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)

Microvascular complications of insulin-dependent diabetes mellitus (IDDM) have been strongly associated with platelet abnormalities, whilst TNF-alpha has been implicated in the pathogenesis of this condition. However, at present it is not clear whether human circulating platelets express TNF-alpha or TNF receptors (TNF-R) or whether impaired expression of these molecules and of the TNF-reactive adhesion molecule ICAM-1 may be associated with platelet abnormalities in patients with IDDM. On this basis we investigated the platelet expression of these molecules in patients with IDDM complicated or uncomplicated by proliferative diabetic retinopathy (PDR) and in healthy subjects. We observed that the proportion of platelets staining for TNF-alpha was significantly higher in IDDM patients with active PDR than in patients without microvascular complications (P = 0.0078), quiescent PDR (P = 0.003) or healthy subjects (P = 0.0013). Patients with active PDR also showed a higher proportion of platelets expressing TNF-RI (P = 0. 0052) and TNF-RII (P = 0.015) than healthy controls or patients with quiescent PDR (P = 0.009 and 0.0006, respectively). In addition, the percentage of ICAM-1+ platelets was significantly higher in patients with active PDR than in patients with quiescent PDR (P = 0.0065) or normal subjects (P = 0.013). There was a direct correlation between platelet expression of TNF-alpha and that of TNF-R in PDR patients, indicating that platelet staining for TNF-alpha may be due to binding of this cytokine to its receptors. The results suggest that increased platelet expression of TNF-alpha, TNF-R and ICAM-1 in IDDM patients may constitute important markers of thrombocyte abnormalities during the development of microvascular complications of diabetes mellitus.
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PMID:Platelet expression of tumour necrosis factor-alpha (TNF-alpha), TNF receptors and intercellular adhesion molecule-1 (ICAM-1) in patients with proliferative diabetic retinopathy. 1054 Jan 81

HIV infection induces an early decrease of cholesterol and a late increase of triglycerides (TG) with a reduction of HDL. These changes are proportional with the lowering of CD4, which reflects the infection's severity. Both the increase of TG synthesis and the decrease of TG catabolism, in relation with a reduction of lipoprotein lipase activity, are responsible of these changes. Moreover, LDL catabolism is enhanced by macrophage scavenger receptors, due to a high proportion of small, dense LDL which are more easily oxidized. Many cytokines (interferon alpha, interleukins, TNF) play probably a pathogenic role in the dyslipidemia. Some HIV patients who received antiproteases may develop lipodystrophy with central obesity, insulino-resistance, glucose intolerance and sometimes diabetes (like in syndrome X). Other patients present a cushingoid, buffalo hump. This complication may be observed also with antiretroviral treatment other than antiproteases. The physiopathology of these findings could be in relation with structural homologies between antiproteases and some important proteins, involved in lipid and adipocyte metabolism. Cardiovascular risk linked to these perturbations is evident. The treatment is not different from the treatment for seronegative, hyperlipidemic patients: struggle against risk factors, diet advices, fibrates or statins. The antiproteases bring huge contribution to the prognosis of AIDS patients but the risk of cardiovascular complications could impair this therapeutic progress. So, it is essential to understand the pathogeny of these complications in order to discover new antiproteases, without these adverse side effects.
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PMID:[Lipids and AIDS]. 1074 83

Recent reports suggest that the pancreas participates in tumor necrosis factor alpha (TNF-A) production during stress, and that the islets are predominantly responsible for such synthesis. In vitro TNF-A and interleukin 1-beta (IL-1-beta) inhibit insulin release from islet beta-cells. We measured the circulating levels of IL-1-beta, TNF-A and islet cell antibody (ICA) in 30 children with IDDM (10 of them at their first presentation), 30 of their non-diabetic siblings, and 30 normal age-matched children. In the non-diabetic children we investigated the early phase of insulin release after intravenous bolus of glucose and evaluated tolerance to oral glucose (OGTT). IL-1-beta and TNF-A concentrations were significantly higher in IDDM-siblings (31.8 +/- 7.7 pg/ml and 650 +/- 155 pg/ml respectively) versus normal children (21.2 +/- 6.4 pg/ml and 383 +/- 122 pg/ml respectively). IL-1-beta and TNF-A concentrations did not differ significantly between the diabetic children and healthy age-matched controls. ICA were detected in 60% of the recently diagnosed diabetic children vs. 30% of those with longer duration of diabetes (3.1 +/- 1.2 years). Despite the significantly high prevalence of ICA in the recently diagnosed children with IDDM, their IL-1-beta and TNF-A concentrations were lower than those for the normal children. In experimental animals these cytokines can induce round cell infiltration (insulinitis) and inhibit insulin secretion by beta-cell. The presence of significantly higher concentrations of these cytokines in IDDM siblings, with high prevalence of ICA (16%), was associated with normal oral glucose tolerance and normal peak insulin response (60 +/- 10.4 mlU/ml) after i.v. glucose bolus compared to normal children (52.3 +/- 9.5 mlU/ml). However, after 2 years of follow up, one of them developed IDDM and another developed IGT but none of the normal controls developed abnormal glucose tolerance. It appears that the process of autoimmune aggression against beta-cells, and its effect on insulin release and glucose homeostasis, is a slow and chronic process. However, the production of these cytokines and consequently the degree of beta-cell destruction, in a genetically susceptible subject, might be enhanced by several factors including viral infections. In summary, IL-1-beta and TNF-A levels can be used as indicators of continuing autoimmune aggression against beta-cells before the development of extensive beta-cell destruction.
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PMID:Interleukin-1-beta, tumor necrosis factor-alpha, insulin secretion and oral glucose tolerance in non-diabetic siblings of children with IDDM. 1077 98

