Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thiazolidinediones are a unique class of compounds that exert direct effects on the mechanisms of insulin resistance and result in improved insulin action and reduced hyperinsulinemia. Troglitazone is the first of these compounds to be approved for use in humans and has the potential not only to reduce glycemia and insulin requirements in type II diabetes but to improve other components of the insulin resistance syndrome including dyslipidemia, hypertension, and accelerated cardiovascular disease. Such compounds also hold promise for the prevention of type II diabetes and for the treatment of other insulin-resistant states including polycystic ovary disease. In addition to the novel mechanism of action through binding and activation of PPARs, troglitazone has other unique advantages, including once-a-day administration, a low incidence of minor side effects, no known drug interactions, hepatic metabolism and secretion, and potent antioxidant properties. Thiazolidinedione compounds such as troglitazone provide an important additional resource for the health care provider in the management of type II diabetes and other components of the insulin resistance syndrome.
 ...
PMID:Thiazolidinediones. 931 15

Insulin resistance is characterized by impaired responsiveness to endogenous or exogenous insulin and often results in the insulin resistance syndrome, a clustering of cardiovascular risk factors that includes abdominal obesity, hypertension, dyslipidemia, glucose intolerance, and hyperinsulinemia. Although the mechanism responsible for insulin resistance has not been completely defined, it is likely due to defective insulin receptor signaling and results in decreased use of glucose. Troglitazone, the first in a new class of drugs, directly decreases insulin resistance by improving insulin-mediated glucose disposal and reduces plasma insulin concentrations. Glycemic control achieved with troglitazone monotherapy is equivalent to that with sulfonylurea and metformin, and when combined with these agents offers additional plasma glucose reduction. Studies are necessary to determine the effect of thiazolidinediones on morbidity and mortality of patients with type 2 diabetes and insulin resistance.
 ...
PMID:The role of troglitazone in treating the insulin resistance syndrome. 975 9

Troglitazone, a newly introduced insulin sensitizer, has been implicated in prevention and treatment of atherosclerotic cardiovascular disease especially associated with type 2 diabetes mellitus and insulin resistance. Beneficial effects of troglitazone on multiple risk factor syndrome have been reported in terms of blood pressure lowering effect and ameliorations of dyslipidemia and hyperinsulinemia. Moreover, in vitro and in vivo studies have shown vasodilating and antiatherogenic effects as well as cardioprotective action of this compound. Thus, troglitazone may have potential to prevent and delay diabetic heart disease and large vessel complications.
 ...
PMID:[Cardiovascular effects of the thiazolidinedione troglitazone]. 1070 72

The thiazolidinediones are a new class of compounds for treatment of type 2 diabetes. Troglitazone became available in the United States in 1997 but was withdrawn from the market in March 2000 because it caused severe idiosyncratic liver injury. Rosiglitazone and pioglitazone have been available since 1999. Because these drugs directly improve insulin resistance and decrease plasma insulin levels (a risk factor for coronary artery disease), they may decrease risk for cardiovascular disease in patients with type 2 diabetes. Research on the non-glucose lowering effects of troglitazone and, to a lesser extent, of rosiglitazone and pioglitazone have demonstrated changes in several cardiovascular risk factors associated with the insulin resistance syndrome. These beneficial effects include a decrease in blood pressure, correction of diabetic dyslipidemia, improvement of fibrinolysis, and decrease in carotid artery intima-media thickness. Other in vitro effects related to the ability of these agents to bind a newly described class of receptors (peroxisome proliferator-activated receptors) may also have implications for atherosclerosis. However, these drugs increase low-density lipoprotein (LDL) cholesterol levels and may favorably change LDL particle size and susceptibility to oxidation (although the implications of the latter changes are not dear). Furthermore, these drugs tend to cause weight gain. The authors' enthusiasm for these drugs has diminished somewhat because of reported adverse events, including rare liver failure. Nevertheless, because of the mechanism of action of the thiazolidinediones, clinical trials designed to determine whether they (or similar "insulin sensitizers") decrease cardiovascular events in people with type 2 diabetes will be of interest.
 ...
PMID:Nonhypoglycemic effects of thiazolidinediones. 1118 21

