Recent evidence suggests that progression of insulin resistance parallels progression of atherosclerosis. Fat plays an integral role in the development of type 2 diabetes and vascular injury. The balance of adipose-derived substances, including free fatty acids, tumor necrosis factor-alpha, leptin, adiponectin, and plasminogen activator inhibitor-1, determine both insulin action and the state of vascular inflammation. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands promote the balance of these substances to enhance insulin-mediated glucose uptake and decrease inflammation. PPAR-gamma ligands reverse the major defect of the insulin resistance syndrome and have important effects that inhibit atherosclerosis, improve endothelial cell function, and attenuate inflammation. Although more research is needed, data suggest that PPAR-gamma ligands may prevent the progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.
"Thiazolidinediones (TZDs) are synthetic ligands also known as glitazones (troglitazone, rosiglitazone, or pioglitazone ) , which can bind and activate the nuclear receptor , peroxisome proliferator-activated receptor (PPAR) . By binding to PPARg, TZDs are implicated in the transcription of several factors involved in the regulation of glucose and lipid metabolism, mainly in the adipose and muscle tissues  . Recent studies showed PPARg expression in the ovary and indicated an important role for this receptor in ovarian functions such as steroid synthesis, angiogenesis, tissue remodeling, cell-cycle regulation, and apoptosis  . "
[Show abstract][Hide abstract] ABSTRACT: Rosiglitazone is PPARγ synthetic activator from the group of thiazolidinediones often used in the treatment of chronic diseases such as type 2 diabetes and other forms of insulin resistance. The present in vitro study assessed the direct effects of rosiglitazone at 25 and 50 μM doses on PPARγ expression, steroid secretion (progesterone - P4, androstenedione - A4, testosterone - T, and estradiol - E2) and protein expression of PPARγ, 3βHSD, CYP17, 17βHSD, CYP19 by porcine ovarian follicles from prepubertal and cycling animals. We analyzed also steroid enzymatic activity by conversion of P5 to P4, P4 to A4 and A4 to T. Our results indicated that rosiglitazone increased significantly PPARγ expression, P4 secretion, 3βHSD activity and protein expression. Rosiglitazone decreased A4 and T secretion by reducing the expression and activity of CYP17 and 17βHSD and did not change E2 secretion and CYP19. Similarly results was observed both in prepubertal and cycling pigs. Our results indicate that these direct effects of rosiglitazone on ovarian steroidogenesis provide a framework for testing several potential new mechanisms of PPAR-γ actions on porcine ovarian function.
"Discovery of this unique property of telmisartan has attracted attention because of its therapeutic potential in elderly patients with obesity, metabolic syndrome, and type 2 diabetes. Several studies have shown that PPARγ plays an important role as a regulator of carbohydrate and lipid metabolism,70,71 and ligands for PPARγ improve insulin sensitivity,72 reduce triglyceride levels,72 decrease risk of atherosclerosis,73 reduce vascular and cardiac effects of hypertension,74 and promote peripheral vasodilation.75–77 "
[Show abstract][Hide abstract] ABSTRACT: Elderly patients (age ≥ 65 years) with hypertension are at high risk for vascular complications, especially when diabetes is present. Antihypertensive drugs that inhibit the renin-angiotensin system have been shown to be effective for controlling blood pressure in adult and elderly patients. Importantly, renin-angiotensin system inhibitors were shown to have benefits beyond their classic cardioprotective and vasculoprotective effects, including reducing the risk of new-onset diabetes and associated cardiovascular effects. The discovery that the renin-angiotensin system inhibitor and angiotensin II type 1 (AT(1)) receptor blocker (ARB), telmisartan, can selectively activate the peroxisome proliferator-activated receptor-γ (PPARγ, an established antidiabetic drug target) provides the unique opportunity to prevent and treat cardiovascular complications in high-risk elderly patients with hypertension and new-onset diabetes. Two large clinical trials, ONTARGET (Ongoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE-I iNtolerant subjects with cardiovascular disease) have assessed the cardioprotective and antidiabetic effects of telmisartan. The collective data suggest that telmisartan is a promising drug for controlling hypertension and reducing vascular risk in high-risk elderly patients with new-onset diabetes.
"Weight loss has been shown to improve whole body and skeletal muscle insulin action in obese patients and compliance to a low-fat diet confers sustained improvements in insulin action after 5 years . A reduction in lipid availability and accumulation within the skeletal muscle is thought to be central to the insulin-sensitizing effects of the thiazolidinedione class of antidiabetic agents . These drugs, which include troglitazone, pioglitazone and rosiglitazone, are potent and selective ligands of the transcription factor PPARγ. Agonists of PPARα, such as the fibrates and WY 14643, are potent hypolipidaemic agents and recent studies indicate that PPARα agonists can also improve insulin sensitivity in association with a decrease in muscle lipids . "
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence suggests that stearoyl-CoA desaturase (SCD), the rate-limiting enzyme of monounsaturated fatty acid biosynthesis, is an important factor in the pathogenesis of lipid-induced insulin resistance. Mice with a targeted disruption of the SCD1 gene have improved glucose tolerance compared to wild-type mice, despite lower fasting plasma insulin levels. Increased SCD activity has been found in insulin-resistant humans and animals, whereas SCD1 deficiency attenuates both diet- and genetically-induced impairment of insulin action. Phosphorylation of serine and threonine residues on insulin receptor, insulin receptor substrates (IRS1 and IRS2), and on Akt has been shown to be the major step in insulin signaling that is altered due to the lack of SCD1. In this review we discuss perturbations in cell signaling and lipid metabolism cascades in insulin-sensitive tissues due to SCD1 deficiency. In particular, we address the role of cellular signaling molecules including free fatty acids, ceramides, fatty acyl-CoAs, AMP-activated protein kinase, protein tyrosine phosphatase 1B as well as of membrane fluidity. While the precise mechanism of SCD action on insulin signaling remains to be clarified, current findings on SCD point to a very promising novel target for the treatment of insulin resistance.
Manal Zahran, Fatma Mohammed Nasr, Amna Ahmed Metwaly, Noha El-Sheikh, Nevine Sherif Ali Khalil, Tarek Harba
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