Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RU-486 or mifepristone is best known as an antiprogestin and an abortifacient, but it has broad medical applicability. The drug is also a potent blocker of corticosteroid receptors, and it has shown promise in the treatment of breast cancer, inoperable meningioma, and cushing's disease. Cushing's is a model for the symptomatology of aging which may involve enhanced response to corticosteroid. RU-486 has reversed the osteoporosis, thinning of skin, muscle atrophy, obesity, adult onset diabetes, depression, hypertension, and immunosuppression associated with this disease. RU-486 may be of value in aiding cervical dilation, lactation, and the treatment of endometriosis. In addition, breast, bowel, kidney tumors, hepatomas, endometrial cancer, and fibrosarcomas can show corticosteroid dependency, suggesting that RU-486 may have clinical value against inoperable tumors. In a preliminary 1987 phase I study, in estrogen-positive, chemotherapy-refractory breast cancer patients in Montpelier, France, Ru-486 produced objective tumor regression (6 of 22) that was prolonged (3 months) in 4 patients. Clinical relief of bone pain was observed in 7 of 23 patients with a decline in carcinoembryonic antigen (CEA) tumor makers in 8 patients. Growing in vitro data also show that RU-486 can directly inhibit breast cancer cell proliferation. RU-486 has application for HIV infection, based on data that there is a serum factor in AIDS patients that enhances corticosteroid lympholysis. IN addition, the immune restorative action of RU-486 suggests that it could counteract the immunosuppression seen in aging, in cancer, or in viral or stress-related disease, which has recently focused clinical attention on its potential in the treatment of senile dementia and depression. Scientific conferences and workshops are needed to alert scientists, physicians, and the public to the potential medical benefits of this drug.
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PMID:RU 486: how abortion politics have impacted on a potentially useful drug of broad medical application. 150 96

Retroviral protease inhibitors used as therapy for HIV-1 infection have been causally associated with serious metabolic side effects, including peripheral lipodystrophy, hyperlipidemia, insulin resistance, and in some cases, overt type 2 diabetes. The etiology of this characteristic clinical syndrome remains unknown. We demonstrate that the HIV protease inhibitor, indinavir, dramatically inhibits insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner (63% inhibition observed with 100 micrometer indinavir). Indinavir treatment did not affect early insulin signaling events or the translocation of intracellular Glut1 or Glut4 glucose transporters to the cell surface. To determine whether indinavir may be directly affecting the intrinsic transport activity of glucose transporters, the Glut1 and Glut4 isoforms were heterologously expressed and analyzed in Xenopus laevis oocytes. Indinavir at 100 microm had no effect on Glut1 transport activity in Xenopus oocytes, whereas Glut4 activity was significantly inhibited (45% inhibition). Similar effects on glucose transport were observed for other HIV protease inhibitors. We conclude that HIV protease inhibitors as a class are capable of selectively inhibiting the transport function of Glut4 and that this effect may be responsible for a major iatrogenic complication frequently observed in HIV patients.
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PMID:The mechanism of insulin resistance caused by HIV protease inhibitor therapy. 1080 89

New-onset diabetes mellitus, clinically similar to type 2 diabetes, will affect a small proportion (1%-6%) of patients infected with human immunodeficiency virus (HIV) who are treated with HIV-1 protease inhibitors (PIs). However, insulin resistance and impaired glucose tolerance will develop during PI treatment in a considerable proportion of patients. Dyslipidemia, abdominal obesity, and loss of peripheral fat frequently coexist with insulin resistance, but it is not clear whether all of these result from a common pathogenic mechanism. Recent data suggest that insulin resistance may also be associated with HIV infection in patients not receiving PI therapy. The long-term consequences of insulin resistance in this population are not known. The effect of switching to other antiretroviral therapies has not been fully determined. Treatment of established diabetes mellitus should generally follow existing guidelines. There is no clinically useful screening test that will determine the existence and degree of insulin resistance in individual patients. It is therefore reasonable to recommend general measures to increase insulin sensitivity in all patients infected with HIV, such as weight reduction for obese persons and regular aerobic exercise.
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PMID:Disorders of glucose metabolism in patients infected with human immunodeficiency virus. 1109 14

