Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokine Interleukin-1 beta (IL-1 beta) is known to exert cytotoxic effects upon rodent beta-cells in vitro by inducing nitric oxide production and has therefore been suggested to play a role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Using the insulin producing rat cell line RINm5F and an electrophoretic mobility shift assay (EMSA), it was presently found that IL-1 beta induced a rapid activation (5 min) of the transcription factor NF-kappa B and that this event was prevented by the protease inhibitor N alpha-p-tosyl-L-lysine chloromethylketone (TLCK). TLCK prevented also IL-1 beta induced nitric oxide production. It is concluded that NF-kappa B activation may be a necessary signal for IL-1 beta induced beta-cell damage and that this process can be modulated by specific protease and NF-kappa B inhibitors.
 ...
PMID:Interleukin-1 beta induced activation of NF-kappa B in insulin producing RINm5F cells is prevented by the protease inhibitor N alpha-p-tosyl-L-lysine chloromethylketone. 807 48

In chronic renal failure (CRF), the ATP-dependent, ubiquitin-proteasome proteolytic pathway is activated with concurrent increases in the transcription of genes encoding proteins of this pathway in muscle. We have shown that the stimuli for these responses include acidosis and glucocorticoids, but other endocrine abnormalities in CRF (e.g., insulin resistance) could contribute to these responses. In fact, a major effect of insulin in muscle is to suppress protein degradation. To examine whether insulin influences the ubiquitin-proteasome pathway, we measured protein degradation in incubated epitrochlearis muscles of diabetic and pair-fed control rats. Muscle proteolysis was increased in pathways that do not involve lysosomes or Ca(2+)-dependent proteases; but MG132, a protease inhibitor that blocks ATP synthesis, eliminated the accelerated rate of protein degradation in diabetic rat muscles. Diabetes mellitus also increased levels of mRNAs encoding ubiquitin (334%), E2 ubiquitin-conjugating enzyme (247%), and the C3 (320%), C5 (349%), and C9 (216%) proteasome subunits in muscle. Finally, transcription of the ubiquitin gene in diabetic rat muscles was increased. Diabetic rats were acidotic, but eliminating acidemia by giving NaHCO3 did not block the increase in muscle proteolysis. Giving diabetic rats insulin prevented the excessive muscle proteolysis, suggesting that insulin acts as a suppressor of the ubiquitin-proteasome pathway. Thus, the insulin resistance of uremia could contribute to muscle protein wasting in CRF.
 ...
PMID:Signals regulating accelerated muscle protein catabolism in uremia. 938 16

Hyperglycemia is an adverse effect that occurs with all protease inhibitors, although few cases have been reported in the literature. Most patients with human immunodeficiency virus infection receiving antiretroviral therapy are also taking at least one protease inhibitor. Patients with a family history of diabetes mellitus may be at a greater risk of developing this adverse effect. It is therefore prudent to monitor all patients starting protease inhibitor therapy for the onset of diabetes or hyperglycemia, particularly those with a family history of diabetes. Baseline fasting plasma glucose or serum glucose level should be measured with follow-up measurements every 3 months for approximately 6-12 months.
 ...
PMID:A review of protease inhibitor-induced hyperglycemia. 991 85

Effective treatment has not yet been established for patients with persistent proteinuria and hypoproteinemia related to advanced diabetic nephropathy. We report three patients with diabetic nephropathy presented with the nephrotic syndrome who showed a marked decrease in proteinuria following the administration of camostat mesilate, a protease inhibitor. Each patient was resistant to treatment with an angiotensin-converting enzyme (ACE) inhibitor and a platelet-aggregation inhibitor. Camostat mesilate, 600 mg/day, orally, caused a marked decrease in urinary protein excretion after the 7th consecutive day of drug administration. There were no serious adverse effects. Its mechanism of action in this respect is not known. Camostat mesilate thus merits clinical trials in the treatment of nephrotic syndrome related to diabetic nephropathy.
J Diabetes Complications
PMID:Effect of camostat mesilate on urinary protein excretion in three patients with advanced diabetic nephropathy. 1023 11

