202 Biochemical Society Transactions (2003) Volume 31, part 1 Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes N. B. Ruderman* 1 , J. M. Cacicedo*, S. Itani*, N. Yagihashi*, A. K. Saha*, J. M. Ye†, K. Chen‡, M. Zou§, D. Carling¶, G. Boden‖, R. A. Cohen§, J. Keaney‡, E. W. Kraegen† and Y. Ido* *Diabetes Unit, Section of Endocrinology and Departments of Medicine and Physiology, Boston University Medical Center, Boston, MA 02118, U.S.A., †Garvan Institute, Sydney, Australia, ‡Division of Cardiology, Boston University Medical Center, Boston MA 02118, U.S.A., §Vascular Biology Unit, Boston University Medical Center, Boston MA 02118, U.S.A., ¶Cellular Stress Unit, MRC Clinical Sciences Center, Hammersmith Hospital, London W12 ONN, U.K., and ‖Clinical Research Center, Temple University, School of Medicine, Philadelphia, PA, U.S.A. Abstract Based on available evidence, we would propose the following. (i) Excesses of glucose and free fatty acids cause insulin resistance in skeletal muscle and damage to the endothelial cell by a similar mechanism. (ii) Key pathogenetic events in this mechanism very likely include increased fatty acid esterification, protein kinase C activation, an increase in oxidative stress (demonstrated to date in endothelium) and alterations in the inhibitor κ B kinase/nuclear factor κ B system. (iii) Activation of AMP-activated protein kinase (AMPK) inhibits all of these events and enhances insulin signalling in the endothelial cell. It also enhances insulin action in muscle; however, the mechanism by which it does so has not been well studied. (iv) The reported beneficial effects of exercise and metformin on cardiovascular disease and insulin resistance in humans could be related to the fact that they activate AMPK. (v) The comparative roles of AMPK in regulating metabolism, signalling and gene expression in muscle and endothelial cells warrant further study. Introduction Insulin resistance is defined as an impaired ability of insulin to produce its usual biological effects at a cellular, organ or whole-body level. In humans, it is characteristically associated with such disorders as obesity, Type 2 diabetes, essential hypertension, endogenous hypertriglyceridaemia and coagulation abnormalities [1,2]. In addition, in part because of the presence of these disorders and in part inde- pendently of them, insulin resistance is a risk factor for premature coronary heart disease [2]. Despite this obser- vation, insulin resistance has been primarily studied in skeletal muscle and the basis for its independent relation to coronary artery disease is poorly understood. In this brief review, we will examine data from our laboratories and others suggesting that common mechanisms could explain the insulin resistance in skeletal muscle and the early endothelial cell damage that is thought to initiate atherosclerotic vascular disease in diabetes. More specifically, the effects of excess glucose and fatty acids, such as are found in patients with diabetes, will be discussed. Excesses of these fuels alone and/or in combination have been shown to cause Key words: acetyl-CoA carboxylase, Akt, atherosclerosis, diacylglycerol, fatty acid oxidation, fuel sensing, oxidative stress, protein kinase C, tumour necrosis factor α. Abbreviations used: ACC, acetyl-CoA carboxylase; AICAR, 5-amino-4-imidazolecarboxamide riboside; AMPK, AMP-activated protein kinase; HUVEC, human umbilical vein endothelial cells; IKK, inhibitor κB kinase; NFκB, nuclear factor κB; PKC, protein kinase C; ROS, reactive oxy- gen species; TNFα, tumour necrosis factor α; FFA, free (non-esterified) fatty acid. 1 To whom correspondence should be addressed (e-mail nruderman@medicine.bu.edu). insulin resistance in skeletal muscle [3–5] and cell damage in cultured endothelium [6–10]. We will explore here the notions (i) that they produce these effects in both tissues by increasing fatty acid esterification and secondarily setting in motion a series of events that include protein kinase C (PKC) activation, increases in oxidative stress and activation of the inhibitor κ B kinase (IKK)/nuclear factor κ B (NFκ B) system, and (2) that activation of the fuel-sensing enzyme AMP- activated protein kinase (AMPK) prevents these events from occurring. Skeletal muscle: malonyl-CoA, fatty acid oxidation and esterification, and insulin resistance In response to an increase in glucose availability, many cells, including those of skeletal muscle, inhibit the oxidation of fatty acids. In contrast, glucose deprivation or an increase in energy expenditure activates fatty acid oxidation. At a cellular level these events are regulated at least in part by changes in the activity of acetyl-CoA carboxylase (ACC), the enzyme that catalyses the synthesis of malonyl-CoA [11–13]. Malonyl- CoA is an allosteric inhibitor of carnitine palmitoyltransferase 1, which controls the transfer of long-chain fatty acyl-CoA from the cytosol into mitochondria where they are oxidized [13,14]. Thus, increases in malonyl-CoA concentration in- hibit fatty acid oxidation and presumably lead to an increase in its esterification, and decreases in malonyl-CoA have the C  2003 Biochemical Society