Effects Of Glitazones Research Articles

Glitazones Exert Multiple Effects onβ-Cell Stimulus-Secretion Coupling

Earlier studies suggest that glitazones exert beneficial effects in patients with type 2 diabetes by directly affecting insulin secretion of β-cells, besides improving the effectiveness of insulin in peripheral tissues. The effects of glitazones on stimulus-secretion coupling (SSC) are poorly understood. We tested the influence of troglitazone and pioglitazone on different parameters of SSC, including insulin secretion (radioimmunoassay), cell membrane potential, various ion currents (patch-clamp), mitochondrial membrane potential (ΔΨ), and cytosolic Ca(2+) concentration (fluorescence). Troglitazone exerted stimulatory, inhibitory, or no effects on insulin secretion depending on the drug and glucose concentration. It depolarized the ΔΨ, thus lowering ATP production, which resulted in opening of ATP-dependent K(+) channels (K(ATP) channels) and reduced insulin secretion. However, it also exerted direct inhibitory effects on K(ATP) channels that can explain enhanced insulin secretion. Troglitazone also inhibited the currents through voltage-dependent Ca(2+) and K(+) channels. Pioglitazone was less effective than troglitazone on all parameters tested. The effects of both glitazones were markedly reduced in the presence of bovine serum albumin. Glitazones exert multiple actions on β-cell SSC that have to be considered as undesired side effects because the influence of these compounds on β-cells is not controllable. The final effect on insulin secretion depends on many parameters, including the actual glucose and drug concentration, protein binding of the drug, and the drug by itself. Troglitazone and pioglitazone differ in their influence on SSC. It can be assumed that the effects of pioglitazone on β-cells are negligible under in vivo conditions.

Pleiotropic Effects of Glitazones: A Double Edge Sword?

Glitazones (thiazolidinediones) are drugs used for diabetes mellitus type 2. By binding to peroxisome proliferator-activated receptor γ (PPARγ) they modulate transcription of genes of carbohydrate and lipid metabolism. Through PPARγ stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential. The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARγ remains yet unclear, since glitazones exert also PPARγ-independent effects. Glitazone chemistry serves as scaffold for synthesizing new compounds with PPARγ-independent pharmacological properties and we report here a preliminary observation of inhibition of vasoconstriction by troglitazone in isolated vessels, an effect that appears fast, reversible, and PPARγ-independent. Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.

The sweetness of glitazones: randomized trials needed

Two observational studies report opposite effects of glitazones on clinical outcomes in patients with ESRD. Given the limited reliability of such studies in the assessment of moderate effects of treatment, however, findings in these articles should prompt the generation of hypotheses rather than dictate changes in clinical practice.

Effects of pioglitazone and rosiglitazone on aortic vascular function in rat genetic hypertension

Glitazones have beneficial antihypertensive effects independent of their insulin-sensitizing action. We have studied the effects of pioglitazone and rosiglitazone on the endothelial ability to counteract vascular smooth muscle contractility in genetic hypertension. To achieve this, we measured isometric responses of aortic segments obtained from spontaneously hypertensive rats. The effects of glitazones on endothelial function were studied by assessing the endothelial modulation of phenylephrine-induced isometric contractions (10 − 9 –10 − 5 M) in the presence or absence of pioglitazone or rosiglitazone (10 − 5 M), added directly to an organ bath or orally administered to the rats (pioglitazone, 10 mg/kg). The role of both NO and prostanoids was analyzed by performing experiments in the presence of N G-nitro- l-arginine methyl ester ( l-NAME) and/or indomethacin (both 10 − 5 M) in the organ bath. Concentration-dependent contractions to l-NAME (10 − 6 –3 × 10 − 4 M) in the presence or absence of glitazones were carried out as an estimation of basal NO release. Pioglitazone, but not rosiglitazone, increased contractile responses to phenylephrine in intact vessels. The contractile responses to phenylephrine obtained in the presence of glitazones were markedly diminished by indomethacin, but enhanced by l-NAME. Analogous results were obtained in aortas from pioglitazone-chronically treated animals. l-NAME concentration-dependent contractions were enhanced by both glitazones. Both glitazones lowered the sensitivity to acetylcholine (10 − 9 –10 − 5 M). In conclusion, pioglitazone and rosiglitazone alter vascular function differentially and through endothelium-dependent mechanisms. These drugs act over the same pathways on the endothelium where they have a dual action, increasing both production of vasoconstrictor prostanoids and NO. The balance between both vasoactive substances determines the vascular response to glitazones.