HIV-lipodystrophy (HIV-LD) is characterized by the loss of body fat from the limbs and face, an increase in truncal fat, insulin resistance, and hyperlipidemia, factors placing affected patients at increased risk for vascular disease. This study evaluated insulin sensitivity and inflammatory status associated with HIV-LD and provides suggestions about its etiology. Insulin sensitivity and immune activation markers were assessed in 12 control subjects and 2 HIV-positive groups, 14 without and 15 with LD syndrome. Peripheral insulin sensitivity (mostly skeletal muscle) was determined with the hyperinsulinemic-euglycemic clamp. Circulating insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) and free fatty acid (FFA) levels, and their response to insulin infusion were indicative of insulin responsiveness of liver and adipose tissue, respectively. Serum levels of soluble type 2 tumor necrosis factor-alpha (TNF-alpha) receptor (sTNFR2) were used as an indicator of immune activation. HIV-LD study subjects had significantly reduced (twofold) peripheral insulin sensitivity, but normal levels of FFA and reduced levels of IGFBP-1, relative to the nonlipodystrophy groups, indicating that the loss of insulin sensitivity was more pronounced in skeletal muscle than in liver or fat. The significant loss of peripheral fat in the HIV-LD group (34%; p <.05) closely correlated with the reduced peripheral insulin sensitivity (p =. 0001). Levels of sTNFR2 were elevated in all HIV-infected study subjects, but they were significantly higher in those with lipodystrophy than without, and sTNFR2 levels strongly correlated with the reduction in insulin sensitivity (p =.0001). Loss of peripheral fat, normal levels of FFA, and reduced levels of IGFBP-1 indicate that insulin resistance in HIV-LD is distinct from type 2 diabetes and obesity. The relationship between the degree of insulin resistance and sTNFR2 levels suggests an inflammatory stimulus is contributing to the development of HIV-associated lipodystrophy.
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PMID:Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. 1151 29

In most countries throughout the world, except those affected by the HIV-Aids epidemic, populations are increasing in size, rapidly getting older, and becoming more sedentary. This combination, along with the adoption of unhealthy habits such as cigarette smoking and consumption of an animal-based rather than a plant-based diet, will result in chronic degenerative diseases becoming the most common cause of disability and premature death throughout the world during the first twenty-five years of this new millennium. As more and more populations acquire the technology that reduces the need to exercise for transportation, occupation or maintaining a household, lack of activity quickly becomes a major risk for coronary heart disease, stroke, hypertension and noninsulin dependent diabetes mellitus. This lack of activity appears to contribute to other disorders such as osteoporosis and selected site-specific cancers. In older persons, inactivity can become a major reason for loss of physical independence and a reduction in their quality of life. Public health approaches will be needed to reverse this trend of increasing "hypokinetic" diseases as the computer/communication revolution becomes worldwide. These public health programs will need to be supported by government and corporate changes in policies that provide time, facilities and incentives for maintaining an appropriately active life-style. The goal should be for all adults to perform at least 30 minutes of moderate to vigorous intensity exercise on most days.
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PMID:[Sports, exercise and health. On the way into a new century]. 1114 77

