules' basement membranes are prior to microalbuminuria. The aim of our clinical study was to establish whether urine and serum TGF beta 1 levels may be significant in prognosing and evaluating a risk for developing diabetic nephropathy. The trial was carried out in 68 patients with type 2 diabetes mellitus and a group of 10 healthy subjects served as control. Urine and serum TGF beta 1 concentrations were evaluated, as well as basic laboratory parameters. After one-year-observation serum creatinine level and microalbuminuria value were investigated in 60 patients with type 2 diabetes mellitus. In patients with type 2 diabetes mellitus both urine and serum TGF beta 1 concentration were elevated. After one-year-observation of patients with type 2 diabetes mellitus it was established that the increase of serum creatinine concentration and that of microalbuminuria value were higher in those patients, whose initial TGF beta 1 levels exceeded normal values. A positive correlation between urine TGF beta 1 level and the progression of renal failure measured by the increase of serum creatinine level was observed. In conclusion, our findings indicate that urine TGF beta 1 level may be a good prognostic factor of the development of diabetic nephropathy in the course of diabetes mellitus.
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PMID:[Urine TGF-beta1 concentration in patients with type II diabetes mellitus--prognostic values]. 1247 94

Transforming growth factor-beta (TGF-beta) has been implicated in the development of diabetic glomerulopathy. In order to evaluate a role of Smad3, one of the major signaling molecules downstream of TGF-beta, in the pathogenesis of diabetic glomerulopathy, Smad3-null mice were made diabetic with streptozotocin injection and analyzed 4 weeks after induction of diabetes. Electron microscopy revealed that the thickness of glomerular basement membrane (GBM) in wild-type diabetic mice was significantly higher than that in non-diabetic mice, whereas no appreciable GBM thickening was found in Smad3-null diabetic mice. Urinary albumin excretion was dramatically increased in wild-type diabetic mice, whereas Smad3-null diabetic mice did not show any overt albuminuria. Northern blotting revealed that mRNA levels of fibronectin and alpha 3 chain of type IV collagen (alpha 3Col4) in renal cortex of wild-type diabetic mice were approximately twice as much as those of non-diabetic mice, whereas their mRNA levels were not increased in Smad3-null diabetic mice. Real-time polymerase chain reaction (PCR) also confirmed diabetes-induced upregulation of fibronectin and alpha 3Col4 in glomeruli of wild-type mice. Glomerular expression of TGF-beta 1, as assessed by real-time PCR, was enhanced to a similar degree in wild-type and smad3-null diabetic mice, indicating that the observed differences between wild-type and Smad3-null mice are not attributable to difference in the expression of TGF-beta 1. These data clearly demonstrate a critical role of Smad3 in the early phase of diabetic glomerulopathy. This may be due at least partly to the present findings that diabetes-induced upregulation of fibronectin and alpha 3Col4 is dependent on Smad3 function.
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PMID:Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy. 1276 30

Knowledge of the sympathetic system is a basic element in the understanding of numerous physiological and physiopathological phenomena. In the two last decades, new pharmacological, biochemical and molecular tools have changed our approach to the roles of beta-adrenoceptors in the cardiovascular system. In the heart, the positive inotropic effect of predominant beta 1-adrenoceptor stimulation is classically recognised. Several studies reveal a significant physiological relevance of the beta 2-adrenoceptor which could activate different signalling pathways in addition to that of cAMP. Moreover, the detection of a third beta-adrenoceptor subtype, beta 3, in human heart, responsible for a negative inotropic effect through a NO signalling pathway, has changed the classically admitted paradigm on the regulation of heart function by the beta-adrenergic system. The identification of atypical beta-adrenoceptors, based on pharmacological tools, led to the discovery of "putative" beta 4-adrenoceptors, which constituted a low affinity state of the beta 1-adrenoceptors. In vessels, all beta-adrenoceptors subtypes, beta 1, beta 2 and beta 3, mediated a vasodilation, but the signalling pathway involved in this effect was variable according to their localization (endothelial or smooth muscle cells), the species and the vascular bed. beta-adrenoceptors are involved in several cardiovascular disease and could constitute a determinant therapeutic target. The efficiency of some beta-blockers used in the treatment of heart failure could result from action on beta 3-adrenoceptors. Moreover, a mutation of the beta-adrenoceptor subtype suggested a role in hypertension and diabetes mellitus.
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PMID:Place of beta 3-adrenoceptors among other beta-adrenoceptor subtypes in the regulation of the cardiovascular system. 1457 45

The thiazolidinedione (TZD) class of antidiabetic drugs, which are ligands for peroxisome proliferator-activated receptor (PPAR)-gamma, has been shown to possess potent anti-inflammatory and antineoplastic actions. Here, we show in mesangial cells that PPAR-gamma agonists inhibit fibronectin expression by transforming growth factor (TGF)-beta 1. TGF-beta 1 enhanced fibronectin mRNA expression, and this enhancement was abrogated by pretreatment with pioglitazone. Electrophoretic mobility shift assay identified that pioglitazone inhibited TGF-beta 1-induced DNA binding of activator protein-1 (AP-1). Pioglitazone inhibited AP-1 reporter activity but not Smad binding elements reporter activity without affecting TGF-beta 1-induced activation of mitogen-activated protein kinases (MAPKs) or Smad2. PPAR-gamma overexpression inhibited TGF-beta 1-induced fibronectin expression as well as the activation of AP-1. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a natural PPAR-gamma ligand, also inhibited TGF-beta1-induced fibronectin expression by suppressing AP-1 activation by TGF-beta 1. 15d-PGJ(2) inhibited the TGF-beta 1-induced MAPK activation. Dominant-negative PPAR-gamma (Delta PPAR-gamma) completely abrogated the inhibitory effect of pioglitazone and incompletely blocked its effect of 15d-PGJ(2) on TGF-beta 1-induced AP-1 reporter activity. Delta PPAR-gamma overexpression did not affect the inhibitory effect of 15d-PGJ(2) on TGF-beta 1-induced MAPK activation. In conclusion, pioglitazone inhibits TGF-beta 1-induced fibronectin expression by inhibiting AP-1 activation dependent on PPAR-gamma, while 15d-PGJ(2) acts through a dual mechanism independent of and dependent on PPAR-gamma activation in mouse mesangial cells.
Diabetes 2004 Jan
PMID:Peroxisome proliferator-activated receptor-gamma ligands inhibit TGF-beta 1-induced fibronectin expression in glomerular mesangial cells. 1469 16

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