1.
Role of PPAR- gamma agonist thiazolidinediones in treatment of pre-diabetic and diabetic individuals: a cardiovascular perspective.
Dumasia, R, Eagle, KA, Kline-Rogers, E, May, N, Cho, L, Mukherjee, D
Current drug targets. Cardiovascular & haematological disorders. 2005;(5):377-86
Abstract
The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARalpha, PPARdelta/beta, and PPARgamma. PPARalpha is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake (beta-oxidation and omega-oxidation). PPARdelta/beta is involved in fatty acid oxidation in muscle. PPARgamma has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARgamma. By activating a number of genes in tissues, PPARgamma increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. There is a sound rationale for the use of TZDs in patients with type 2 diabetes mellitus and promising preliminary data in patients with patients with pre-diabetes. In patients with type 2 diabetes, thiazolidinediones had been shown to decrease mean HbA(1c)by 1.5% and lower HbA(1c) to less than 7% in 30% of patients. Decreased muscle insulin resistance primarily mediates the glucose lowering effect. In addition, there are several nonhypoglycemic effects of TZDs which may be beneficial to both diabetics and patients with pre-diabetes. These include effects on lipid metabolism, blood pressure, endothelial function, atherosclerotic plaque, coagulation, and albuminuria. In a pilot study, we recently demonstrated that insulin sensitizers such as thiazolidinediones appear to be associated with better clinical outcomes compared to insulin providers in diabetic patients presenting with acute coronary syndromes. In another study, we showed that the prediabetic state is a marker for worse prognosis in patients with acute coronary syndromes. In this article, we review the existing literature on the effectiveness of PPAR-gamma agonists in patients with either overt diabetes or a prediabetic state.
2.
Troglitazone therapy improves endothelial function to near normal levels in women with polycystic ovary syndrome.
Paradisi, G, Steinberg, HO, Shepard, MK, Hook, G, Baron, AD
The Journal of clinical endocrinology and metabolism. 2003;(2):576-80
Abstract
Obese women with polycystic ovary syndrome (PCOS) exhibit impaired endothelial function, which is strongly and directly correlated with both testosterone levels and insulin resistance. Endothelial dysfunction is considered a potent risk factor for macrovascular disease. Because troglitazone (Tgz) improves both hormonal profiles and insulin sensitivity, we tested whether Tgz treatment ameliorates endothelial function in these patients. We studied leg blood flow (LBF) responses to graded intrafemoral artery infusion of the endothelium-dependent vasodilator methacholine chloride (MCh) and to a 4-h hyperinsulinemic euglycemic clamp (120 mU/m(2) x min) in 10 PCOS, before and after 3 months treatment with Tgz (600 mg/d). A group of 13 obese women (OBW) matched for age, weight, body fat (>40% in both groups), blood pressure, and total cholesterol served as controls. PCOS patients exhibited elevated free testosterone (fT) and triglycerides (TG) and lower high density lipoprotein cholesterol levels compared with OBW [14.0 +/- 1.0 vs. 3.7 +/- 0.6 pmol/liter (P < 0.0001), 1.60 +/- 0.28 vs. 0.94 +/- 0.09 mmol/liter (P < 0.02), and 0.91 +/- 0.04 vs. 1.1 +/- 0.04 mmol/liter (P < 0.005), respectively]. Tgz treatment reduced fT levels, but did not improve the TG and high density lipoprotein profile [to 9.7 +/- 2.8 pmol/liter (P < 0.007), 1.49 +/- 0.34 mmol/liter (P = NS), and 0.93 +/- 0.07 mmol/liter (P = NS), respectively]. Basal LBF was unchanged after Tgz. In PCOS compared with OBW, insulin stimulated glucose disposal (52.7 +/- 6.6 vs. 85.5 +/- 4.4 micromol/kg fat-free mass x min; P < 0.0005) and vasodilation (increase in LBF, 22 +/- 14% vs. 59 +/- 15%; P < 0.05) were significantly improved after Tgz treatment to 68.8 +/- 7.2 micromol/kg fat-free mass x min (P < 0.0001) and 101 +/- 48% (P < 0.03), respectively. The increase in LBF in response to MCh in PCOS was markedly more pronounced after treatment (P < 0.01, by ANOVA) and was similar to that observed in OBW. Before Tgz treatment, maximal LBF increments in response to MCh were 130 +/- 25% and 233 +/- 29% in PCOS and OBW, respectively (P < 0.01). After Tgz treatment, PCOS values improved, achieving increments similar to those in OBW (245 +/- 45%; P < 0.04). Tgz treatment in PCOS improves both hormonal and metabolic features. These modifications are associated with improvement of endothelial function, suggesting that Tgz could be a useful tool to reduce the risk of macrovascular disease in women with PCOS and perhaps in other insulin-resistant syndromes.