Insulin resistance (IR) in the context of highly active antiretroviral therapy (HAART) is becoming more common in HIV-infected patients. Patients with chronic hepatitis C virus (HCV) infection have an increased risk of IR and type 2 diabetes mellitus. A cross-sectional study was performed to investigate whether chronic HCV infection constitutes a risk factor for IR in HIV-HCV-coinfected patients undergoing HAART. Inclusion criteria were positive HCV viremia and a sustained increase of alanine aminotransferase of at least twice the normal value. A total of 29 HIV-HCV patients, 76 HIV patients, and 121 HCV controls were tested for IR and body mass index (BMI). IR was measured using the homeostasis model assessment. In HIV-HCV and HIV patients, fat redistribution and lipid profile were assessed. There was no significant difference in age, CD4 cell count, HIV viral load, or duration of HAART between the HIV-HCV and HIV groups. HIV-HCV patients and HCV controls had a significant increase in IR when compared with HIV patients (0.25 +/- 0.28 and 0.21 +/- 0.34 versus 0.04 +/- 0.37; p =.01 and p =.003, respectively). Lipoatrophy was observed more frequently in HIV-HCV patients in comparison with HIV patients (41% versus 14%; p =.003). In HIV-HCV patients, total cholesterol and triglyceride levels were significantly lower than in HIV patients. In multivariate analysis, IR, BMI, triglyceride levels, and peripheral fat wasting were the independent variables associated with HCV infection. Our findings suggest that chronic HCV infection is a significant factor associated with the development of metabolic abnormalities and with modifications in body composition in HIV patients receiving antiretroviral treatment.
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PMID:Association between insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy. 1146 43

Insulin resistance is a common metabolic disorder. It plays an important role in the metabolic syndrome (or syndrome X), type 2 diabetes, obesity and in the lipodystrophic syndromes recently described, associated with treatments of HIV disease and represent a worrying cardiovascular risk. However, its pathophysiology remains poorly understood in these situations. Syndromes of major insulin resistance, although rare, allow investigations of the mechanisms leading to alterations in the insulin transduction pathways. Mutations of the insulin receptor gene have been discovered in rare patients. Therefore alterations at the post-receptor level are probably causative in other cases. Furthermore, the role of body fat repartition seems determinant in the apparition of insulin resistance, as attested by the clinical characteristics of lipodystrophies, either congenital or acquired. The two lipodystrophic syndromes which molecular defect is identified are the familial partial lipodystrophy of the Dunnigan type, due to mutations of the lamin A/C gene, and the congenital generalized lipodystrophy, linked to alterations in the protein seipin. However, their physiopathology remains mysterious. Lamin A/C is indeed an ubiquitous nuclear protein, which is also mutated in a genetic squelettic and/or cardiac myopathy, and seipin is a protein of unknown function mainly expressed in brain. Progresses in the understanding of these syndromes, in particular lipodystrophies which can be considered as caricatural models of the metabolic syndrome, will probably allow to clarify the physiopathology of the more common forms of insulin resistance.
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PMID:[Major insulin resistance syndromes: clinical and physiopathological aspects]. 1183 62

In the last few years there has been an explosion of research that has improved our understanding of the pathogenesis of Type 2 diabetes mellitus (DM-2) and has led to the development of new oral antidiabetic drugs. Thiazolidinediones (TZDs) are the newest of these antidiabetic agents. TZDs are insulin sensitisers that depend on the presence of insulin for their action. They target insulin resistance, which is thought to play a central role in DM-2 and the associated metabolic syndrome characterised by central obesity, hypertension, dyslipidemia and hypercoagulability, all leading to increased cardiovascular morbidity and mortality. As a result, TZDs have the potential to improve other conditions associated with the metabolic syndrome, in addition to their glycaemic action. TZDs act by activating peroxisome proliferator-activated receptor (PPAR) phi a nuclear receptor implicated not only in lipid and glucose metabolism but other physiological functions as well. TZDs may have wide clinical applications beyond DM-2, as they can potentially be used to treat other conditions associated with insulin resistance and PPAR-phi receptors, such as impaired glucose tolerance, polycystic ovarian syndrome and HIV lipodystrophy.
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PMID:Thiazolidinediones in the treatment of type 2 diabetes. 1199 32