Five polymorphic regions (a to e) have been recognized within the TNF gene region. These polymorphisms appear to be of biological importance as individual alleles have been associated with higher production of TNF and/or an increased risk of rheumatoid arthritis or diabetes mellitus. We report here the detection of four new alleles designated a14 (122 bp), b8 (131 bp), b9 (132 bp), and d0 (122 bp) in patients with rheumatoid arthritis and normal controls from the Pacific Northwest. This increases to 39 the number of alleles now recognized at these loci.
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PMID:Identification of four novel dinucleotide repeat polymorphisms in the TNF-alpha and TNF-beta genes. 1077 54

The contemporary presence of organomegaly, skin manifestations, polyneuropathy, endocrinopathy and monoclonal component characterises the POEMS syndrome, often associated with osteosclerotic myeloma and Castelman's disease and more frequent in the Japanese. Clinical manifestations seem to be related to the production of many interleukins, mainly IL-1, IL-6 and TNF. Several endocrinopathies have been described, the most frequent being diabetes. Only one previous case of hypoparathyroidism associated with the syndrome has been described in medical reviews. Polyneuropathy is often sensitivo-motory and skin disease accounts for Raynaud phenomenon, skin pigmentation, hypertricosis and others. We describe the case of a 74-year-old man who underwent clinical examination for weakness mainly in the legs. Clinical and instrumental data showed rhabdomyolysis due to hypoparathyroidism. The contemporary presence of a monoclonal band of light chains on proteic electrophoresis, organomegaly and distal leg neuropathy allowed us to make a diagnosis of POEMS syndrome.
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PMID:A man with worsening weakness. 1078 Jan 92

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.
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PMID:Endothelial function and hemostasis. 1079 71

In the cascade hormone--second messenger--cellular G-proteins (GTP binding proteins), impairment can occur also at the last step: Mutant G-proteins may amplify the response (e.g. hypophyseal and thyroid adenomas) or reduce it (pseudohypoparathyreosis, testitoxicosis). Other new group of diseases appears to be anexinopathy: Among anexins belong also lippocortins and impairments occur in the hemocoagulation. "Reverse endocrinology" is a process description when the recognition of receptor (called an "orphan receptor") comes earlier than that of the hormone: Such receptors are known for several steroid hormones, retinoids and eicosanoids and it appears they are important also in the metabolism of cholesterol. A single antigen--glutamic acid decarboxylase (GAD), can cause autoimmune disease as the immuno-dependent diabetes (IDDM). Treatment of the skin T-cell lymphoma by some retinoids can result in hypothyroidism. Retrotransposones are example of the human genome modification with yet unknown clinical manifestations. Hepatocytal growth factor reveals to be the hope for treatment of cirrhosis. Search for effective peroral insulin substitutes is at present based on testing of various metabolites of fungi. Antibodies against TNF (tumor necrosis factor) become tested as "anti-cytokine therapy" in patients with rheumatoid arthritis. Some other suggestions for new ways of treatment is also listed, including the intranasal administration of estradiol.
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PMID:[Endocrinology 1998-1999]. 1083 33

Adipose tissue only accounts for a relatively small proportion (< 10%) of the peripheral glucose utilization in response to insulin. However, the fat cells may still play an important role in insulin resistance and Syndrome X through, for instance, its endocrine functions (production of leptin, TNF alpha, PAI-1, etc.) and involvement in lipid metabolism (FFA release and hydrolysis of triglycerides). The fat cells are also highly sensitive to insulin and may thus be used to elucidate molecular mechanisms for insulin resistance in man. Examinations of the intracellular signaling mechanisms for insulin in fat cells from individuals with Type 2 diabetes revealed markedly lower insulin-stimulated PI3-kinase activity. This was due to a pronounced reduction in the cellular expression of the docking protein, IRS 1, whereas expression of IRS 2 was normal. However, IRS 2-associated PI3-kinase activity was only approximately one-third of that found to be associated with IRS 1 in normal cells. Downstream activation and serine phosphorylation of PKB/Akt by insulin were also markedly reduced in Type 2 diabetes. Furthermore, the dose-response curve for this effect of insulin was similar to that for glucose transport in both normal and Type 2 diabetic cells. Thus, these data show that both PI3-kinase and PKB activation by insulin are markedly reduced in Type 2 diabetes. We also examined whether an attenuated activation of PI3-kinase by insulin can be seen in non-diabetic insulin-resistant states. Approximately 30% of healthy subjects with at least two first-degree relatives with Type 2 diabetes exhibited perturbations in IRS-1 expression and signaling. These individuals were characterized by insulin resistance as well as other markers of Syndrome X. Thus, impaired IRS-1 expression and downstream signaling events in fat cells in response to insulin are associated with insulin resistance and Syndrome X.
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PMID:Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes. 1084 57

