651 10.2217/17460875.3.6.651 © 2008 Future Medicine ISSN 1746-0875 Future Lipidol. (2008) 3(6), 651–664 part of Future Lipidology Review Insulin resistance is a common condition that is believed to play a main role in the patho- genesis of the metabolic syndrome (MS), obes- ity and Type 2 diabetes (T2DM), as well as cardiovascular disease [1] . The prevalence of all these conditions is growing at an unexpected rate, probably owing to exacerbation of insulin resistance as a consequence of increased caloric intake and decreased energy expenditure. Recent studies have suggested that lifestyle modification, based on weight reduction and increased physical activity, can prevent or delay development of T2DM and MS in high-risk subjects [2] . Weight reduction and an improve- ment in fitness are both associated with sig- nificant amelioration of insulin sensitivity, sup- porting a strong link between impaired insulin action and metabolic/cardiovascular diseases. The possibility that insulin resistance may play a central role in the clustering of multiple car- diovascular risk factors was initially proposed by Reaven when he noticed how often insulin- resistance was associated with impaired glu- cose tolerance, hypertension and dyslipidemia [3] . Subsequently, the mechanisms relating impaired insulin action with components of the MS have been explored. It is the purpose of this review to provide an overview of the mecha- nisms through which insulin resistance (and concomitant hyperinsulinemia) leads to altera- tion of circulating lipoproteins. However, dysli- pidemia is just an aspect of a more generalized disturbance of lipid metabolism associated with insulin resistance. Common to this condition is accretion of lipids in adipose tissue (particularly at the visceral level) as well as outside the adi- pose tissue (i.e., ectopic accumulation in liver, muscle, pancreas, heart and vessels). Therefore, this review will also provide a comprehensive approach to explore how ectopic lipid accu- mulation, lipotoxicity and altered lipoprotein metabolism may all be entangled to generate increased cardiovascular risk. Insulin resistance & atherogenic dyslipidemia In insulin-resistant individuals, such as those with T2DM and MS, it is common to find characteristic changes from the normal lipid and lipoprotein pattern. These changes include elevation of triglycerides (TG), reduction of HDL-cholesterol (HDL-C), a concomitant increase of ApoB and increased small dense LDL in the face of normal or slightly elevated LDL-cholesterol (LDL-C). This combination of lipid and lipoprotein alterations is associated with significant risk of cardiovascular disease so that it is referred to as ‘atherogenic dyslipidemia’ [4] . In spite of articulate changes in the lipid pro- file, as highlighted by Ginsberg et al. , it is the effect of insulin resistance on the assembly and secretion of VLDL, ApoB and TG – which plays a central role in the development of atherogenic dyslipidemia [5] . Insulin resistance and lipid disorders Roberto Miccoli † , Cristina Bianchi, Giuseppe Penno & Stefano Del Prato † Author for correspondence: Department of Endocrinology & Metabolism, Univerity of Pisa, Via Paradisa 2, 56124 Pisa, Italy n Tel.: +39 050 995 136 n Fax: +39 050 541 521 n rmiccoli@immr.med.unipi.it The dyslipidemia of insulin resistance is characterized by elevated levels of triglycerides (TGs), low HDL-cholesterol and small dense LDL particles. Many of these features are affected by the reduction in insulin sensitivity, with a central role played by abnormalities in assembly and secretion of VLDL. Postprandial hyperlipidemia is common in insulin-resistant individuals, probably owing to reduced lipolysis of nascent chylomicrons. Increased exchange of HDL cholesteryl esters for TGs is associated with lipolysis of HDL-TG by hepatic lipase and this produces dysfuntional particles that are less stable than normal particles and contribute to decreased reverse cholesterol transport. On the other hand, TG accumulation has been described as dangerous for several tissues, the so-called lipotoxicity, particularly for pancreatic β -cells where it results in impairment of glucose-stimulated insulin secretion and accelerated apoptosis. Recently, islet dysfunction and loss of insulin secretion have also been associated with alterations of plasma and islet cholesterol levels. A more comprehensive appreciation of reciprocal effects of insulin resistance and atherogenic dyslipidemia should guide the physician in a more conscious therapeutic decision. Keywords β-cell failure n diabetes n insulin resistance n triglyceride metabolism For reprint orders, please contact: reprints@futuremedicine.com