This study assessed glucose tolerance, insulin sensitivity and lipid parameters in HIV-infected patients presenting with lipodystrophy during HAART including protease inhibitors. Fourteen consecutive patients from Rothschild Hospital treated with HAART and presenting with marked facial lipoatrophy were evaluated. A 75 g oral glucose tolerance test (OGTT) with measurement of plasma glucose, insulin, proinsulin and free fatty acids at T0, 30, 60, 90 and 120 min was performed. Lipid parameters (triglycerides, cholesterol, apolipoproteins A1 and B) were studied as well as nutritional and inflammatory markers (albumin, prealbumin, transferrin, haptoglobin, orosomucoid, C-reactive protein), endocrine and cytokine parameters (thyrotropin, cortisol, leptin, interleukin-6), HIV viral load and CD4-lymphocyte count. These patients were compared with 20 non-lipodystrophic protease inhibitor-treated patients. The measurements performed during OGTT showed that among the 14 lipodystrophic patients, 11 (79%) presented with diabetes (5 patients) or normal glucose tolerance but with insulin resistance (6 patients). This frequency was strikingly different in the group of nonlipodystrophic patients, which included only 4 (20%) presenting with diabetes (1 patient), or impaired glucose tolerance (2 patients), or normal glucose tolerance but with insulin resistance (1 patient). Hypertriglyceridaemia was present in 11 lipodystrophic (79%) versus 7 nonlipodystrophic patients (35%). Nutritional and endocrine measurements were normal. An abnormal processing of proinsulin to insulin was excluded. Thus, lipodystrophy during HAART was associated with diabetes, insulin resistance and hypertriglyceridaemia. Diabetes, diagnosed by basal and/or 120 min-OGTT glycaemia, seems more frequent than previously described. The therapeutic consequences of these results deserve evaluation in clinical trials.
Diabetes Metab 1999 Sep
PMID:Diabetes, insulin resistance and dyslipidaemia in lipodystrophic HIV-infected patients on highly active antiretroviral therapy (HAART). 1049 91

In 1997, and mainly in 1998 and 1999, a lipodystrophic syndrome with central obesity, peripheral fat loss, hyperlipidemia, hyperglycemia and insulin-resistant-diabetes II, was described as the most frequent manifestation of toxicity of HIV1 virostatic therapy, associated with protease inhibitors (PI) in 83% of the patients who used them for 10 months. Almost similar syndromes had been published before the latter, due, for example, to graft vs host reaction, or autoimmunity against insulin receptors, or to caloric excess in the presence of androgens (the mediator being hyperinsulinemia). Carr and Cooper have presented an original pathophysiological mechanism for the PI-associated syndrome, residing in 63% homology between HIV1-protease and the 3-low-density-lipoprotein-receptor-related protein (LRP), and in 53% homology between this virus enzyme and retinoid-binding-protein type 1 (CRAB1). The treatment should be more subtle than those of common obesity and/or type II diabetes. This HIV1-protease inhibitor toxicity can be prevented by alternating several antiproteases in short sequences of the different ones.
 ...
PMID:Human obesity and thinness, hyperlipidemia, hyperglycemia, and insulin resistance associated with HIV1 protease inhibitors. Prevention by alternating several antiproteases in short sequences. 1066 36

Antiretroviral therapy (ART) is frequently associated with metabolic alterations, including insulin resistance and diabetes mellitus. In this pilot study, we evaluated the effect of the PPARgamma activator troglitazone on ART-associated insulin resistance in HIV-infected patients with ART-associated diabetes mellitus. Six patients with protease inhibitor (PI)-associated diabetes mellitus, lipodystrophy and dyslipidemia were treated with troglitazone 400 mg q.d. for 3 months. Previous oral antidiabetics were discontinued prior to the study. At baseline and after 3 months, insulin sensitivity (intravenous insulin tolerance test), body composition (multifrequence bioelectrical impedance analysis) and fat distribution (CT scan quantification) were assessed. Glycaemic control (fasting and postprandial blood glucose, fructosamine, glycosylated haemoglobin) and serum lipid status were determined monthly. In four of the six patients, there was a clear improvement in insulin sensitivity, resulting in a reversal of insulin resistance in two of these patients. Overall, there was an increase in lean body mass and a decrease in total body fat. The volume of visceral adipose tissue decreased whilst the volume of subcutaneous adipose tissue increased. Total cholesterol, LDL and HDL cholesterol increased, and total triglycerides and VLDL-cholesterol decreased. No adverse effects such as hepatotoxicity were observed. Treatment with troglitazone 400 mg q.d. can ameliorate and in some cases even reverse ART-associated insulin resistance. Therefore, further studies including non-diabetic patients with ART-associated insulin resistance may be helpful in evaluating the long-term effects of thiazolidinediones on ART-associated insulin resistance and other metabolic complications, such as adipose maldistribution and dyslipidaemia.
 ...
PMID:Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus. 1081 54