In this study, the anti-inflammatory actions of the peroxisome proliferator-activated receptor (PPAR)-gamma agonists 15-deoxy-delta 12,14-prostaglandin J2 (15-d-delta 12,14-PGJ2) and troglitazone have been examined. Treatment of RAW 264.7 cells and CD-1 mouse peritoneal macrophages with lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) results in inducible nitric oxide synthase (iNOS), inducible cyclooxygenase (COX-2) and interleukin-1 (IL-1) expression, increased production of nitric oxide, and the release of IL-1. In a concentration-dependent manner, 15-d-delta 12,14-PGJ2 inhibits each of these proinflammatory actions of LPS + IFN-gamma, with half-maximal inhibition at approximately 0.5 microg/ml and complete inhibition at 1-5 microg/ml. The inhibitory actions of 15-d-delta 12,14-PGJ2 on LPS + IFN-gamma-induced inflammatory events are not associated with the inhibition of iNOS enzymatic activity or macrophage cell death, but appear to result from an inhibition of iNOS and IL-1 transcription. In addition, the anti-inflammatory actions of 15-d-delta 12,14-PGJ2 are not limited to peritoneal macrophages, as 15-d-delta 12,14-PGJ2 prevents TNF-alpha + LPS-induced resident islet macrophage expression of IL-1beta and beta-cell expression of iNOS stimulated by the local release of IL-1 in rat islets. 15-d-delta 12,14-PGJ2 appears to be approximately 10-fold more effective at inhibiting resident islet macrophage activation (in response to TNF + LPS) than IL-1-induced nitrite production by beta-cells. Two mechanisms appear to be associated with the antiinflammatory actions of both 15-d-delta 12,14-PGJ2 and troglitazone: 1) the direct inhibition of cytokine- and endotoxin-stimulated iNOS and IL-1 transcription; and 2) the inhibition of IL-1 signaling, an event associated with PPAR-gamma agonist-induced activation of the heat shock response (as assayed by heat shock protein 70 expression). These findings indicate that the PPAR-gamma agonists, troglitazone and the J series of prostaglandins, are potent anti-inflammatory agents that prevent cytokine- and endotoxin-stimulated activation of peripheral and resident tissue macrophages and cytokine-induced iNOS expression by beta-cells by the inhibition of transcriptional activation and induction of the heat shock response.
Diabetes 2000 Mar
PMID:Anti-inflammatory actions of 15-deoxy-delta 12,14-prostaglandin J2 and troglitazone: evidence for heat shock-dependent and -independent inhibition of cytokine-induced inducible nitric oxide synthase expression. 1086 55

Leptin and TNF alpha are thought to influence blood pressure. Therefore, the aim of our study was to investigate leptin and TNF alpha levels and their association with blood pressure, sex steroids, insulin, creatinine and lipids in type 2 diabetic patients. In 424 type 2 diabetic patients (79 hypertensive females [+Hf], 79 normotensive females [-Hf]; 133 hypertensive males [+Hm], 133 normotensive males [-Hm]) matched for sex, age and BMI serum leptin levels were measured by RIA and TNF alpha, insulin, estradiol, progesterone by ELISA as well as free testosterone by RIA. Leptin levels were comparable in +Hf and -Hf (16.5 +/- 1.0 microg/l vs 16.3 +/- 1.0 microg/l) but higher in +Hm as compared to -Hm (8.3 +/- 0.47 microg/l vs 6.5 +/- 0.34 microg/l; p<0.05). In addition, in comparison to -Hm serum levels of insulin (190 +/- 10 pmol/l vs 161 +/- 11 pmol/l; p< 0.005) and also of creatinine (118.6 +/- 3.6 micromol/l vs 101.7 +/- 2.3; p< 0.0001) were higher in +Hm. Pearson's Correlation coefficient revealed a positive correlation between levels of leptin and diastolic blood pressure (p<0.05) and also between leptin and insulin (p<0.001) in males, however, only before correction for BMI. No correlation between leptin and creatinine was found in males and females. Levels of TNF alpha were comparable in all subgroups. No correlation between levels of TNF alpha and serum leptin levels, blood pressure and insulin was found. In females TNF alpha was positively correlated with creatinine (p<0.001) and in males positively with progesterone (p<0.001). Taken together, higher serum leptin levels were found in hypertensive type 2 diabetic males as compared to normotensives, which may be related to the BMI and higher levels of insulin. These findings are accompanied by a trend to lower levels of free testosterone in hypertensive type 2 diabetic males. TNF alpha levels were comparable in female and male hypertensive and normotensive type 2 diabetic subjects.
Exp Clin Endocrinol Diabetes 2000
PMID:Elevated levels of leptin and insulin but not of TNF alpha are associated with hypertension in type 2 diabetic males. 1096 56


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