Over the last few years, there has been a considerable reduction in the mortality and morbidity associated with HIV patients, due to the use of protease inhibitors which have led to a true revolution in the treatment of this infection. A new problem has arisen with the increased life expectancy: the onset of a plurimetabolic syndrome characterized by hypertriglyceridaemia, hypercholesterolaemia and hyperglycaemia; in addition to anomalies in composition and distribution of body fat (central obesity and loss of peripheral fat) due to the associated lipodystrophy. As a result of the metabolic alterations, there is an increase in the risk of cardiovascular disease. Hyperglycaemia is the result of insulin resistance and is detected in between 13.6% and 46% of patients, possibly leading to type 2 diabetes (diagnosed in between 2.4% and 7% of the patients). These alterations have been documented as potentially related with the use of protease inhibitors and other drugs used in the handling of HIV patients. The appropriate treatment of altered metabolism of carbohydrate requires: 1) a customized dietary approach depending on individual BMI and lipid alterations; 2) a physical exercise programme; 3) the use of insulin sensitization drugs: metformin and thiazolidinediones and, where the therapeutic goals are not achieved or there is a contraindication for oral hypoglycaemic drugs; 4) insulin therapy with regimens similar to other diabetic patients.
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PMID:[Changes in carbohydrate metabolism in the HIV/AIDS patient]. 1214 14

Micronised fenofibrate is a synthetic phenoxy-isobutyric acid derivative (fibric acid derivative) indicated for the treatment of dyslipidaemia. Recently, a new tablet formulation of micronised fenofibrate has become available with greater bioavailability than the older capsule formulation. The micronised fenofibrate 160mg tablet is bioequivalent to the 200mg capsule. The lipid-modifying profile of micronised fenofibrate 160mg (tablet) or 200mg (capsule) once daily is characterised by a decrease in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels, a marked reduction in plasma triglyceride (TG) levels and an increase in high-density lipoprotein cholesterol (HDL-C) levels. Micronised fenofibrate 200mg (capsule) once daily produced greater improvements in TG and, generally, in HDL-C levels than the hydroxymethylglutaryl coenzyme A reductase inhibitors simvastatin 10 or 20 mg/day, pravastatin 20 mg/day or atorvastatin 10 or 40 mg/day. Combination therapy with micronised fenofibrate 200mg (capsule) once daily plus fluvastatin 20 or 40 mg/day or atorvastatin 40 mg/day was associated with greater reductions from baseline than micronised fenofibrate alone in TC and LDL-C levels. Similar or greater changes in HDL-C and TG levels were seen in combination therapy, compared with monotherapy, recipients. Micronised fenofibrate 200mg (capsule) once daily was associated with significantly greater improvements from baseline in TC, LDL-C, HDL-C and TG levels than placebo in patients with type 2 diabetes mellitus enrolled in the double-blind, randomised Diabetes Atherosclerosis Intervention Study (DAIS) [> or =3 years follow-up]. Moreover, angiography showed micronised fenofibrate was associated with significantly less progression of coronary atherosclerosis than placebo. Micronised fenofibrate has also shown efficacy in patients with metabolic syndrome, patients with HIV infection and protease inhibitor-induced hypertriglyceridaemia and patients with dyslipidaemia secondary to heart transplantation. Micronised fenofibrate was generally well tolerated in clinical trials. The results of a large (n = 9884) 12-week study indicated that gastrointestinal disorders are the most frequent adverse events associated with micronised fenofibrate therapy. Elevations in serum transaminase and creatine phosphokinase levels have been reported rarely with micronised fenofibrate. In conclusion, micronised fenofibrate improves lipid levels in patients with primary dyslipidaemia; the drug has particular efficacy with regards to reducing TG levels and raising HDL-C levels. Micronised fenofibrate is also effective in diabetic dyslipidaemia; as well as improving lipid levels, the drug reduced progression of coronary atherosclerosis in patients with type 2 diabetes mellitus. The results of large ongoing studies (e.g. FIELD with approximately 10 000 patients) will clarify whether the beneficial lipid-modifying effects of micronised fenofibrate result in a reduction in cardiovascular morbidity and mortality.
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PMID:Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia. 1221 67


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