Blutzuckereinstellung bei kardialen Erkrankungen

The early and differentiated optimization of glucose level is essential for the improvement of the cardiovascular outcome. In all stages of cardiac disease, the primary goal is to reach near-normoglycemia. The DIGAMI-1 and 2 studies as well as the Munich Myocardial Infarction Registry successfully demonstrate, that the intensification of treatment with insulin therapy reduces the mortality of myocardial infarction. Glucose-insulin-infusion is advantageous with regard to the use of a well-controllable therapeutic approach. In non-acute cardiac disease, oral treatment strategies and insulin therapy are successful alone or in combination. Acarbose and metformin have been shown to be able to successfully prevent cardiovascular disease. New evidence of positive effects of glitazones with regard to reduction of the rate of restenosis and optimization of endothelial function is currently emerging. Prognosis of cardiovascular disease is significantly influenced by glucose control. There is evidence that the relationship between glycemia and cardiovascular events extends far beyond the diabetic threshold. This can be detected even in impaired glucose tolerance and the non-diabetic range. There is evidence that postprandial glycemia is crucial for the extent of cardiovascular risk. This has also been emphasized by the DECODE-study.

Effects of glitazones on blood pressure and vascular structure in mesenteric resistance arteries and basilar artery from genetically hypertensive rats

1. The effects of two of the glitazone (thiazolidinedione) class of drugs, namely rosiglitazone and pioglitazone, on blood pressure and vascular remodelling in the New Zealand genetically hypertensive (GH) rat model were investigated. 2. In the first study, a GH group given rosiglitazone (5 mg/kg per day) from the age of 7 to 12 weeks was compared with a GH control group. In the second study, GH rats were given either pioglitazone, simvastatin, valsartan or combinations of pioglitazone with simvastatin or valsartan (all drugs at a dose of 10 mg/kg per day). 3. Tail-cuff systolic blood pressure was measured weekly. At the end of the experiment, blood vessels were fixed by perfusion and samples of mesenteric resistance arteries (MRA), second-order branches and basilar artery were embedded in Technovit and serial sections were cut and stained with Giemsa for stereological analysis. Media width, medial cross-sectional area and lumen diameter were determined and the ratio of media width/lumen diameter was calculated. 4. Rosiglitazone significantly reduced blood pressure in GH rats. 5. In MRA, rosiglitazone had a hypotrophic effect on media, reduced lumen diameter and reduced media/lumen ratio (P<0.001). 6. In basilar artery, there was also a hypotrophic effect of rosiglitazone on media and reduced media/lumen ratio (P<0.001). 7. Pioglitazone slowed down the rate of blood pressure increase with age in GH rats and had a greater effect on blood pressure when given in combination with simvastatin. 8. Pioglitazone had a hypotrophic effect on the media of MRA and basilar artery. The hypotrophic effect was enhanced when pioglitazone was given in combination with simvastatin. The media/lumen ratio was reduced by pioglitazone; in MRA, combination treatment with simvastatin reduced the ratio further to normal and, with valsartan, to below normal. In basilar artery, the media/lumen ratio was reduced further by both combination treatments, but was lowest in the pioglitazone-valsartan combination group. 9. The significant effects on MRA and basilar artery structure (and, thus, haemodynamics) seen after rosiglitazone monotherapy and after pioglitazone, given alone and in combination with simvastatin or valsartan, may well indicate a glitazone class effect on vascular structure and, hence, cardiovascular function.

Glitazones and heart failure: critical appraisal for the clinician.

Mr S. is a 46-year-old East-Indian male with typical manifestations of the cardiovascular dysmetabolic syndrome of insulin resistance (type II diabetes, obesity, dyslipidemia, hypertension, and elevated levels of high-sensitivity C-reactive protein). His medications include ramipril, simvastatin, enteric-coated aspirin, metformin, and glyburide. He has no symptoms of cardiac ischemia or congestive heart failure and has preserved left ventricular function. Over the past few months his glycemic control has been inadequate, and a decision to initiate an insulin sensitizer (glitazone) is made. Treatment is initiated with rosiglitazone 4 mg twice daily, with marked improvement in glycemic control and other components of the cardiovascular dysmetabolic syndrome. Approximately 6 months after initiation of therapy, your junior resident receives a phone call from Mr S, who is extremely anxious and distraught about the possibility of developing heart failure on glitazone therapy. The resident and the patient request your expert opinion about the effects of glitazones on cardiac function and associated hemodynamics. Insulin resistance has been increasingly recognized as a central metabolic disturbance predisposing a patient to hypertension, hyperlipidemia, premature atherosclerosis, left ventricular hypertrophy, and endothelial dysfunction.1 In addition to being a powerful risk marker for the development of cardiovascular disease, insulin resistance is also closely related to cardiac dysfunction and heart failure.2 Thiazolidinediones (TZD; glitazones) are peroxisome proliferator-activated receptor (PPAR) agonists that specifically augment insulin sensitivity and counter insulin resistance in patients with the cardiovascular dysmetabolic syndrome. Currently, there are 2 commercially available glitazones, rosiglitazone and pioglitazone. Troglitazone was withdrawn from the market because of hepatic side effects. The PPAR family is composed of 3 subtypes. TZDs bind with high affinity to the PPARγ isoform. The PPARγ isoform is found in the heart,3–6 endothelium, vascular smooth muscle (including atherosclerotic lesions and neointima formed after angioplasty), liver, skeletal muscle, monocytes/macrophages, and many other …