The potency of highly active antiretroviral therapy, including protease inhibitors have led to declining morbidity and mortality in patients with HIV infection. However the use of protease inhibitors is associated with onset of morphologic and metabolic disorders. A syndrome of lipodystrophy has been described. It is characterized by fast wasting of the face and limbs, and a central adiposity, breast hypertrophy and buffalo neck. The prevalence of lipodystrophy in patients treated with protease inhibition is about 60%. The principal metabolic disorders are lipid abnormalities, principally hypertriglyceridemia. New onset of diabetes mellitus is less frequent. The pathogenesis of these abnormalities unknown. Insulin resistance seems to be a common feature of protease inhibitor associated metabolic an morphologic side-effects.
 ...
PMID:[Metabolic complications associated with use of protease inhibitors]. 1092 55

The Otsuka Long-Evans Tokushima fatty (OLETF) rat is an animal model of type 2 diabetes, characterized by abdominal obesity, insulin resistance, hypertension, and dyslipidemia. To elucidate the underlying molecular mechanism of obesity and its related complications, we used representational difference analysis and identified the genes more abundantly and specifically expressed in the visceral adipose tissue (VAT) of obese OLETF rats compared with the diabetes-resistant counterpart, that is, Long-Evans Tokushima Otsuka (LETO) rats. By Northern blot analysis, we confirmed the differential expression of 13 genes, including 3 novel genes. The upregulated expression of well-characterized lipid metabolic enzymes, such as lipoprotein lipase, phosphoenolpyruvate carboxykinase, and cholesterol esterase, were observed in VAT of OLETF rats. We demonstrated the differential expression of secreted proteins in VAT of OLETF rats, such as thrombospondin 1 and contrapsin-like protease inhibitor. In contrast to lipid enzymes, the secreted proteins revealed exclusive mRNA expression and they were not detected in VAT of LETO rats. Furthermore, the novel genes OL-16 and OL-64 were also expressed specifically in VAT of OLETF rats and were absent in that of LETO rats and other tissues, including subdermal and brown adipose tissues. The C-terminal partial amino acid sequence of OL-64 revealed that it showed approximately 40% homology with alpha(1)-antitrypsin and it seemed to be a new member of the serine proteinase inhibitor (SERPIN) gene family. VAT of OLEFT rats had a unique gene expression profile, and the accumulated VAT-specific known and novel secreted proteins may play a role(s) in the pathogenesis of obesity and its related complications.
 ...
PMID:Identification of genes specifically expressed in the accumulated visceral adipose tissue of OLETF rats. 1101 3

We describe the case of a young HIV-positive patient undergoing three-drug antiretroviral therapy that included a protease inhibitor for 9 months, who was admitted to the hospital with an acute myocardial infarction. A coronary angiogram revealed occlusion caused by a thrombus in the proximal third of the anterior descending artery. Complete recanalization was obtained after an angioplasty was performed. At the time of the infarction, only the triglyceride levels were found to be high. Metabolic alterations associated with the prolonged use of protease inhibitors have been described such as an increase in the triglyceride and cholesterol serum levels, diabetes, resistance to insulin, lipodystrophy, and pancreatitis. The consequences of chronic hyperlipidemia are well known in the medical literature, especially premature coronary artery disease. No family history of coronary artery disease was identified in this patient. Whether the genesis of this localized coronary thrombosis was due to a change in the metabolism of the vascular endothelium caused by the protease inhibitors, or by related dyslipidemia, is still to be determined. In this case, the data suggest a strong link between coronary insufficiency and prolonged use of the protease inhibitor.
 ...
PMID:Acute Myocardial Infarction in a 34-Year-Old HIV-Positive Female Patient While Undergoing Active Antiretroviral Therapy Containing a Protease Inhibitor. 1108 68


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>