The observed reduction in macrovascular outcomes in the United Kingdom Progressive Diabetes Study (UKPDS) trial in patients with type 2 diabetes mellitus (DM), treated intensively with insulin or sulfonylureas, was of borderline significance (p = 0.052). This may be because of the role of factors other than glycemic control in the etiology of macrovascular disease. The UKPDS and other studies have suggested that lipid parameters are potent predictors of adverse outcomes in patients with type 2 DM. In patients with DM, dyslipidemia is characterized by elevated serum triglycerides and low high density lipoprotein-cholesterol (HDL-C) with normal total serum cholesterol levels and usually accompanied by an elevation of atherogenic, small, dense low density lipoprotein-cholesterol (LDL-C) particles. Dyslipidemia is only partly corrected by dietary and lifestyle modifications and pharmacological glycemic control in patients with DM. Several guidelines, including those published by the New Zealand Heart Foundation, suggest that lipid-modifying therapies are appropriate in patients considered to be at high or very high risk of a cardiac event. This includes patients with established vascular disease. Some recent studies suggest that patients with type 2 DM have risk comparable to patients without DM, but have experienced previous myocardial infarction (MI). Subgroup analysis of trials including the Scandinavian Simvastatin Survival Study (4S) and Cholesterol and Recurrent Events (CARE), which included patients with DM, have shown a significant reduction in adverse outcomes, although many patients with DM and dyslipidemia were excluded. Of lipid-lowering drugs, fibric acid derivatives are probably the most appropriate for patients with DM and dyslipidemia and their role is being evaluated in large, long-term outcome studies such as Fenofibrate Intervention and Event Lowering in Diabetes (FIELD). Thiazolidinediones, a new class of compound for treating patients with type 2 DM, primarily exert their glucose-lowering effect by increasing insulin sensitivity at the level of skeletal muscle, and to a lesser extent, at the liver by decreasing hepatic glucose output. Some of their actions are mediated through binding and activation of the peroxisome proliferator-activated receptor-gamma, a nuclear receptor that has a regulatory role in differentiation of cells, especially adipocytes. The nonhypoglycemic effects of thiazolidinediones, therefore, offer additional potential mechanisms for benefit in patients with type 2 DM and insulin resistance. Thiazolidinediones increase serum HDL-C levels. Troglitazone and pioglitazone have been shown to decrease serum triglyceride levels. Rosiglitazone, conversely has no significant effect on serum triglyceride levels. All of the thiazolidinediones increase serum LDL-C levels (pioglitazone to a lesser extent), although changes in the size of the LDL fraction may render it less susceptible to oxidation and, therefore, less atherogenic. A randomized comparative trial needs to be undertaken to determine whether true differences exist between the thiazolidinediones. Longer studies need to be undertaken to assess their effect on cardiovascular outcomes.
 ...
PMID:Management of co-existing diabetes mellitus and dyslipidemia: defining the role of thiazolidinediones. 1472 95

Cardiovascular disease (CVD) is the most critical global health threat, which contributes more than one third of global morbidity. CVD includes heart disease, vascular disease, atherosclerosis, stroke and hypertension. The most important independent risk factors for CVD include dyslipidemia along with hypertension, obesity, sedentary lifestyle, diabetes and chronic inflammation. These factors are directly regulated by diet, metabolism and physical activity. Diets rich in fat and carbohydrate coupled to sedentary lifestyles have contributed to the increase in dyslipidemia, type 2 diabetes, obesity and CVD in the world. Discovery of Peroxisome Proliferator Activated Receptors (PPARs) as a key regulator of metabolic pathways has led to significant insight into the mechanisms regulating these processes. Three PPAR subtypes, encoded by distinct genes, are designated as PPAR-alpha, PPAR-delta (also know as beta) and PPAR-gamma. PPARs act as nutritional sensors that regulate a variety of homeostatic functions including metabolism, inflammation and development. PPAR-alpha is the main metabolic regulator for catabolism whereas PPAR-gamma regulates anabolism or storage. PPARs are expressed in the cardiovascular system such as endothelial cells, vascular smooth muscle cells and monocytes/macrophages. It has been shown that they play an important role in the modulation of inflammatory, fibrotic and hypertrophic responses. In 1997, a Glaxo patent described that Troglitazone (first PPAR-gamma ligand to reach market) reduced TNF-induced VCAM1 expression in HUVECs indicating the potential benefit in atherosclerosis. A series of patents from Eli Lilly and Dr. Reddy's Laboratories Ltd. between 1999 and 2005 described a variety of PPAR-alpha and -alpha,gamma dual ligands in a number of patents having glucose, triglyceride, cholesterol lowering, HDL elevating and body weight reducing activity. Patents from Metabolex and Tularik in 2001 and 2002 described the beneficial effects of SPPARM molecules for insulin resistance and diabetes, without showing concern on PPAR-gamma related side effects such as edema and body weight. GSK and Takeda described the potential effects of PPAR-delta modulators during 2001 to 2004 in few patents. Several clinical and preclinical studies have demonstrated the beneficial effects of PPAR ligands on various cardiovascular risk factors. This review intends to capture some of the key studies in this area as is described in some recent patents and literature.
 ...
PMID:Role of PPAR in cardiovascular diseases. 1822 Oct 86